Study protocol for a multi-level cross-sectional study on the equitable reach and implementation of coordinated specialty care for early psychosis.
Approximately 115,000 young adults will experience their first episode of psychosis (FEP) each year in the USA. Coordinated specialty care (CSC) for early psychosis is an evidence-based early intervention model that has demonstrated effectiveness by improving quality of life and reducing psychiatric symptoms for many individuals. Over the last decade, there has significant increase in the implementation of CSC programs throughout the USA. However, prior research has revealed difficulties among individuals and their family members accessing CSC. Research has also shown that CSC programs often report the limited reach of their program to underserved populations and communities (e.g., ethnoracial minorities, rural and low socioeconomic neighborhoods). Dissemination and implementation research focused on the equitable reach and implementation of CSC is needed to address disparities at the individual level. The proposed study will create a novel integrative multi-level geospatial database of CSC programs implemented throughout the USA that will include program-level data (e.g., geocoded location, capacity, setting, role availability), provider-level data (race, ethnicity, professional credentials), and neighborhood-level census data (e.g., residential segregation, ethnic density, area deprivation, rural-urban continua, public transit time). This database will be used to characterize variations in CSC programs by geographical location and examine the overall reach CSC programs to specific communities. The quantitative data will be combined with qualitative data from state administrators, providers, and service users that will inform the development of dissemination tools, such as an interactive dashboard, that can aid decision making. Findings from this study will highlight the impact of outer contextual determinants on implementation and reach of mental health services, and will serve to inform the future implementation of CSC programs with a primary focus on equity.


PDGF-BB exhibited therapeutic effects on rat model of bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis and osteogenesis.
The mechanism and effective treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) are still uncertain. Our previous study revealed that zoledronate (ZOL) preferentially inhibited osteoclasts formation and platelet-derived growth factor-BB (PDGF-BB) secretion, causing suppression of angiogenesis and osteogenesis in vitro. The present study aimed to elucidate whether PDGF-BB had therapeutic effects on rat model of BRONJ by enhancing angiogenesis and angiogenesis. Firstly, rat model of BRONJ was established by ZOL and dexamethasone administration, followed by teeth extraction. The occurrence of BRONJ was confirmed and detected dead bone formation by maxillae examination, micro-CT scan and HE staining (10/10). Compared to control rats (0/10), both angiogenesis and mature bone formation were suppressed in BRONJ-like rats, evidenced by enzyme-linked immunosorbent assay (ELISA) for VEGF (P < 0.01), immunohistochemistry of CD31 (P < 0.05) and OCN (P < 0.01). Moreover, in the early stage of bone healing, the number of preosteoclasts (P < 0.001) and PDGF-BB secretion (P < 0.05) were significantly decreased in bisphosphonates-treated rats, along with the declined numbers of microvessels (P < 0.05) and osteoblasts (P < 0.05). In vitro study, CCK8 assay, alizarin red S staining and western blot assay showed that mandible-derived bone marrow mesenchymal stem cells (BMMSCs) in BRONJ-like rats presented suppressed functions of proliferation, osteogenesis and angiogenesis. Interestingly, recombinant PDGF-BB was able to rescue the impaired functions of BMMSCs derived from BRONJ-like rats at more than 10 ng/ml. Then fibrin sealant with or without recombinant PDGF-BB were tamped into the socket after debridement in BRONJ rats. After 8 weeks, fibrin sealant containing PDGF-BB showed significant therapeutic effects on BRONJ-like rats (bone healing: 8/10 vs 3/10, P < 0.05) with enhancing microvessels and mature bone formation. Our study suggested that the inhibition of angiogenesis and osteogenesis, the potential mechanisms of BRONJ, might partly result from suppression of PDGF-BB secretion in the early stage of bone healing. PDGF-BB local treatment after debridement might avail the healing of BRONJ by increasing angiogenesis and osteogenesis.


Natural killer cells and other innate lymphoid cells in cancer.
Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.


Effect of digital messages from health professionals on COVID-19-related outcomes: A systematic review of randomized controlled trials.
Effectiveness of health professionals' messages via digital tools on COVID-19-related outcomes remains unknown. In this systematic review, we examined this issue by searching randomized controlled trials in six databases until August, 2022 (PROSPERO, CRD 42022350788). Risk of bias was assessed using revised Cochrane risk-of-bias tool. Primary outcomes were COVID-19 infections, preventive behaviors, and factors that support behavioral change. Seven trials with 16 reports (some reported two or more outcomes) were included. One trial showed that physician videos distributed by Facebook ads significantly reduced COVID-19 infections. Five of 6 reports showed that interventions can promote non-pharmaceutical preventive behaviors, vaccination, or information-seeking behaviors and half of the results were significant. Interventions improved the factors that support behavioral change. 14 reports had some concerns of bias risk and 2 had high risk of bias. Our findings suggest that digital messages by health professionals may help reduce COVID-19 infections through promoting behavioral change.


Inhibition of IκB kinase by thalidomide increases hepatitis C virus RNA replication.
Hepatic fibrosis is an integral element in the progression of chronic liver disease. Elevated hepatic interleukin (IL)-8 is an important contributor to fibrosis in patients chronically infected with the hepatitis C virus (HCV). Thalidomide has been used to reduce liver inflammation and fibrosis in HCV-infected patients, but its impact on HCV replication remains unclear. This study examined the effect of thalidomide on HCV replication in vitro. Results revealed that while thalidomide reduced IL-8 and nuclear factor kappa B (NF-κB) activity by 95% and 46% in Huh-7 cells, increasing concentrations of thalidomide correlated with a linear rise in HCV replication (17-fold at 200 μm). The NF-κB inhibitors, wedelolactone and NF-κB activation inhibitor-1, which mimic the actions of thalidomide by preventing phosphorylation and activation of IκB kinase (IKK) and hence block NF-κB activity, increased HCV RNA by 18- and 19-fold, respectively. During in vitro HCV replication in Huh-7 cells, we observed a 30% increase in IKKα protein and 55% decrease in NF-κB(p65)/RelA protein relative to cellular β-actin. Ectopic expression of IKKα to enhance the inactive form of IKK in cells undergoing virus replication led to a 13-fold increase in HCV RNA. Conversely, enhanced expression of NF-κB(p65)/RelA in infected cells resulted in a 17-fold reduction in HCV RNA. In conclusion, HCV RNA replication was significantly augmented by the inhibition of IKK activation and subsequent NF-κB signalling, whereas a restoration of NF-κB activity by the addition of NF-κB/RelA markedly reduced HCV replication. This study lends added importance to the role of the NF-κB signalling pathway in controlling HCV replication.


[In vitro sensitivity of Aspergillus to terbinafine: comparative study on amphotericin B, 5-fluorocytosine and ketoconazole].
Terbinafine, a new antifungal agent derived from allylamine, effective by oral route, was tested against 32 different strains of Aspergilli to determine its in vitro efficiency compared with amphotericin B, 5-fluorocytosine and ketoconazole. Antifungal sensitivity was determine by the MIC method in liquid and solid mediums (Sabouraud, Casitone, YMA, YMB, YNB): with MIC between 0.005 and 5 micrograms/ml, whatever the species and the techniques, terbinafine is more efficient than amphotericin B, ketoconazole (0.5 to 100 micrograms/ml) and 5-FC (1-greater than 100 micrograms/ml).


Predicting small ligand binding sites in proteins using backbone structure.
Specific non-covalent binding of metal ions and ligands, such as nucleotides and cofactors, is essential for the function of many proteins. Computational methods are useful for predicting the location of such binding sites when experimental information is lacking. Methods that use structural information, when available, are particularly promising since they can potentially identify non-contiguous binding motifs that cannot be found using only the amino acid sequence. Furthermore, a prediction method that can utilize low-resolution models is advantageous because high-resolution structures are available for only a relatively small fraction of proteins. SitePredict is a machine learning-based method for predicting binding sites in protein structures for specific metal ions or small molecules. The method uses Random Forest classifiers trained on diverse residue-based site properties including spatial clustering of residue types and evolutionary conservation. SitePredict was tested by cross-validation on a set of known binding sites for six different metal ions and five different small molecules in a non-redundant set of protein-ligand complex structures. The prediction performance was good for all ligands considered, as reflected by AUC values of at least 0.8. Furthermore, a more realistic test on unbound structures showed only a slight decrease in the accuracy. The properties that contribute the most to the prediction accuracy of each ligand were also examined. Finally, examples of predicted binding sites in homology models and uncharacterized proteins are discussed. Binding site prediction results for all PDB protein structures and human protein homology models are available at http://sitepredict.org/.


Combined hearing screening and genetic screening of deafness among Hakka newborns in China.
Hearing loss (HL) can severely impact the quality of human life. To explore strategies for clinical interventions, we investigated hearing screening coupled with genetic testing of deafness among Hakka newborns. The testing was performed on 4205 newborns who born in Heyuan of Guangdong province between December 2018 and November 2019. Hearing screening used otoacoustic emission(OAE) coupled with automatic auditory brainstem response(AABR). A total of 13 hot spot mutations in GJB2, SLC26A4, mtDNA, and GJB3 genes were screened using PCR accompanied by flow-through hybridization technology. Among the 4205 newborns, the number of 47 individuals who failed the hearing testing accounted for 1.12%(47/4205). The genetic screening displayed that 176 individuals(4.19%,176/4205) discovered to carry more than one mutant site. The gene carrier frequency of GJB2, SLC26A4, GJB3, and mtDNA was 2.24%, 1.76%, 0.19%, and 0.07% respectively. The most carried mutations were GJB2 c.235del (2.05%), followed by SLC26A4 c.IVS7-2A > G(1.38%). A total of 216 (5.14%, 216/4205) high-risk children detected by combined hearing screening and genetic screening of deafness. Pairwise comparison (1.12% vs 4.19% vs 5.14%) showed significant differences for the positive rate of detection(χ 2 = 11.045, P < 0.001). The difference was no statistical significance between neonatal demographics information and genetic mutations using logistic regression analysis(all P > 0.05). Among Hakka newborns in Heyuan, the carrier rate of GJB2 c.235delC was the highest. Combining with two screening methods will effectually increase the detection rate of neonatal deafness and play an essential role in clinical intervention.


Subcutaneous reduction clitoroplasty.
Congenital clitoral hypertrophy should be corrected in infancy. Most surgeons perform a total clitroectomy or one of several kinds of clitoral recession procedures. There are some reasons for dissatisfaction with both of these alternatives. An operation in which the corpora cavernosum are resected subcutaneously and the glans sutured to the pubis preserves blood supply and sensation and results in a perineal appearance close to normal. The author has performed this operation infive cases of clitoral hypertrophy associated with adrenogenital syndrome and suggests a wider trial of procedure.


Stimulation of monocyte procoagulant activity by adherence to different surfaces.
During in vitro incubation for several hours human circulating blood leucocytes developed procoagulant activity (PCA) which was identified as tissue thromboplastin-like activity and which remained specifically associated with monocytes. Adherence of monocytes to glass stimulated these cells to generate PCA. When cuprophane was used, both the degree of adherence of monocytes and PCA generation by these cells was significantly less. In addition, when the monocytes were incubated upon a monolayer of cultured endothelial cells only minor PCA generation was detectable. After incubation on glass the non-adherent monocytes had negligible PCA in comparison to the adherent monocytes. Protein synthesis inhibitors (cycloheximide and actinomycin D) inhibited PCA generation but did not affect monocyte adherence. These results demonstrate that adherence of monocytes is a stimulus for the generation of PCA.


The correction for bias in prevalence estimation with screening tests.
The concern that the South Oaks Gambling Screen (SOGS) and other screening tests have a relatively high rate of false positive errors which results in overestimation of the true prevalence in general population studies is shown to be unfounded. False positives are seen to be a necessary but not sufficient condition for overestimation. It is demonstrated that the proper research question is whether the sample prevalence estimator is biased, and, if so, in which direction. One solution to the problem of bias is shown to depend on the availability of estimates of the error rates of the test.


Correction to: Skin bridge loop stoma: outcome in 45 patients in comparison with stoma made on a plastic rod.
The name of the author was incorrectly spelled as "Filippo Carannant". The correct spelling is "Filippo Carannante" and is now presented correctly in this article.


Admission levels of soluble CD137 are increased in patients with acute pancreatitis and are associated with subsequent complications.
The progression of acute pancreatitis to necrotizing pancreatitis which often results in high morbidity and mortality is difficult to predict. Here we report that serum concentrations of sCD137 are increased in patients with acute pancreatitis. Admission levels and 10-day median sCD137 levels positively correlate with markers of biliary pancreatitis and the 10-day sCD137 median is significantly higher in metabolic than in alcoholic pancreatitis. Serum concentrations of sCD137 at time of admission and the 10-day median of sCD137 correlate with the Ranson and APACHE II disease scores but not with the radiological Balthazar and Schroeder scores that reflect pancreatic and peripancreatic necrosis. Further, sCD137 levels correlate with the probability of complications and lethality. The association of sCD137, a product of activated T cells, with the severity of acute pancreatitis suggests that T cells contribute to the pathogenesis of acute pancreatitis.


[Biopsies of the kidney, prostate and urinary bladder].
Biopsies of the kidney, prostate and urinary bladder are amongst the most frequent interventions in urology. A correct indication, preparation and performance are important to achieve good results and low complication rates. In this review complication management in biopsies of the kidney, prostate and urinary bladder are discussed. A selective search of the literature, with emphasis on systematic reviews and larger cohort studies was performed. Complication rates are generally low. However, certain factors such as coagulation disorders, anatomical malformations, accompanying morbidities or antibiotic resistance may play a significant role and increase rates of complications. Especially complications such as hematuria and injury of contiguous organs are described in the literature. Biopsies of the kidney, prostate and urinary bladder can be performed with low complication rates if general and specific factors in the planning of the intervention and prevention of complications are considered.


Effect of the number of cycles of docetaxel + S-1 therapy on long-term survival in adjuvant chemotherapy for stage III gastric cancer. A pooled analysis of the OGSG0604 and OGSG1002 trials.
S-1 plus docetaxel (DS) therapy followed by S-1 is the standard of care in Japan in postoperative adjuvant chemotherapy for stage III gastric cancer, but long-term survival and the number of DS cycles required are unclear. The purpose of this study was to investigate the impact of the number of cycles of DS therapy on the 5-year survival in stage III gastric cancer in a pooled analysis of two phase II trials (OGSG0604 and OGSG1002). Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled in this pooled analysis. They received DS therapy for four or eight cycles, followed by S-1 until 1 year postgastrectomy. The 5-year overall survival (OS) and the 5-year disease free survival (DFS) by the landmark analysis was evaluated. In total, 113 patients from the OGSG0604 and OGSG1002 trials were enrolled in this study. The landmark analysis showed a 5-year OS that was better with four to eight cycles of DS therapy than with one to three cycles of DS therapy, with the best 5-year OS of 77.4% (95% confidence interval, 66.5-90.1%) for eight cycles. The 5-year DFS was approximately 66% when four or eight cycles of DS therapy were given. Although eight cycles of DS therapy may prolong prognosis, the present study did not provide a clear conclusion as to how many DS therapy cycles are needed to improve prognosis after D2 gastrectomy for stage III gastric cancer. Registration number: UMIN00000714 and UMIN000004440.


Immunoadsorption can improve cardiac function in transplant candidates with non-ischemic dilated cardiomyopathy associated with diabetes mellitus.
Diabetes mellitus (DM) is a risk factor for death from heart failure (HF) in patients with dilated cardiomyopathy (DCM) but DM patients are less eligible for heart transplantation (HTx) and DM is a risk factor for death also after HTx. New therapies are therefore necessary to improve survival of diabetic DCM patients. Immunoadsorption (IA) can improve heart function in DCM but its usefulness for therapy of DM-associated DCM is unknown. We assessed this aspect. Cardiac function and HTx-free survival were evaluated in diabetic HTx-candidates with DCM who underwent IA (Globaffin(®), a broadband-immunoadsorber containing synthetic peptide-GAM(®)) in 6/2003-6/2012 (follow-up 1-10 yrs). Non-diabetic HTx-candidates with DCM who received IA in the same time-period served as controls. Before and after IA patients were tested for serum β1-autoantibodies (β1-AABs). We evaluated 31 patients with and 31 without DM. Before IA there were no differences between the 2 groups in LV size, LVEF and β1-AAB levels. However, DM patients were older, their HF duration was longer and their peak oxygen-uptake was lower (p < 0.005). During the 1st post-IA year in both groups there was a decrease in LV size and improvement in both LVEF and NYHA-class (p < 0.05). Post-IA 3-year HTx-free survival and prevalence of responders to IA in patients with and without DM was 81.3 ± 8% and 78.4 ± 8%, respectively and 73.3% and 67.7%, respectively. Post-IA 3-year freedom from β1-AAB reappearance in patients with and without DM reached 72.1 ± 9.0% and 71.1 ± 8.6%, respectively. IA improves heart function, exercise tolerance and Tx-free survival in patients with DM-associated end-stage DCM. Our results also suggest that IA can delay HTx-listing, improve survival on HTx lists and even spare some diabetic patients from HTx, benefits of particular importance for these patients who are at high risk for pre-HTx and post-HTx mortality.


Cooperative dimerization of a stably folded protein directed by a flexible RNA in the assembly of the HIV Rev dimer-RRE stem II complex.
The binding of the HIV-1 Rev protein as an oligomer to a viral RNA element, the Rev-response element (RRE), mediates nuclear export of genomic RNA. Assembly of the Rev-RRE ribonucleoprotein (RNP) complex is nucleated by the binding of the first Rev molecule to stem IIB of the RRE. This is followed by stepwise addition of a total of ~six Rev molecules along the RRE through a combination of RNA-protein and protein-protein interactions. RRE stem II, which forms a three-way junction consisting of stems IIA, IIB and IIC, has been shown to bind to two Rev molecules in a cooperative manner, with the second Rev molecule binding to the junction region of stem II. The results of base substitutions at the stem II junction, and characterization of stem II junction variants selected from a randomized library showed that an "open" flexible structure is preferred for binding of the second Rev molecule, and that binding of the second Rev molecule to the junction region is not sequence-specific. Alanine substitutions of a number of Rev amino acid residues implicated to be important for Rev folding in previous structural studies were found to result in a dramatic decrease in the binding of the second Rev molecule. These results support the model that proper folding of Rev is critical in ensuring that the flexible RRE is able to correctly position Rev molecules for specific RNP assembly, and suggests that targeting Rev folding may be effective in the inhibition of Rev function.


Studies on deficiency of Schwann cell basal lamina and deformation of collagen fibres induced by beta-aminopropionitrile in cultures of developing rat peripheral neurons.
The morphological analysis in culture of superior cervical ganglia and dorsal root ganglia showed the following: (1) collagen fibres external to the neurite bundles were larger than those inside the neurite bundles in both control and BAPN-treated cultures; (2) there was much more irregularity of shape in external than in internal fibres in dorsal root ganglia with BAPN; (3) there was reduced basal lamina formation by Schwann cells in both types of ganglia (Okada & Bunge, 1981); (4) basal lamina formation in the superior cervical ganglion was reduced as the days of treatment with BAPN increased (from 94.7% with one day of treatment to 66.7% with 8 days of treatment; (5) in the dorsal root ganglion preparation, the myelin internode was shorter in BAPN (105.1 micron +/- 34.5 micron) than in control media (127.8 micron +/- 32.8 micron: P less than 0.001); (6) there was no significant difference in thickness of myelin between controls (2.9 micron +/- 0.9 micron) and those treated with BAPN (2.7 micron +/- 0.7 micron: 0.05 less than P less than 0.1); (7) the node of Ranvier was more elongated in BAPN (5.1 micron +/- 4.1 micron) than in control media (2.5 micron +/- 0.8 micron; P less than 0.01). The relationship between connective tissue abnormalities caused by BAPN and of the basal lamina formation of myelin-forming cells affected by BAPN is discussed.


Disciplining cattle reproduction: Veterinary reproductive science, bull infertility, and the mid-twentieth century transformation of Swedish dairy cattle breeding.
From the 1940s, reproductive physiology and livestock genetics transformed dairy cattle breeding and became, in conjunction with the new reproductive technology of artificial insemination, important drivers of agricultural modernization in most countries with significant dairying. While this is well known, we know less about the longer-term interplay between specifically veterinary interests in reproduction and the institutional development of cattle breeding. In the present paper, I therefore examine the veterinary disciplining of cattle reproduction-its constitution as a veterinary scientific discipline and the extension of veterinary control over it-in mid-twentieth century Sweden. I show how veterinary scientists derived legitimacy for their fledgling discipline by engaging with the problems of practical breeding, and that in doing so they also exercised influence over breeding's development. By making bulls' reproductive disturbances visible and framing them as hereditary, they undermined the conservative interests of commercial breeders. The development of veterinary reproductive science thereby played an important role in reshaping the culture, economy, and regulations of cattle breeding in Sweden as it shifted from a prewar regime dominated by elite breeders to a postwar regime that, ostensibly, served all dairy farmers in the country.


Co-delivery of doxorubicin and tumor-suppressing p53 gene using a POSS-based star-shaped polymer for cancer therapy.
In this work, a star-shaped polymer consisting of a cationic poly[2-(dimethylamino) ethyl methacrylate] (PDMAEMA) shell and a zwitterionic poly[N-(3-(methacryloylamino) propyl)-N,N-dimethyl-N-(3-sulfopropyl) ammonium hydroxide] (PMPD) corona was grafted from a polyhedral oligomeric silsesquioxanes (POSS)-based initiator via atomic transfer radical polymerization (ATRP). The reported star-shaped polymer could form stable micelles in aqueous solutions even in the presence of serum. In addition, anti-cancer drug doxorubicin and tumor-suppressing p53 gene were loaded in the process of micelle formation. The formed polyplex was biocompatible and highly efficient for both drug and gene delivery. Furthermore, the polyplex was able to cause a high apoptotic rate of tumor cells both in vitro and in vivo. This combination delivery strategy offers a promising method for cancer therapy and can be used for further clinical applications.


Primary tooth enamel loss after manual and mechanical microabrasion.
This study's purpose was to assess the amount of dental enamel loss on primary incisors after manual or mechanical microabrasion with a phosphoric acid/pumice paste. Ten exfoliated primary maxillary incisors were bisected faciolingually and the resulting 20 halves were randomly assigned to 2 groups: group 1 (N = 10)-manual technique (plastic spatula); and group 2 (N = 10)-mechanical technique (rubber cup attached to a low-speed handpiece). Microabrasion was performed on the buccal surface using an abrasive paste prepared with 37% phosphoric acid and pumice. Ten 20-second applications alternated with 20-second risings were performed in each group. Enamel thickness measurements made under stereomicroscopy before and after microabrasion were analyzed statistically by analysis of variance and pairwise t test. There was a statistically significant difference (P = .003) between the manual and mechanical techniques. The mechanical technique produced a mean enamel loss of 274.16 microm (66% of total enamel thickness), while the mean enamel loss with the manual technique was 152.59 microm (39% of total enamel thickness). Manual microabrasion using a plastic spatula removed less enamel, but was sufficient to eliminate most superficial stains and defects, and may be a viable option for the microabrasive technique on primary teeth.


Neurofibrosarcoma - complicating neurofibromatosis-I: case report and review of relevant literature.
Neurofibromatosis I is a multi systemic genetic and progressive disorder. Malignancy is one of the several complications and frequency of neurofibrosarcoma is significantly higher in NF-I patients. Neurofibromatosis was noted at 2 years after birth and overtime became malignant for which a below the knee amputation was done at the age of 29 years. Malignant transformation probably occurred prior to excision of the tumour at 26 years. Recurrence within 18 months is suggestive of inadequate excision and of a slow growing tumour. Diagnosis was missed despite previous presentation to other hospitals. This case presentation and review of literature highlights the need for early diagnosis and follow up, education of the patients and their families and the need for histological diagnosis for lesion removed to achieve overall improvement in morbidity and mortality. neurofibromatosis I, neurofibrosarcoma.


Is nitrification the only cause of microbiologically induced chloramine decay?
Ammonia degradation was investigated in three batch reactors with differing initial concentrations of bacteria present in the same filtered water source based on pre-treatment filtration techniques. The potential for the bacterial community to degrade the ammonia present was determined in the absence of monochloramine, simulating a distribution system where a loss of disinfectant residual has occurred. Nitrification was observed in only one of the three batch reactors, whereas rapid microbiologically induced chloramine decay was present in two reactors. Results suggest that the microbial decay factor is not a valid tool for indication of nitrification, but may be used as an indicator of the occurrence of rapid monochloramine decay. Intact bacterial cell numbers did not to correlate with changes in ammonia, nitrite or nitrate concentrations and hence did not correlate with the nitrification observed. Neither use of the microbial decay factor or monitoring of ammonia oxidising prokaryotes provided an early indication for the occurrence of nitrification. Hence, monitoring of ammonia and nitrite would still be the most suitable tool for indicating nitrification.


Potential Impacts of a Pandemic on the US Farm Labor Market.
An outbreak of COVID-19 among farmworkers could have significant impacts on the workers, agricultural producers, and the consumers. Farmers are implementing new labor management practices to slow the spread of the virus among workers. Since immigration is temporarily restricted, farmers may have difficulty securing a sufficient workforce. We test whether changes in the unemployment rate affected H-2A guest worker demand before the pandemic and find a statistically significant negative impact. Nevertheless, we expect that H-2A recruitment will be vital to sustaining agricultural production. We conclude by discussing potential long-term impacts of the pandemic on farm labor supply and demand.


Oxidative stress-mediated epidermal growth factor receptor activation regulates PM2.5-induced over-secretion of pro-inflammatory mediators from human bronchial epithelial cells.
Exposure to PM2.5 has been associated with increased morbidity and mortality of lung diseases although the underlying mechanisms have not been fully uncovered. Airway inflammation is a critical event in the pathogenesis of lung diseases. This study aimed to examine the role of oxidative stress and epidermal growth factor receptor (EGFR) in PM2.5-induced pro-inflammatory response in a human bronchial epithelial cell line, BEAS-2B. BEAS-2B cells were exposed to 0, 20, 50, 100 and 150 μg/ml of PM2.5. Secretion of pro-inflammatory mediators including interleukin-6 (IL-6), IL-8 and IL-1β was determined using enzyme linked immunosorbent assay. Levels of intracellular reactive oxygen species (ROS) were determined using flow cytometry. Phosphorylation of the EGFR was examined with immunoblotting. PM2.5 exposure increased the secretion of IL-6, IL-8, and IL-1β in a concentration-dependent fashion. Moreover, exposure to PM2.5 elevated intracellular levels of ROS, and phosphorylation of the EGFR (Y1068). Pretreatment of BEAS-2B cells with either an antioxidant or a specific EGFR inhibitor significantly reduced PM2.5-induced IL-6, IL-8 and IL-1β secretion, implying that both oxidative stress and EGFR activation were involved in PM2.5-induced pro-inflammatory response. Furthermore, pre-treatment of BEAS-2B cells with an antioxidant significantly blunted PM2.5-induced EGFR activation, suggesting that oxidative stress was required for PM2.5-induced EGFR activation. PM2.5 exposure induces pro-inflammatory response in human bronchial epithelial cells through oxidative stress-mediated EGFR activation.


Visual perception and macular integrity in non-classical CLN2 disease.
Patients with CLN2 suffer from epileptic seizures, rapid psychomotor decline and vision loss in early childhood. The aim of the study was to provide longitudinal ophthalmic data of patients with confirmed genetic mutation and non-classical disease course, marked by later onset, protracted progression and prolonged life span. Prospective, observational study to assess visual acuity, retinal features (Weil Cornell Ophthalmic Score), central retinal thickness (CRT) measured by optical coherence tomography and general disease progression (Hamburg CLN2 motor language score) in non-classical CLN2 patients. All patients received intracerebroventricular enzyme replacement therapy with cerliponase alfa. Mean age at last follow-up was 12.4 years; mean follow-up time 2.6 years. All cases demonstrated a stable Hamburg motor language CLN2 Score and Weill Cornell LINCL Ophthalmic Severity Score. Visual function remained stable in 4/6 patients, 2/6 patients showed a decrease, 4/6 cases had a stable CRT and 2/6 showed a reduction of CRT. One patient showed a massive macular thinning and low vision. A correlation with a specific mutation or age could not be verified. The presented longitudinal study characterizes the variable ocular involvement in non-classical CLN2 disease and contributes to the natural history description. The functional and morphologic data outline the necessity of regular ophthalmic examination. Ocular phenotyping and description of retinal degeneration in non-classical CLN2 disease.


Molecular diagnosis: Implications for ophthalmology.
The effort to subdivide diseases and to individualize therapies based on characteristics of the patient has been labeled precision medicine. Jameson and Longo define precision medicine as "treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations" (Jameson and Longo, 2015). We illustrate how molecular diagnosis can be applied to orbital inflammatory disease to achieve the goals of precision medicine.


Tabanidae (Diptera) of saudi arabia.
Samples were collected from southern, central and eastern regions of Saudi Arabia using Malaise traps and sweep nets. Nine species of Tabanidae were identified, two for the first time from Saudi Arabia, Hybomitra peculiaris (Szilády) and Atylotus pulchellus (Loew). Therefore, the total number of Tabanidae in Saudi Arabia is 31 species. Remarks of the species recorded in this study were given. A key to the genera of Tabanidae occurring in the Arabian Peninsula is also provided. Available literature for Saudi Arabian Tabanidae is summarized and provided. It is concluded that the tabanid fauna of Saudi Arabia is more similar to that of the Palaearctic region than to the Afrotropical region.


Real-World Evidence on the Clinical Characteristics and Management of Patients with Chronic Lymphocytic Leukemia in Spain Using Natural Language Processing: The SRealCLL Study.
The SRealCLL study aimed to obtain real-world evidence on the clinical characteristics and treatment patterns of patients with chronic lymphocytic leukemia (CLL) using natural language processing (NLP). Electronic health records (EHRs) from seven Spanish hospitals (January 2016-December 2018) were analyzed using EHRead® technology, based on NLP and machine learning. A total of 534 CLL patients were assessed. No treatment was detected in 270 (50.6%) patients (watch-and-wait, W&W). First-line (1L) treatment was identified in 230 (43.1%) patients and relapsed/refractory (2L) treatment was identified in 58 (10.9%). The median age ranged from 71 to 75 years, with a uniform male predominance (54.8-63.8%). The main comorbidities included hypertension (W&W: 35.6%; 1L: 38.3%; 2L: 39.7%), diabetes mellitus (W&W: 24.4%; 1L: 24.3%; 2L: 31%), cardiac arrhythmia (W&W: 16.7%; 1L: 17.8%; 2L: 17.2%), heart failure (W&W 16.3%, 1L 17.4%, 2L 17.2%), and dyslipidemia (W&W: 13.7%; 1L: 18.7%; 2L: 19.0%). The most common antineoplastic treatment was ibrutinib in 1L (64.8%) and 2L (62.1%), followed by bendamustine + rituximab (12.6%), obinutuzumab + chlorambucil (5.2%), rituximab + chlorambucil (4.8%), and idelalisib + rituximab (3.9%) in 1L and venetoclax (15.5%), idelalisib + rituximab (6.9%), bendamustine + rituximab (3.5%), and venetoclax + rituximab (3.5%) in 2L. This study expands the information available on patients with CLL in Spain, describing the diversity in patient characteristics and therapeutic approaches in clinical practice.


Data on structural and composition-related merits of gC3N4 nanofibres doped and undoped with Au/Pd at the atomic level for efficient catalytic CO oxidation.
Precise design of graphitic carbon nitride (gC3N4) nanostructures is of grand importance in different catalytic applications. This article emphasizes additional data on the fabrication of metal-free gC3N4 nanofibres (gC3N4NFs) and its associated structural and composition analysis compared with Au/Pd co-doped gC3N4 nanofibres (Au/Pd/gC3N4NFs). The data is including the typical fabrication process of metal-free gC3N4 nanofibers and its SEM, TEM, and element mapping analysis beside Raman, and FTIR spectra relative to Au/Pd/gC3N4NFs. We also investigated the catalytic CO oxidation durability testes on Au/Pd/gC3N4NFs compared to Pd/gC3N4NFs and Au/gC3N4NFs. The presented data are associated with the research article entitled "Rational synthesis of one-dimensional carbon nitride-based nanofibers atomically doped with Au/Pd for efficient carbon monoxide oxidation." [1].


Classifying sepsis from photoplethysmography.
Sepsis is a life-threatening organ dysfunction. It is caused by a dysregulated immune response to an infection and is one of the leading causes of death in the intensive care unit (ICU). Early detection and treatment of sepsis can increase the survival rate of patients. The use of devices such as the photoplethysmograph could allow the early evaluation in addition to continuous monitoring of septic patients. The aim of this study was to verify the possibility of detecting sepsis in patients from whom the photoplethysmographic signal was acquired via a pulse oximeter. In this work, we developed a deep learning-based model for sepsis identification. The model takes a single input, the photoplethysmographic signal acquired by pulse oximeter, and performs a binary classification between septic and nonseptic samples. To develop the method, we used MIMIC-III database, which contains data from ICU patients. Specifically, the selected dataset includes 85 septic subjects and 101 control subjects. The PPG signals acquired from these patients were segmented, processed and used as input for the developed model with the aim of identifying sepsis. The proposed method achieved an accuracy of 76.37% with a sensitivity of 70.95% and a specificity of 81.04% on the test set. As regards the ROC curve, the Area Under Curve reached a value of 0.842. The results of this study indicate how the plethysmographic signal can be used as a warning sign for the early detection of sepsis with the aim of reducing the time for diagnosis and therapeutic intervention. Furthermore, the proposed method is suitable for integration in continuous patient monitoring.


Advances in spray products for skin regeneration.
To date, skin wounds are still an issue for healthcare professionals. Although numerous approaches have been developed over the years for skin regeneration, recent advances in regenerative medicine offer very promising strategies for the fabrication of artificial skin substitutes, including 3D bioprinting, electrospinning or spraying, among others. In particular, skin sprays are an innovative technique still under clinical evaluation that show great potential for the delivery of cells and hydrogels to treat acute and chronic wounds. Skin sprays present significant advantages compared to conventional treatments for wound healing, such as the facility of application, the possibility to treat large wound areas, or the homogeneous distribution of the sprayed material. In this article, we review the latest advances in this technology, giving a detailed description of investigational and currently commercially available acellular and cellular skin spray products, used for a variety of diseases and applying different experimental materials. Moreover, as skin sprays products are subjected to different classifications, we also explain the regulatory pathways for their commercialization and include the main clinical trials for different skin diseases and their treatment conditions. Finally, we argue and suggest possible future trends for the biotechnology of skin sprays for a better use in clinical dermatology.


Tackling the Pandemic a Year Later: Burnout Among Home Palliative Care Clinicians.
The COVID-19 pandemic strongly challenged healthcare workers, disrupting their work routine and impacting on their professional life. A previous investigation explored levels of burnout and psychological morbidity among palliative care professionals (PCPs) during COVID-19 first wave. To update data about burnout and psychological morbidity among PCPs after a year of COVID-19 pandemic. The same questionnaires on burnout (Maslach Burnout Inventory, MBI) and psychological morbidity (General Health Questionnaire 12 items, GHQ-12) were administered a year after. Differences in MBI and GHQ-12 scores obtained in the two studies (COVID2020 and COVID2021), as well as distributions of PCPs showing burnout symptoms and psychological morbidity were analyzed and compared. We also explored the association between the three dimensions of burnout and socio-demographic and professional characteristics. The sample consisted of 145 PCPs (59% physicians and 41% nurses). Response rate (70.4%) was quite similar to the previous study (73.2%). No differences were observed in the frequency of burnout between COVID2021 and COVID2020; the PCPs in COVID2021 reported marginally higher level of EE (P = .049) and this result is confirmed in physicians (P = .010) while no difference was observed in nurses (P = .326). In addition, the percentage of cases showing psychological morbidity significantly decreased. Our findings show stable levels of burnout and decreasing levels of psychological morbidity among PCPs one year after the onset of the COVID-19 pandemic. However, more research is needed to detail the significance of emotional exhaustion dimension, a variable influenced by the survey.


Cervical pedicle screw guiding jig, an innovative solution.
Pedicle screws are one the commonest used modality in spinal instrumentation. However, the method of pedicle screw fixation in cervical spine as compared to thoracic and lumbar spine is still technically demanding because it carries the risk of catastrophic damage to the surrounding neurovascular structures We have utilized virtual planning and 3D (3-dimension) printing to develop a patient specific jig to guide the accurate placement of pedicle screws. A patient with bifacetal dislocation C7 over D1 classified as flexion-distraction injury type 3 who was planned for decompression and fusion by posterior instrumentation at C6, C7, D1 and D2 was selected. A CT scan with 1 mm cuts was used to produce DICOM images of the same. Using these DICOM images virtual planning was done on MIMICS and 3 MATICS software to create patient specific jigs. These jigs were then 3D printed using a 3D printer and used for accurate placement of pedicle screws intra-operatively after adequate sterilization. Our procedure is low cost but high technology based. It is simple, accurate, and very cost effective. The technology transfer is very easy and can be adopted easily.


Inflammatory markers and overall survival in older adults with cancer.
Our aim was to evaluate the prognostic impact of three inflammatory markers - neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR) and lymphocyte monocyte ratio (LMR) - on overall survival (OS) in older adults with cancer. Our sample includes 144 patients age ≥ 65 years with solid tumor cancer who completed a cancer-specific Geriatric Assessment (GA) from 2010 to 2014 and had pretreatment CBC with differential. NLR was dichotomized a previously reported cut-off value of 3.5, while PLR and LMR were dichotomized at the median. Cox proportional hazards models evaluated whether NLR, PLR and LMR were predictive of OS independent of covariates including a recently developed 3-item GA-derived prognostic scale consisting of (1) "limitation in walking several blocks", (2) "limitation in shopping", and (3) "≥ 5% unintentional weight loss in 6 months". Median age was 72 years, 53% had breast cancer, 27% had stage 4 cancer, 14% had Karnofsky Performance Status (KPS) < 80, 11% received less intensive than standard treatment for stage, and 39% had NLR > 3.5. In univariable analysis, higher NLR and PLR and lower LMR were significantly associated with worse OS. NLR remained a significant predictor of OS (HR = 2.16, 95% CI; 1.10-4.25, p = .025) after adjusting for cancer type, stage, age, KPS, treatment intensity, and the GA-derived prognostic scale. NLR > 3.5 is predictive of poorer OS in older adults with cancer, independent of traditional prognostic factors and the GA-derived prognostic scale.


Renal fungal ball: an unusual sonographic finding.
Fungal infections of the urinary tract tend to occur in the drainage structures instead of the renal parenchyma. In patients with systemic candidiasis, the kidney is vulnerable to the formation of cortical abscesses or obstructive intrarenal masses ("fungal balls"), usually at the ureteropelvic junction. We describe the case of a boy who presented with dysuria, fever, and chills. Sonographic examination showed mild enlargement of both kidneys and moderate dilatation of the pelvicaliceal system bilaterally. A well-defined, echogenic, oval, mobile mass measuring 2.5 x 2.0 cm, without posterior acoustic shadowing, was visualized in the pelvis of the left kidney. The upper and middle ureters were dilated bilaterally. A urine culture revealed hyphae of Candida albicans. The child received systemic antifungal therapy with fluconazole for 3 weeks. Follow-up sonography showed complete resolution of the mass (a fungal ball) with residual hydronephrosis.


A comparison of the efficacy of fixed versus removable functional appliances in children with Class II malocclusion: A systematic review.
To systematically compare the efficacy of fixed and removable functional appliances in Class II malocclusion in terms of morphological and patient-centred outcomes. A comprehensive search of electronic databases without language or time restrictions was undertaken, applying a pre-specified search strategy. Supplementary electronic searching of orthodontics journals and references list of included studies was performed. Randomized (RCTs) and controlled (CCTs) clinical trials involving children under 16 years with Class II malocclusion and overjet more than 5mm were included. A range of clinician- and patient-centred outcomes were evaluated and compared. Risk of bias assessment was carried out using the Cochrane Collaboration tool. Only four clinical trials were found to meet our criteria, of which two were RCTs, comparing the Herbst and the Twin Block appliances. Two further CCTs, compared the Activator to the Forsus and the Twin Force Bite Corrector, respectively. One study was assessed to be at unclear and the remaining at high risk of bias, precluding meta-analysis. There was also significant clinical heterogeneity in terms of methodology, type of intervention and the measured outcomes. Both modalities were effective in correcting the overjet with little differences found in cephalometric changes and a shortage of data concerning patient-centred outcomes. There is little evidence concerning the relative effectiveness of fixed and functional appliances or in relation to patient experiences and perceptions of these treatment modalities. Further well-designed clinical trials assessing the relative merits of both clinician- and patient-centred outcomes are needed.


Treatment Engagement as a Predictor of Therapy Outcome Following Cognitive Behaviour Therapy for Autistic Children.
Active engagement in one's therapy is a key contributor to successful outcomes. Research on child engagement in cognitive behaviour therapy (CBT) has largely focused on youth without autism. This longitudinal study examined multiple indicators of child engagement in relation to outcomes for autistic children who took part in CBT for emotion regulation. Data were collected from 60 autistic children who were between 8 and 13 years of age (86.7% male; Mage = 9.58 years, SD = 1.44 years; 75% White). Indicators of child engagement included independent observer ratings of in-session involvement, as measured by the Child Involvement Rating Scale, and therapist ratings of the therapeutic relationship and homework completion using single-item measures. Indicators of engagement were measured at early (i.e., first third), middle (i.e., mid third), and late (i.e., final third) stages of treatment. Parent-reported emotion regulation was the primary treatment outcome, as measured by the Emotion Regulation Checklist. After controlling for pre-treatment scores, in-session involvement significantly predicted some aspects of post-treatment emotion regulation, whereas therapeutic relationship and homework completion did not. Child in-session involvement throughout therapy may be particularly relevant for treatment change. Addressing issues related to in-session involvement early in treatment may help to promote therapeutic success for autistic children.


Does antihypertensive treatment with renin-angiotensin system inhibitors prevent the development of diabetic kidney disease?
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. Renin-angiotensin system (RAS) inhibitors are the first-line treatment for diabetic patients with hypertension. However, whether RAS inhibitors prevent the development of DKD remains controversial. We conducted a retrospective cohort study quantifying the preventive effect of antihypertensive treatment with RAS inhibitors on DKD, using data from specific health check-ups and health insurance claims. The study subjects were 418 patients with diabetes and hypertension, drawn from health insurance societies located in Fukuoka and Shizuoka prefectures in Japan. The subjects were divided into three groups, according to the type of antihypertensive treatment they received. They were then compared in terms of the development of DKD, using the diagnostic codes from ICD-10. Thirty subjects (6.2%) developed DKD during the study period between April 2011 and September 2013. RAS inhibitor treated group showed a significantly lower risk of DKD [adjusted odds ratio (AOR) = 0.35; 95% confidential interval (CI): 0.16-0.76] compared with the no treatment group. We conclude that antihypertensive treatment with RAS inhibitors is potentially useful for preventing the development of DKD.


The challenge of separating and determining biologically active electrostatically stabilized silanates using the high-performance liquid chromatography technique.
We present the results of research on the optimal conditions for the separation and determination of newly obtained hypercoordinated compounds, which belong to the group of electrostatically stabilized silanates. The research involved five stationary and four mobile phases. The best selectivity was obtained using the graphite phase and the mobile phase consisting of acetonitrile/water (80/20). The maximum selectivity of the determined electrostatically stabilized silanates was 1.13 and 1.06 for (1), (2), (3); 1.10 and 1.15 for (4), (5), (6); and 1.12 and 1.15 for (7), (8), (9). The octadecyl phase (which is recommended as standard) did not yield satisfactory results.


Identification of 1-alkyl-2-acyl-3-(2',3'-diacylglycerol)glycerols, a new type of lipid class, in harderian gland tumors of mice.
A new class of alkyl glycerolipids, 1-alkyl-2-acyl-3-(2',3'-diacylglycerol)glycerols, was identified in lipid extracts prepared from harderian gland tumors of mice. After saponification, this lipid class yielded 1-alkyl-3-(1'-glycerol)glycerols. Identification was based on mass spectrometry, proton nuclear magnetic resonance spectroscopy, infrared spectroscopy, and chromatography of various derivatives and appropriate standards that were synthesized. The alkyl moieties of this unique lipid class consisted of saturated aliphatic chains with chain lengths of 14 to 20 carbon atoms. The acyl moieties were mostly saturated and monounsaturated aliphatic chains ranging from 14 to 24 carbon atoms. The alkyl and acyl moieties of 1-alkyl-2-acyl-3-(2',3'-diacylglycerol)glycerols were similar to those of alkyldiacylglycerols present in the same tissue, except for the presence of monounsaturated alkyl moieties in the latter. 1-Alkyl-2-acyl-3-(2', 3'-diacylglycerol)glycerols were only found in trace amounts in the normal harderian glands of mice. The total quantity of the alkyl and acyl moieties with a chain length greater than 20 carbon atoms in the alkyldiacylglycerols from tumors were considerably lower than those found in normal harderian glands of mice. This is the first report of the presence of bisglyceryl ether lipids in mammalian tissue; its unique chemical structure is consistent with the type of ether-linked lipid products that could be synthesized in the reaction catalyzed by alkyldihydroxyacetone-P synthase.


Structural basis for specific ligation of the peroxisome proliferator-activated receptor δ.
The peroxisome proliferator-activated receptor (PPAR) family comprises three subtypes: PPARα, PPARγ, and PPARδ. PPARδ transcriptionally modulates lipid metabolism and the control of energy homeostasis; therefore, PPARδ agonists are promising agents for treating a variety of metabolic disorders. In the present study, we develop a panel of rationally designed PPARδ agonists. The modular motif affords efficient syntheses using building blocks optimized for interactions with subtype-specific residues in the PPARδ ligand-binding domain (LBD). A combination of atomic-resolution protein X-ray crystallographic structures, ligand-dependent LBD stabilization assays, and cell-based transactivation measurements delineate structure-activity relationships (SARs) for PPARδ-selective targeting and structural modulation. We identify key ligand-induced conformational transitions of a conserved tryptophan side chain in the LBD that trigger reorganization of the H2'-H3 surface segment of PPARδ. The subtype-specific conservation of H2'-H3 sequences suggests that this architectural remodeling constitutes a previously unrecognized conformational switch accompanying ligand-dependent PPARδ transcriptional regulation.


Outcomes of treatment modalities for ruptured intracranial aneurysms based on age - A meta-analysis.
Data comparing the effect of age on outcomes of patients who underwent either endovascular coiling (EVC) or neurosurgical clipping (NSC) for ruptured intracranial aneurysms remains limited. To better elucidate the preferred intervention for ruptured aneurysm management by presenting the results of our systematic review of the literature that evaluated the potential advantages of the two interventions between different age groups. Systematic review of PubMed and Embase was performed (2002 - June 10, 2019) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2013 guidelines. Median ages of EVC and NSC cohorts were 54 and 56, respectively. Ages below the median were used in our "younger" cohort; ages above the median were used in our "older" cohort. We reviewed 13 studies on 7,137 patients. In the younger cohort, there were 2840 (EVC: 1412, NSC: 1428) patients. In the older cohort, there were 4297 (EVC: 2552, NSC: 1745) patients. Overall, there was a significant difference in functionality between EVC (77.70%) and NSC (69.23%) (OR=1.69; 95% C.I.: 1.10-2.60, p = 0.0212). In our younger cohort, functionality was significantly different between EVC (77%) and NSC (69%) (OR=1.54; 95% C.I.: 1.29-1.84, p < 0.001). For the older cohort, there was no significant difference in functionality, complications, or efficacy. We have highlighted the importance of considering age prior to deciding which intervention is most appropriate for ruptured aneurysms, with higher morbidity and mortality with NSC versus EVC in the younger population.


Treatment and Survival in Patients with Chronic Myeloid Leukemia in a Chronic Phase in West Iran.
CML includes 30% of all leukemias, and occurs from childhood to old age. The present study was a retrospective analysis of chronic phase CML patients registered to a Hematology Clinic in Kermanshah, Iran, with checking of treatment options. Between 2002 and 2014, 85 CML patients referred to our hematology clinic were enrolled in our study. We surveyed age, sex, B-symptoms, splenomegaly, Sokal score, Hasford score, treatment and survival in all patients. Philadelphia chromosome analysis was conducted for each patient by conventional cytogenetics. We compared treatment in the patients with three drugs, imatinib, hydroxyurea (HU) and interferon alpha (IFN-α). The mean age of the patients at diagnosis was 47.5 ± 14.5 years (range, 23-82 years), with 43 (50.6%) being male. Some 13 (15.3%) were referred to our clinic for the first time with B-symptoms and 44 patients (51.8%) had splenomegaly. The Sokal score for 77 (90.6%) was low, 4 (4.7%) was intermediate and 4(4.7%) was high, but Hasford (Euro) scores for all patients were low. The 5-year survival rate for treated patients with imatinib, imatinib plus HU and imatinib plus HU plus IFN-α was 90.5%, 81.1% and 55.6%, respectively The results show that imatinib therapy alone provides better survival in CML patients compared to HU or IFN-α. Combinations of IFN-α and/or HU with imatinib probably reduce survival.


Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation.
Saturated fatty acids (FA) exert adverse health effects and are more likely to cause insulin resistance and type 2 diabetes than unsaturated FA, some of which exert protective and beneficial effects. Saturated FA, but not unsaturated FA, activate Jun N-terminal kinase (JNK), which has been linked to obesity and insulin resistance in mice and humans. However, it is unknown how saturated and unsaturated FA are discriminated. We now demonstrate that saturated FA activate JNK and inhibit insulin signaling through c-Src activation. FA alter the membrane distribution of c-Src, causing it to partition into intracellular membrane subdomains, where it likely becomes activated. Conversely, unsaturated FA with known beneficial effects on glucose metabolism prevent c-Src membrane partitioning and activation, which are dependent on its myristoylation, and block JNK activation. Consumption of a diabetogenic high-fat diet causes the partitioning and activation of c-Src within detergent insoluble membrane subdomains of murine adipocytes.


Intervention in child abuse: experience in Liverpool.
The subsequent life events and development of 50 abused Liverpool children who had been removed from their parents and taken into the care of the Local Authority have been determined. Information was obtained by interviewing the district social worker responsible for each child's supervision. Medical progress and school performance was assessed in each case. Following their period in care, 26 children have had an unsatisfactory outcome indicated by the presence, either alone or in combination, of abnormal physical development, emotional disturbance, poor educational progress and occurrence of further abuse. Rehabilitation at home after varying periods of time was attempted for 25 children, five of whom suffered further abuse. The prognosis was worse the older the child on reception into care and the more placements while in care. The children who best survived their experiences after being taken into care were those for whom an early decision was made to sever parental contact and to place the child permanently with a substitute family.


Interferon-gamma regulation of major histocompatibility class I gene expression in rat cells containing the adenovirus 12 E1A oncogene.
Interferon-gamma (IFN gamma) treatment of cells expressing the Ad12 E1A oncogene results in an increase in MHC class I antigen expression. The effect of IFN gamma upon both the steady-state level of class I mRNA and the in vitro rate of initiation of transcription of class I genes was studied in a rat cell line containing the Ad12 E1A gene. Results obtained showed a marked increase in steady-state level of cytoplasmic class I mRNA; however, a concomitant increase in the rate of transcription of class I genes was not observed. In contrast IFN gamma was shown to markedly increase the rate of transcription of class I genes in primary baby rat kidney cells.


NAD-dependent dehydrogenase bioelectrocatalysis: the ability of a naphthoquinone redox polymer to regenerate NAD.
Electron mediation between NAD-dependent enzymes using quinone moieties typically requires the use of a diaphorase as an intermediary enzyme. The ability for a naphthoquinone redox polymer to independently oxidize enzymatically-generated NADH is demonstrated for application to glucose/O2 enzymatic fuel cells.


Echocardiographic and hemodynamic correlates of diastolic closure of mitral valve and diastolic opening of aortic valve in severe aortic regurgitation.
Acute severe aortic regurgitation (AR) is characterized by a steep increase in left ventricular end-diastolic pressure, exceeding left atrial pressure and occasionally equilibrating with aortic diastolic pressure. These pressure phenomena correlate with the M-mode echocardiographic (echo) findings of diastolic closure of the mitral valve (DCMV) and diastolic opening of the aortic valve (DOAV). Six men, aged 23 to 48 years, with recent-onset, severe AR were evaluated by M-mode echo and pressures at cardiac catheterization. DCMV was seen in all 6 patients and DOAV in 4. Near-constant time intervals from the preceding R wave of the electrocardiogram to DCMV and DOAV were seen, even in 3 patients with varying RR intervals (1 with atrial fibrillation and 2 with asynchronous and demand atrial pacing). When the RR intervals were shorter than these intervals, DCMV and DOAV did not occur. Increasing the heart rate in the 2 patients by atrial pacing resulted in a marked decrease in left ventricular end-diastolic pressure. In conclusion, DCMV and DOAV have a near constant relation to the preceding R wave of the electrocardiogram, DCMV with competence of the mitral valve must be present for DOAV to occur, DOAV indicates that the diastolic blood pressure equals left ventricular end-diastolic pressure, and heart rate is an important factor influencing the hemodynamic and echocardiographic parameters in recent-onset, severe AR.


A correlative study of the binding of dexamethasone in hypothalamic blocks in vitro with its ability to inhibit the release of bioactive corticotrophin-releasing factor.
Rat hypothalamic blocks incubated in vitro were used to study the characteristics of binding of [3H]dexamethasone and other steroids to cytosolic binding sites. Cytosols prepared following incubation of the tissue with [3H]dexamethasone for 2 h contained specifically bound steroid in amounts that depended upon the concentration of potassium (but not sodium) ions in the extracting buffer. There was an increase in bound [3H]dexamethasone extracted as the potassium ion concentration increased up to 0.1 M, but not beyond. Dexamethasone, when added to hypothalami in vitro caused a biphasic inhibition of bioactive corticotrophin-releasing factor (CRF) release, and the extent of the second phase of inhibition was dose-related. 11-Epicortisol, when added in a 100-fold molar excess over dexamethasone was able to prevent the second phase of inhibition caused by the latter steroid, as in the binding studies it was able to cause a 50% reduction in the binding of [3H]dexamethasone. In the functional studies it was shown that 11-epicortisol was able to "rescue" the tissue from dexamethasone-mediated delayed inhibition of CRF secretion if added to the blocks 30 min (but not later) after the agonistic steroid.


Memory function before and after whole brain radiotherapy in patients with and without brain metastases.
To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases. Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast. Before therapy, prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p < 0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT. The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.


Evidence for the influence of seagrasses on the benthic nitrogen cycle in a coastal plain estuary near Beaufort, North Carolina (USA).
A study was undertaken to evaluate the interrelationship between the presence of seagrasses, Zostera marina and Halodule wrightii, and the physical and chemical properties of sediments in a coastal plain estuary near Beaufort, North Carolina. In sediments underlying a cover of seagrass, silt-clay, organic matter, exchangeable ammonium, ammonium dissolved in pore waters and total nitrogen were larger than in unvegetated profiles. The magnitude of the physical and chemical properties of sediments varied according to the location of the station in relation to the vegetation, as well as the continuity in the distribution of the seagrass. The largest pools of nitrogen, the finest sediment texture, and the greatest organic matter content were in sediments associated with the mid bed regions of seagrass meadows, intermediate at the edges of the bed and small isolated patches of grass, and least in unvegetated substrate.General conclusions from this study are: 1) once established, seagrasses appear capable of modifying the sediment texture as well as the organic matter and nitrogen content; 2) nitrogen accumulates beneath the vegetation suggesting that vegetated sediments are sinks; however, functional recycling mechanisms seem to be operating as suggested by the larger magnitude of remineralized nitrogen in the vegetated profiles; and 3) the establishment of seagrasses in this geographical region are not necessarily restricted by the sediment properties measured in this study. These data and conclusions are discussed in regard to an application of contemporary theories of ecosystem development to seagrass systems.


Acute lethality of D- and L-ethionine in Swiss mice.
The acute, 7-day LD50 in Swiss mice of D-ethionine administered intraperitoneally, was determined as 185 mg/kg with 95% confidence limits of 163 and 210 mg/kg. L-ethionine, the stereoisomer, which is more potent in inhibiting liver RNA synthesis, was not lethal at 2500 mg/kg. This acute toxicity of D-ethionine was suppressed by L-methionine and adenine. Blood accumulation in the thoracic cavity and pericardium was the probable cause of death.


Interventional ductoscopy for pathological nipple discharge.
Despite the low likelihood of malignancy, it is recommended that patients who have pathologic nipple discharge (PND) undergo duct excision. Intraductal papilloma is well-known most frequent cause of PND. Our goal is to determine whether the ductoscopic retrieval of a solitary papilloma is feasible and/or therapeutic for patients with PND. The accompanying video demonstrates this interventional ductoscopic approach. Consented patients who had been diagnosed with PND were recruited to have ductoscopic exploration. Patients with palpable masses and suspicion of malignancy on ultrasound or mammography were excluded. Under local anesthesia, ductoscopy was performed using LaDuScope-T flex with an outer diameter of 1.1 mm, which allows extraction of a single papilloma with a microbasket (380 μm) via a working channel. Patients with sessile single papilloma or failure on ductoscopic extraction underwent ductoscopically guided microductectomy. Success was determined by recurrence of PND and by standard radiological examinations. Three patients presented in the video had negative cytology and normal conventional diagnostic imaging. Two patients diagnosed with a nonsessile single papilloma underwent successful ductoscopic extraction. The interventional examination times of those patients were 30 and 35 min. Patient who had a sessile papilloma underwent ductoscopically guided microductectomy. These patients had no recurrence of discharge or suspicious of malignancy after 5 years follow-up. Interventional ductoscopy provides an incisionless therapeutic option for patients diagnosed with a papillary nonsessile benign lesion that causes PND.


Computerized tomography in the management of intracranial bleeding in hemophilia.
Computerized tomography was used to evaluate the severity of six episodes of suspected intracranial bleeding in four patients with hemophilia. In all instances the CT scan rapidly provided information on the extent and location of the intracranial hemorrhage. Results of the initial scan provided a rational basis for therapy, and subsequent scans were a noninvasive means of evaluating the effects of treatment. If available, computerized tomography is a valuable aid in the management of the hemophiliac patient with intracranial bleeding.


Expression of sialyl-Tn predicts the effect of adjuvant chemotherapy in node-positive breast cancer.
Sialyl-Tn (STn) is a carcinoma-associated carbohydrate determinant expressed on cancer-associated mucins and has the structure NANA alpha(2-6)alpha GalNAc. Expression of STn in colon and ovarian cancer is associated with a poor prognosis independent of tumour grade, stage or histological type. We have examined 237 cases of primary breast cancer for expression of this antigen using the antibody HB-STn (Dako). The frequency of STn expression was 31% in the whole group, 36% in the node-negative and 28% in the node-positive group. Survival was lower, but not significantly so, in the STn-positive group (P = 0.07), but this effect was highly significant for patients with node-positive disease (P < 0.002), the curves for node-negative disease being coincident (P = 0.31). In node-positive disease the effect was limited to those receiving adjuvant chemotherapy (P = 0.001). In a multivariate (Cox) analysis on the whole group STn staining, combined with adjuvant chemotherapy, showed a highly significant correlation with survival. In STn-negative cases, adjuvant chemotherapy improved survival (relative risk 2.3, 95% confidence intervals 1.4-3.9), whereas adjuvant chemotherapy did not influence survival in patients which expressed STn (relative risk 1.1, 95% confidence intervals 0.6-2.2). Thus, by either direct or indirect mechanisms, STn positivity appears to be a marker of resistance to adjuvant chemotherapy.


Energetic Trinitro- and Fluorodinitroethyl Ethers of 1,2,4,5-Tetrazines.
Several new energetic ethyl ethers of 1,2,4,5-tetrazine have been synthesized. These molecules display good thermal stability, good oxygen balance, and high densities. Included in these studies are a 2,2,2-trinitroethoxy 1,2,4,5-tetrazine and two fluorodinitroethoxy 1,2,4,5-tetrazines. One of these compounds was converted into the di-N-oxide derivative. The sensitivity of these materials towards destructive stimuli was determined, and overall the materials show promising energetic performance properties.


The protective effect of platelet released growth factors and bone augmentation (Bio-Oss®) on ethanol impaired osteoblasts.
Chronic alcohol consumption is a known limiting factor for bone healing. One promising strategy to improve bone augmentation techniques with Bio-Oss® in oral and maxillofacial surgery might be the supportive application of platelet-concentrated biomaterials as platelet-released growth factor (PRGF). To address this matter, we performed an in vitro study investigating the protective effects of PRGF and Bio-Oss® in ethanol (EtOH) treated osteoblasts. The SAOS-2 osteosarcoma cell line, with and without EtOH pretreatment was used. The cell viability, proliferation and alkali phosphatase activity (ALP) after application of 0%, 5% and 10% PRGF and Bio-Oss® were assessed. The application of PRGF and Bio-Oss® in EtOH impaired osteoblasts showed a significant beneficial influence increasing the viability of the osteoblasts in cell culture. The synergistic effect of Bio-Oss® and 5% PRGF on the proliferation of osteoblasts was also demonstrated. Bio-Oss® only in combination with PRGF increases the alkaline phosphatase (ALP) activity in EtOH pretreated cells. These results indicate that the simultaneous application of PRGF and Bio-Oss® inhibits EtOH induced bone healing impairment. Furthermore, in the cells, PRGF induced a protective mechanism which might promote bone regeneration.


A new, alternative risk score for sarcopenia in Chinese patients with type 2 diabetes mellitus.
To develop a new, alternative sarcopenia risk score to screen for sarcopenia in type 2 diabetes patients in China and to demonstrate its validity. The data for this study came from a multicenter, cross-sectional study that had been designed to estimate the prevalence of sarcopenia among adults with type 2 diabetes and had been conducted in several hospitals in Beijing, China. A total of 1125 participants were randomly divided into two groups: an exploratory population and a validation population. A multivariable logistic regression model using the backward stepwise likelihood ratio method to estimate the probability of sarcopenia was fitted with candidate variables in the exploratory population. A new, alternative sarcopenia risk score was developed based on the multivariable model. The internal and external validations were performed in the exploratory and validation populations. The study was registered at Chinese Clinical Trial Registry (ChiCTR-EOC-15006901). The new, alternative sarcopenia risk score included five variables: age, gender, BMI, total energy intake per day, and the proportion of calories supplied by protein. The score ranged from - 2 to 19. The area under the receiver operating characteristic (ROC) curve of the risk score for the prediction of sarcopenia in type 2 diabetes patients was 0.806 (95% CI 0.741-0.872) and 0.836 (95% CI 0.781-0.892) in the exploratory and validation populations, respectively. At the optimal cutoff value of 12, the sensitivity and specificity of the score for the prediction of sarcopenia were 70.9% and 81.0% in the exploratory population and 53.7% and 88.8% in the validation population, respectively. The Hosmer-Lemeshow goodness-of-fit test showed a good calibration with the risk score in external validation (χ2 = 4.459, P = 0.813). The new, alternative sarcopenia risk score appears to be an effective screening tool for identification of sarcopenia in Chinese patients with type 2 diabetes in clinical practice. Clinical trial registration Chinese Clinical Trial Registry, ChiCTR-EOC-15006901.


Lactoferrin in relation to acute phase proteins in sera from newborn infants with severe infections.
Serum lactoferrin concentrations were elevated in 22 out of 49 newborn infants with suspected and verified severe bacterial as well as viral infections, suggesting that this protein resembled an acute phase reactant. In the infants suspected of having septicemia, high concentrations of C-reactive protein appeared to indicate a severe bacterial infection. Like lactoferrin, however, haptoglobin, orosomucoid, alpha 1-antitrypsin and alpha 1-antichymotrypsin discriminated only poorly or not at all between infants with severe bacterial infections and those in which such infections were unlikely. Thus, serum CRP concentrations remained the most valuable of the acute phase reactants tested as an aid in ruling out septicemia in the neonatal period.


Catecholamine concentrations during exposure of resting man to the heat of a standard sweat test.
1. Normal subjects were heated for 45 min with a heat cradle under the conditions used to investigate sweating clinically. 2. Skin temperatures on the chest and in the external auditory meatus rose but concentrations of noradrenaline and adrenaline decreased during heating. 3. There was no change in adrenoceptor affinity or number as a result of the heat exposure. 4. There was little change in blood pressure and heart rate and no dysrhythmias were observed with an electrocardiogram. 5. It is concluded that heating with a heat cradle is generally not stressful and that there is a reduction in sympathetic nervous activity involving noradrenergic or adrenergic transmission during the procedure.


Chitosan-Placental ECM Composite Thermos-Responsive Hydrogel as a Biomimetic Wound Dressing with Angiogenic Property.
Attempts are being made to develop an ideal wound dressing with excellent biomechanical and biological properties. Here, a thermos-responsive hydrogel is fabricated using chitosan (CTS) with various concentrations (1%, 2.5%, and 5% w/v) of solubilized placental extracellular matrix (ECM) and 20% β-glycerophosphate to optimize a smart wound dressing hydrogel with improved biological behavior. The thermo-responsive CTS (TCTS) alone or loaded with ECMs (ECM-TCTS) demonstrate uniform morphology using SEM. TCTS and ECM1%-TCTS and ECM2.5%-TCTS show a gelation time of 5 min at 37 °C, while no gel formation is observed at 4 and 25 °C. ECM5%-TCTS forms gel at both 25 and 37 °C. The degradation and swelling ratios increase as the ECM content of the hydrogel increase. All the constructs show excellent biocompatibility in vitro and in vivo, however, the hydrogels with a higher concentration of ECM demonstrate better cell adhesion for fibroblast cells and induce expression of angiogenic factors (VEGF and VEGFR) from HUVEC. Only the ECM5%-TCTS has antibacterial activity against Acinetobacter baumannii ATCC 19606. The data obtained from the current study suggest the ECM2.5%-TCTS as an optimized smart biomimetic wound dressing with improved angiogenic properties now promises to proceed with pre-clinical and clinical investigations.


Corticosteroids and Immune Suppressive Therapies in Horses.
Immune suppressive therapies target exaggerated and deleterious responses of the immune system. Triggered by exogenous or endogenous factors, these improper responses can lead to immune or inflammatory manifestations, such as urticaria, equine asthma, or autoimmune and immune-mediated diseases. Glucocorticoids are the most commonly used immune suppressive drugs and the only ones supported by robust evidence of clinical efficacy in equine medicine. In some conditions, combining glucocorticoids with other pharmacologic and nonpharmacologic treatments, such as azathioprine, antihistamine, bronchodilators, environmental management, or desensitization, can help to decrease dosages and associated side effects.


The stability of methyl and ethyl phosphotriesters in DNA in vivo.
C57BL male mice were injected with N-methyl-N-nitrosourea (MNUA) or N-ethyl-N-nitrosourea (ENUA) and the concentration of alkyl phosphotriesters in the DNA of lung, liver, brain, kidney, spleen and thymus determined from the extent of degradation induced in isolated DNA by alkali. The same total dose of reagent was given either as a single injection (i.p.) or by weekly injections carried out over 5-20 weeks. Methyl phosphotriesters induced in liver, lung and kidney by the single injection were lost with a half-life of about 7 days, in brain the loss was more rapid, t1/2 = 2-3 days. During the multiple injections the observed t1/2 was 16 days. Ethyl phosphotriesters formed in the DNA of lung, liver, kidney and brain were much more stable than the methyl derivatives, t1/2 = 10-15 weeks. Phosphotriesters formed in the DNA of spleen and thymus disappeared very quickly after the single injection presumably as a result of dilution due to DNA replication. No accumulation of phosphotriesters occurred in the DNA of these tissues during the multiple injections. The general pattern of the results suggests that phosphotriesters are not excised by cellular repair systems.


Efficacy and Safety of Surgery for Benign Prostatic Obstruction in Patients with Preoperative Urinary Catheter.
Purpose: To evaluate the efficacy and safety of benign prostatic obstruction (BPO) surgery in patients with preoperative urinary catheterization. Patients and Methods: We conducted a multi-institutional retrospective study including all patients who failed a trial without catheter (TWOC) after acute urinary retention (AUR) between January 2017 and January 2019. Patients with neurogenic bladder, prostate cancer, or urethral stricture were excluded from the analysis. Patients underwent either monopolar/bipolar transurethral resection of the prostate (TURP), photoselective vaporization of the prostate (PVP), prostate artery embolization (PAE), open prostatectomy (OP), or endoscopic enucleation. The primary endpoint was 12-month urinary catheter-free survival without using benign prostatic hyperplasia medications. Results: One hundred seventy-one consecutive men (median age: 71 years; median prostate volume: 75 cm3) underwent BPO surgery, including 48 (28%) TURP, 62 (36.3%) PVP, 21 (12.3%) endoscopic enucleation, 15 (8.8%) PAE, and 25 (14.6%) OP. The median duration of preoperative urinary catheterization was 69 days (interquartile range 46-125). The 12-month urinary catheter-free survival rate was 84.8% (145/171). Satisfactory voiding returned to 121 patients (70.8%). On backward stepwise multivariable analysis, PVP (odds ratio [OR] 0.27 [0.10-0.69]; p = 0.008), PAE (OR 5.27 [1.28-27.75]; p = 0.03), endoscopic enucleation (OR 0.08 [0-0.49]; p = 0.023), OP (OR 0.10 [0.01-0.57]; p = 0.034), Charlson score (OR 1.36 [1.14-1.66]; p = 0.001), and number of preoperative TWOC failure (OR 2.53 [1.23-5.51]; p = 0.014) were significantly associated with catheter-free survival. Conclusions: In this multi-institutional retrospective study, including patients with preoperative catheterization, the overall success rate of BPO surgery was 70.8% after 1-year follow-up. Compared with TURP, enucleation methods and PVP were associated with better catheter-free survival, whereas PAE was associated with higher risk of AUR recurrence.


Loss of PTEN expression is an independent predictor of favourable survival in endometrial carcinomas.
We and others previously reported the prognostic significance of PTEN mutational status on favourable survival in endometrial carcinomas. Here, we demonstrate that loss of PTEN expression in immunohistochemistry is an independent prognostic marker for favourable survival in endometrial carcinomas. We conducted immunohistochemical analyses of PTEN, PIK3CA, phosphorylated Akt (p-Akt), and p27 in primary endometrial carcinomas from 221 patients. Mutation of PTEN was analysed further. Expression of PTEN was lost in 56 patients (25%), and PIK3CA was overexpressed in 159 patients (72%). Overexpression of PIK3CA was associated with p-Akt overexpression (P<0.001), which was in turn associated with loss of nuclear p27 expression (P=0.028). Loss of PTEN expression was found to be associated with endometrioid histology (P=0.03), and was inversely associated with the presence of lymphovascular space invasion (P=0.03). Univariate and multivariate survival analyses revealed that factors of PTEN loss, age <70, histological grade 1, early International Federation of Gynecology and Obstetrics (FIGO) stage, and absence of lymphovascular invasion were independent prognostic indicators for better overall survival (P=0.03, 0.04, 0.01, <0.001, and 0.03, respectively). The subset analysis showed a stronger tendency of PTEN loss towards favourable survival in advanced-stage (III and IV) disease than in early-stage (I and II) disease (P=0.05 vs 0.14). Moreover, our mutational analysis demonstrated that PTEN expression loss was associated with PTEN-truncating mutations (P=0.03). The current observations further support the prognostic significance of PTEN aberration on favourable outcome in endometrial carcinomas, providing useful implications for the individualised management of the disease.


The total rehabilitation of Graves' ophthalmopathy.
The concept of enlarging the orbital space in some patients with Graves' ophthalmopathy is usually acceptable. Controversial, however, are 1. the indications for enlarging the space, 2. the sequence of therapy that is most successful in restoring the eyes to near normal, and 3. the value of enlarging the orbital space and its relationship to non-surgical alternatives. Since 1669 a personal experience with more than 600 eyes in over 300 patients using the transantral route to orbital decompression has accumulated. From the surgical experience plus exposure to other non-surgically treated patients, a concept of total management of Graves' ophthalmopathy has evolved. The technical aspects of decompression through the sinuses are straight forward. The key to a satisfactory operation is a complete transantral ethmoidectomy; a less than complete ethmoidectomy will eliminate a predictable result. Transantral decompresssion as a single procedure will not successfully palliate all aspects of Graves' ophthalmopathy. Eye muscles and lid procedures in a timely sequence may be needed to complete rehabilitation. Perfect eyes are seldom obtained but the goal of satisfied patients is realistic. This essay will emphasize technical aspects, theoretical advantages, as well as pitfalls and limitations of the transantral orbital decompression.


Biochemical characterization and insecticidal activity of isolated peptides from the venom of the scorpion Centruroides tecomanus.
The venom of scorpions is a mixture of components that constitute a source of bioactive molecules. The venom of the scorpion Centruroides tecomanus contains peptides toxic to insects, however, to date no toxin responsible for this activity has yet been isolated and fully characterized. This communication describes two new peptides Ct-IT1 and Ct-IT2 purified from this scorpion. Both peptides contain 63 amino acids with molecular weight 6857.85 for Ct-IT1 and 6987.77 Da for Ct-IT2. The soluble venom was separated using chromatographic techniques of molecular size exclusion, cationic exchange, and reverse phase chromatography, allowing the identification of at least 99 components of which in 53 the insecticidal activity was evaluated. The LD50 determined for Ct-IT1 is 3.81 μg/100 mg of cricket weight, but low amounts of peptides (0.8 μg of peptide) already cause paralysis in crickets. The relative abundance of these two peptides in the venom is 2.1% for Ct-IT1 and 1% for Ct-IT2. The molecular masses and N-terminal sequences of both insecticidal toxins were determined by mass spectrometry and Edman degradation. The primary structure of both toxins was compared with other known peptides isolated from other scorpion venoms. The analysis of the sequence alignments revealed the position of a highly conserved amino acid residue, Gly39, exclusively present in anti-insect selective depressant β-toxins (DBTXs), which in Ct-IT1 and Ct-IT2 is at position Gly40. Similarly, a three-dimensional structure of this toxins was obtained by homology modeling and compared to the structure of known insect toxins of scorpions. An important similarity of the cavity formed by the trapping apparatus region of the depressant toxin LqhIT2, isolated from the scorpion Leiurus quinquestriatus hebraeus, was found in the toxins described here. These results indicate that Ct-IT1 and Ct-IT2 toxins have a high potential to be evaluated on pests that affect economically important crops to eventually consider them as a potential biological control method.


Immune cells transcriptome-based drug repositioning for multiple sclerosis.
Finding target genes and target pathways of existing drugs for drug repositioning in multiple sclerosis (MS) based on transcriptomic changes in MS immune cells. Based on transcriptome data from Gene Expression Omnibus (GEO) database, differentially expressed genes (DEGs) in MS patients without treatment were identified by bioinformatics analysis according to the type of immune cells, as well as DEGs in MS patients before and after drug administration. Hub target genes of the drug for MS were analyzed by constructing the protein-protein interaction network, and candidate drugs targeting 2 or more hub target genes were obtained through the connectivity map (CMap) database and Drugbank database. Then, the enriched pathways of MS patients without treatment and the enriched pathways of MS patients before and after drug administration were intersected to obtain the target pathways of the drug for MS, and the candidate drugs targeting 2 or more target pathways were obtained through Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We obtained 50 hub target genes for CD4+ T cells in Fingolimod for MS, 15 hub target genes for Plasmacytoid dendritic cells (pDCs) and 7 hub target genes for Peripheral blood mononuclear cells (PBMC) in interferon-β (IFN-β) for MS. 6 candidate drugs targeting two or more hub targets (Fostamatinib, Copper, Artenimol, Phenethyl isothiocyanate, Aspirin and Zinc) were obtained. In addition, we obtained 4 target pathways for CD19+ B cells and 15 target pathways for CD4+ T cells in Fingolimod for MS, 7 target pathways for pDCs and 6 target pathways for PBMC in IFN-β for MS, most of which belong to the immune system and viral infectious disease pathways. We obtained 69 candidate drugs targeting two target pathways. We found that applying candidate drugs that target both the "PI3K-Akt signaling pathway" and "Chemokine signaling pathway" (e.g., Nemiralisib and Umbralisib) or applying tyrosine kinase inhibitors (e.g., Fostamatinib) may be potential therapies for the treatment of MS.


The analysis of aging and elderly age quality in empirical research: data based on University of the Third Age (U3A) students.
The aim of the study was to evaluate aging and elderly age quality in elderly individuals and persons entering the elderly age participating U3A continuous education courses. The research included 255 students of the U3A located in Bydgoszcz, Poland. The research included 235 women and 20 men of mean age 64.43 years. The dominant group was persons with secondary education (65.9%), and higher education (28.2%) as well as married (54.5%). All of the subjects included in the study were fully mobile. The study was conducted based on authors' original questionnaire which consisted of 24 questions and a basic personal data form surveying age, gender, marital status, level of education as well as self-reported illnesses and health problems. The research assumed the majority of positive responses as the sign of happy aging and experiencing one's own old age. Positive correlation was observed between the statement that human beings influence quality and shape of their lives, and therefore they are responsible for their own life. The higher the level of fulfilling aims in life the more frequently elderly age was perceived as a happy period. In the research data there was a relationship observed between levels of education and discrimination, i.e., the higher level of education the fewer cases of discrimination experienced: χ(2)=12.992 (df=2; p<0.01). Moreover, a very weak correlation was observed between marital status and a sense or absence of sense of emptiness in life ρ=0.128; p<0.05. The most appreciated values in life, according to the subjects were health, happiness in family and mental efficiency. The biggest worries concerned serious diseases and being dependent on other people. Most often indicated ways to lead happy elderly life were being active and open to people as well as showing optimistic attitude. The research, which was conducted on a relatively large group of people (n=255), proves positive aging direction among the elderly and persons entering late adulthood period who attend continuous education courses at U3A.


Anaerobic power and muscle strength in human immunodeficiency virus-positive preadolescents.
To determine the anaerobic power and muscle strength of preadolescents with human immunodeficiency virus (HIV). Cross-sectional design. Human performance laboratory at the University District Hospital at the Puerto Rico Medical Center. Fifteen preadolescents (8 girls and 7 boys) with a classification of HIV A and B attending an investigational treatment program at the University Pediatric Hospital. Fifteen seronegative control subjects matched by age and gender also were included. The power of the lower extremities was measured with use of the Wingate Anaerobic Power Test on a MONARK cycle ergometer (mean power in watts). Local muscle strength of the dominant knee extensors (peak torque/body weight × 100) was tested with an isokinetic dynamometer set at 60 deg/s. Statistical analysis was performed with the Wilcoxon signed-rank test, and statistical significance was accepted at an α level of <.05. No significant differences between the control group and study group were detected on muscle strength testing. The study group presented a lower anaerobic power (mean power) compared with control subjects (P = .04). This exploratory study suggests that HIV-infected preadolescents present lower anaerobic power compared with uninfected control subjects. Our findings of impaired anaerobic capacity can have clinical implications in this population because most of the activities of daily living, such as play, leisure, and sport activities, are short term and high intensity (anaerobic) in nature.


Unusual benign bladder tumor of Brunn nest origin.
An unusual bladder tumor consisting of proliferating benign Brunn nests is described. The tumor occurred in a forty-five-year-old man who presented with hematuria. The tumor recurred in the same location one and one-half years later and again caused hematuria. The tumor is distinguished from inverted papilloma of the bladder.


Secretion of calcitonin gene-related peptide from baby rat thyroid glands in vitro.
Thyroid glands from 8-day-old rat pups were incubated in serum-free medium for 6 hr. Both calcitonin (CT) and calcitonin gene-related peptide (CGRP) released into medium were measured by radioimmunoassay. In 6 separate experiments CGRP was easily detected in medium in ng/ml concentrations. In 4 of the 6 experiments, where CT release was stimulated by high medium [Ca], the concentration of CGRP in medium showed a positive, significant correlation with the medium CT concentration (r = 0.41-0.69, p less than .05- less than .01). The results are in concert with reports describing the presence of CGRP in the C-cell, and they further show that CGRP, as well as CT, can be secreted by C-cell.


Partial recovery of visual extinction by pavlovian conditioning in a patient with hemispatial neglect.
Patients with parietal lesions and unilateral spatial neglect (USN) are unable to detect or respond to information in the contralesional side of space. However, some residual sensory processing may still occur and overcome inattention symptoms when contralesional stimuli are perceptually or biologically salient, as shown for emotional faces or voices. These effects have been attributed to enhanced neural responses of sensory regions to emotional stimuli, presumably driven by feedback signals from limbic regions such as the amygdala. However, because emotional faces and voices also differ from neutral stimuli in terms of physical features, the affective nature of these effects still remains to be confirmed. Here we report data from a right parietal patient in whom left visual extinction was reduced for contralesional visual stimuli following pavlovian aversive conditioning, relative to the same stimulus before conditioning, and relative to similar but non-conditioned stimuli. This reduction of visual extinction was thus mediated by the emotional meaning of stimuli acquired through implicit learning. Functional magnetic resonance imaging also showed that conditioned visual stimuli elicited greater activation in right visual cortex, relative to the non-conditioned stimuli, together with differential activations in amygdala. These results support the hypothesis that emotional appraisal, not only the processing of perceptual features, may partly restore attention to salient information in contralesional space. These findings open new perspectives to improve rehabilitation strategies in neglect, based on affective and motivational signals.