The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery.
The selective antithrombotic fondaparinux is more effective than the low-molecular-weight heparin enoxaparin for prevention of venous thromboembolism (deep-vein thrombosis [DVT] or pulmonary embolism) in patients undergoing major orthopedic surgery, but its cost-effectiveness is undetermined. To evaluate the cost-effectiveness of fondaparinux relative to enoxaparin as prophylaxis against venous thromboembolism (VTE) for patients undergoing total hip replacement, total knee replacement or hip fracture surgery in the UK. A decision analysis model was created simulating the impact of fondaparinux and enoxaparin on patient outcomes and costs over various time points up to 5 years following surgery. The main outcome measures were treatment costs per patient and the incidence of clinical VTE and VTE-related deaths. A weighted (combined) cohort reflects the proportion of patients undergoing these procedures in 2000/2001. In the combined cohort, compared with enoxaparin, fondaparinux is expected to produce 20 fewer clinical VTE events and 3.2 fewer VTE-related deaths per 1000 procedures at 5 years. Cost savings at 5 years are pound 27 per patient with fondaparinux (discounted at 6% per year). In each of the three surgical groups, fondaparinux leads to lower expected costs per patient and to a smaller number of VTE events and VTE-related deaths. RESULTS are sensitive to the price difference between fondaparinux and enoxaparin and variation in the rate of late DVT. The analysis is robust to variations in all other key parameters. Compared with enoxaparin, fondaparinux is more effective and reduces costs to the healthcare system. At current prices, fondaparinux is the recommended strategy in the UK for prophylaxis following major orthopedic surgery.


Diversity of phage integrases in Enterobacteriaceae: development of markers for environmental analysis of temperate phages.
Viruses are the most abundant biological entities in aquatic systems. Temperate bacteriophages have enormous influences on microbial diversity, genetic exchange and bacterial population dynamics. However, development of molecular tools for their detection in the environment has been problematic. The integrase gene is used here as a molecular marker to analyse the diversity of temperate bacteriophages in a population of freshwater bacteria. Interrogation of the GenBank database revealed 32 non-cryptic enteric phage integrase sequences, leading to the development of a suite of 11 degenerate primer sets specific to the extant sequences elucidated. Application of these primer sets to enterobacterial isolates recovered from a freshwater pond and the temperate phages induced from them revealed a number of diverse integrase genes, including novel integrase-like sequences not represented in the databases. This highlights the potential of utilizing the integrase gene family as a marker for phage diversity.


Preverbal infants' sensitivity to grammatical dependencies.
During their first months of life, infants can already distinguish function words (e.g., pronouns and determiners) from content words (e.g., verbs and nouns). Little research has explored preverbal infants' sensitivity to the relationships between these word categories. This preregistered study examines whether French-learning 8- and 11-month-olds track the grammatical dependencies between determiners and nouns as well as pronouns and verbs. Using the Visual Fixation Procedure, infants were presented with lists containing either grammatical (e.g., tu manges "you eat", des biberons "some bottles") or ungrammatical (e.g., des manges "some eat", tu biberons "you bottle") phrases. In Experiment 1 (N = 59), the lists involved common nouns and verbs, while in Experiment 2 (N = 28), only common verbs were used. Eleven-month-olds showed a clear preference for correct over incorrect co-occurrences in both experiments, while 8-month-olds showed a trend in the same direction. These results suggest that before their first birthday, infants' storage and access of words and word sequences are sufficiently sophisticated to include the means to track categorical dependencies. This early sensitivity to co-occurrence patterns may be greatly beneficial for constraining lexical access and later on for learning novel words' syntactic and semantic properties.


Anticancer potential of metabolic compounds from marine actinomycetes isolated from Lagos Lagoon sediment.
Thirty-two actinomycetes strains were isolated from sediment samples from 12 different sites at Lagos Lagoon and identified using standard physiological and biochemical procedures as well as 16S rDNA gene sequence analysis. Secondary metabolites were extracted from the strains and their anticancer activity on the K562 (Human acute myelocytic leukemia), HeLa (cervical carcinoma), AGS (Human gastric), MCF-7 (breast adenocarcinoma) and HL-60 (Human acute promyelocytic leukemia) cell lines was determined. The metabolic extracts exhibited cytotoxicity with IC50 values ranging from 0.030 mg/mL to 4.4 mg/mL. The Streptomyces bingchenggensis ULS14 extract was cytotoxic against all the cell lines tested. The bioactivity-guided extraction and purification of the metabolic extracts from this strain yielded two purified anticancer compounds: ULDF4 and ULDF5. The structures of the extracted compounds were determined using spectroscopic analyses, including electrospray ionization mass spectrophotometer and nuclear magnetic resonance (1 Dimensional and 2 Dimensional), and were shown to be structurally similar to staurosporine and kigamicin. The IC50 of ULDF4 and ULDF5 against the HeLa cell line was 0.034 μg/mL and 0.075 μg/mL, respectively. This study is the first to reveal the anticancer potential of actinomycetes from Lagos Lagoon, which could be exploited for therapeutic purposes.


Usability evaluation of mobile phone technologies for capturing cancer patient-reported outcomes and physical functions.
By eliminating the requirement for participants to make frequent visits to research sites, mobile phone applications ("apps") may help to decentralize clinical trials. Apps may also be an effective mechanism for capturing patient-reported outcomes and other endpoints, helping to optimize patient care during and outside of clinical trials. We report on the usability of Digital BioMarkers for Clinical Impact (DigiBioMarC™ (DBM)), a novel smartphone-based app used by cancer patients in conjunction with a wearable device (Apple Watch®). DBM is designed to collect patient-reported outcomes and record physical functions. In a fully decentralized "bring-your-own-device" smartphone study, we enrolled 54 cancer patient and caregiver dyads from Kaiser Permanente Northern California (KPNC) from October 2020 through March 2021. Patients used the app for at least 28 days, completed weekly questionnaires about their symptoms, physical functions, and mood, and performed timed physical tasks. Usability was determined through a subset of the Mobile App Rating Scale (MARS), the full System Usability Scale (SUS), the Net Promoter Score (NPS), and semi-structured interviews. We obtained usability survey data from 50 of 54 patients. Median responses to the selected MARS questions and the mean SUS scores indicated above average usability. The NPS from the semi-structured interviews at the end of the study was 24, indicating a favorable score. Cancer patients reported above average usability for the DBM app. Qualitative analyses indicated that the app was easy to use and helpful. Future work will emphasize implementing further patient recommendations and evaluating the app's clinical efficacy in multiple settings.


Novel tetrahydropyran-based bacterial topoisomerase inhibitors with potent anti-gram positive activity and improved safety profile.
Novel antibacterial drugs that are effective against infections caused by multidrug resistant pathogens are urgently needed. In a previous report, we have shown that tetrahydropyran-based inhibitors of bacterial type II topoisomerases (DNA gyrase and topoisomerase IV) display potent antibacterial activity and exhibit no target-mediated cross-resistance with fluoroquinolones. During the course of our optimization program, lead compound 5 was deprioritized due to adverse findings in cardiovascular safety studies. In the effort of mitigating these findings and optimizing further the pharmacological profile of this class of compounds, we have identified a subseries of tetrahydropyran-based molecules that are potent DNA gyrase and topoisomerase IV inhibitors and display excellent antibacterial activity against Gram positive pathogens, including clinically relevant resistant isolates. One representative of this class, compound 32d, elicited only weak inhibition of hERG K(+) channels and hNaV1.5 Na(+) channels, and no effects were observed on cardiovascular parameters in anesthetized guinea pigs. In vivo efficacy in animal infection models has been demonstrated against Staphylococcus aureus and Streptococcus pneumoniae strains.


Paired leaky mode spatial light modulators with a 28° total deflection angle.
In this Letter, we present a paired set of waveguide spatial light modulators (SLMs) capable of a maximum light deflection nearing 28° for red. This deflection, which is several times larger than the angular sweep of current, state-of-the-art modulators, is made possible by the unilateral, near-collinear waveguide nature of the leaky mode interaction. The ability to double angular output in this way, which is either not possible or not practical in other SLMs, is possible in leaky mode devices, thanks to the absence of zero-order light and the lack of high-order outputs. This combined structure has angular deflection high enough to enable color holographic video monitors that do not require angular magnification. Furthermore, the low cost and high angular deflection of these devices may make it possible to make large arrays for flat-screen video holography.


Speciation of the catalytic oxygen evolution system: [MnIII/IV2(mu-O)2(terpy)2(H2O)2](NO3)3 + HSO5-.
[MnIII/IV2(-O)2(terpy)2(OH2)2](NO3)3 (1, where terpy = 2,2':6'2' '-terpyridine) + oxone (2KHSO5 x KHSO4 x K2SO4) provides a functional model system for the oxygen-evolving complex of photosystem II that is based on a structurally relevant Mn-(-O)2-Mn moiety (Limburg, J.; et al. J. Am. Chem. Soc. 2001, 123, 423-430). In this study, electron paramagnetic resonance, ultraviolet-visible spectroscopy, electrospray ionization mass spectrometry, X-ray absorption spectroscopy, and gas-phase stable isotope ratio mass spectrometry were utilized to identify the title compounds in the catalytic solution. We find that (a) O2 evolution does not proceed through heterogeneous catalysis by MnO2 or other decomposition products, that (b) O atoms from solvent water are incorporated into the evolved O2 to a significant extent but not into oxone, that (c) the MnIII/IV2 title compound 1 is an active precatalyst in the catalytic cycle of O2 evolution with oxone, while the MnIV/IV2 oxidation state is not, and that (d) the isotope label incorporation in the evolved O2, together with points a-c above, is consistent with a mechanism involving competing reactions of oxone and water with a "MnV=O" intermediate in the O-O bond-forming step.


Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil.
The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.


Development and initial validation of the thyroid cancer module of the M. D. Anderson Symptom Inventory.
The M. D. Anderson Symptom Inventory (MDASI) and its modules measure common symptoms related to cancer and its treatment. We report the development and initial validation of the MDASI-Thyroid Cancer module (MDASI-THY). A list of thyroid-cancer-specific symptoms was generated through focus groups and interviews with thyroid cancer patients, clinicians and researchers. These MDASI-THY items were added to the original MDASI and administered to 60 patients with thyroid cancer. Symptom prevalence and severity were evaluated, along with the reliability and content, construct and known-group validity of the MDASI-THY. Cognitive debriefing performed on a subset of patients indicated that the MDASI-THY items were clear, concise, relevant and easy to understand. Fatigue, drowsiness, sleep disturbance, distress and difficulty remembering were the 5 most prevalent and severe symptoms. Twenty-eight percent of patients had moderate to severe fatigue (>or=5 on a 0-10 scale). Average severity was 1.28 and 1.29 for the symptom and interference subscales, respectively. MDASI-THY symptoms were severer for patients with poorer performance status. Cronbach alpha-values were 0.76, 0.85 and 0.92 for the thyroid-specific symptom items, core symptom subscale and interference subscale, respectively. This study demonstrates preliminary evidence for the validity and reliability of the MDASI-THY.


Protection of monkeys against Shiga toxin induced by Shiga toxin-liposome conjugates.
We previously reported that the purified Shiga toxins (Stx) Stx1 and Stx2, when coupled with liposomes, induced substantial production of anti-Stx1 and anti-Stx2 IgG antibody, respectively, in mice. The levels of anti-Stx antibody in the sera of mice immune to Stx-liposome correlated well with the protection against subsequent challenge with Stx. Furthermore, mice immunized with a mixture of Stx1-liposome and Stx2-liposome were successfully protected against oral infection with cytotoxin-producing Escherichia coli O157:H7. In this study, the induction of protection against Stx2 by Stx2-liposomes was evaluated in monkeys. Stx2-liposomes induced a substantial amount of anti-Stx2 IgG antibodies as well as Stx2 neutralizing antibodies in monkeys. Test monkeys were successfully protected against challenge with lethal doses of Stx2. Moreover, these monkeys showed no apparent symptoms, while nonimmunized control monkeys died within 4 days with hemorrhagic gastroenteritis and renal disorder. In addition, as shown by other cases involving antigen-liposome conjugates, Stx2-liposome did not induce anti-Stx2 IgE antibody production, though it stimulated the production of a substantial amount of anti-Stx2 IgG antibodies. These results suggest that Stx-liposome conjugates may serve as candidate vaccines to induce protection against death caused by cytotoxin-producing E. coli infection.


[The Study of Associations of Polymorphisms of Candidate Gene of Cardiovascular Diseases With Reduction of Glomerular Filtration Rate in Patients With ST Segment Elevation Myocardial Infarction].
to study associations of polymorphic genetic variants of inflammatory response, endothelial function, lipid metabolism, and blood coagulation with impaired renal function in patients with ST elevation myocardial infarction (STEMI). We enrolled in the study 171 patients admitted to the Kemerovo Cardiology Dispensary within 24 hours after onset of STEMI. All patients underwent genotype identification of 25 polymorphic variants of 18 major candidate genes for cardiovascular disease. Genotyping was performed with DNA chip SINKAR-1 (Institute of Medical Genetics and LLC "Genomic Diagnosis"). Glomerular filtration rate (GFR) was estimated using serum creatinine level measured at admission. Comparison of allelic and genotype frequencies of the studied polymorphisms revealed that angiotensin-converting enzyme (ACE) gene rs4291 was associated with decreased GFR: odds ratio (OR) for carriers of rare TT genotype was 2.31 [1.01-5.25], =0.043. Analysis of genotype combinations of ACE rs4343 polymorphism and hepatic lipase gene (LIPC) rs1800588 showed that AA genotype of rs4343 polymorphism in combination with CC genotype of rs1800588 polymorphism was associated with lowest risk of renal dysfunction, whereas GG and AG genotypes of ACE rs4343 in combination with TT and CT genotypes of LIPC rs1800588.


[Histological observation on gingival fibers of upper molar region].
The purpose of this study was to investigate the structures and functions of the gingival fibers extending in the mesiodistal direction (mesiodistal fibers) in the human gingiva of the upper molar region. They were observed by light and scanning electron microscopes. The findings are as follows: 1. There is a large number of mesiodistal fibers in the buccal gingiva of the upper molar region. 2. In addition to the factor of the space, there exists a close relation between the development of the mesiodistal fibers of the buccal gingiva and the function in its region. 3. The mesiodistal fibers are made up of primary and secondary fiber bundles. 4. The bundles of the mesiodistal fibers compose the three dimensional network and are twisted.


Influences of dietary supplementation with Lepidium meyenii (Maca) on stallion sperm production and on preservation of sperm quality during storage at 5 °C.
Stallion semen is damaged by oxidative stress during cooling and transport. Semen processing and extenders have been tested to improve the fertilizing capacity of semen and to preserve semen during transport. Dietary supplementation with natural antioxidants has been proposed to prevent oxidative damages. In this study, for the first time, the effect of dietary supplementation with Lepidium meyenii (Maca) on the characteristics of fresh and chilled stallion semen was evaluated. Maca is a traditional Andean crop used as a nutraceutical for the fertility-enhancing properties that are linked with antioxidant activity. The diet of five stallions was supplemented with 20 g of Maca powder daily for a total of 60 days. A control group of five stallions received the same diet without Maca. Semen was collected once before the administration of Maca (D0), twice during the administration at 30 and 60 days (D30 and D60), and finally twice at 30 and 60 days after the end of the administration (D90 and D120). Ejaculates were processed for cooled shipping at 5 °C and evaluated in the laboratory for total and progressive motility, acrosome integrity, and lipid peroxidation after collection and after 24, 48, and 72 h of storage. Dietary supplementation with Maca improved sperm concentration (from 213 ± 80.4 to 447 ± 73.1 × 106 spz/mL) and total sperm count (from 10,880 ± 4377 to 24,783 ± 4419 × 106 spz). The beneficial effects of Maca supplementation on motility and acrosome integrity in the raw semen were detected from the end of treatment with Maca (D60) until the end of the study (D120). Furthermore, during cooling storage, total motility, progressive motility, and acrosome integrity declined more slowly in the Maca-treated group than in the control group. Lipid peroxidation did not change during cooling storage in either group and did not show a significant difference between the two groups. In this study, the dietary supplementation with Maca increased sperm production and stabilized semen quality during chilled storage.


Synthesis and electroluminescent properties of soluble poly(3,6-fluorene) and its copolymer.
Soluble poly(3,6-fluorene) and its copolymer were synthesized by nickel-catalyzed coupling. Poly(3,6-fluorene) exhibited the optical band gap of 3.6 eV, the emission maximum at 347 nm, and the HOMO level of -6.05 eV. These results confirm that 3,6-linkage is an effective way to get wide band gap conjugated polymers. Furthermore, its copolymer containing triarylamine moieties emits deep-blue light, which means that the adjustable blue light emission can be obtained from their copolymers via energy transfer.


Glycogen Metabolism and Rheumatoid Arthritis: The Role of Glycogen Synthase 1 in Regulation of Synovial Inflammation via Blocking AMP-Activated Protein Kinase Activation.
To investigate the role of glycogen metabolism in regulating rheumatoid fibroblast-like synoviocyte (FLS)-mediated synovial inflammation and its underlying mechanism. FLSs were separated from synovial tissues (STs) obtained from rheumatoid arthritis (RA) patients. Glycogen content was determined by periodic acid Schiff staining. Protein expression was analyzed by Western blot or immunohistochemistry. Gene expression of cytokines and matrix metalloproteinases (MMPs) was evaluated by quantitative real-time PCR. FLS proliferation was detected by EdU incorporation. Migration and invasion were measured by Boyden chamber assay. Glycogen levels and glycogen synthase 1 (GYS1) expression were significantly increased in the ST and FLSs of RA patients. TNF-α or hypoxia induced GYS1 expression and glycogen synthesis in RA FLSs. GYS1 knockdown by shRNA decreased the expression of IL-1β, IL-6, CCL-2, MMP-1, and MMP-9 and proliferation and migration by increasing AMP-activated protein kinase (AMPK) activity in RA FLS. AMPK inhibitor or knockdown AMPK could reverse the inhibitory effect of GYS1 knockdown on the inflammatory response in RA FLSs; however, an AMPK agonist blocked RA FLS activity. We further determined that hypoxia-inducible factor-1α mediates TNF-α- or hypoxia-induced GYS1 expression and glycogen levels. Local joint depletion of GYS1 or intraperitoneal administration with an AMPK agonist ameliorated the severity of arthritis in rats with collagen-induced arthritis. Our data demonstrate that GYS1-mediated glycogen accumulation contributes to FLS-mediated synovial inflammation in RA by blocking AMPK activation. In our knowledge, this is a first study linking glycogen metabolism to chronic inflammation. Inhibition of GYS1 might be a novel therapeutic strategy for chronic inflammatory arthritis, including RA.


Ophthalmic irrigants: a current review and update.
The search for an ideal intraocular irrigating solution is of paramount importance to te ophthalmic surgeon. An intraocular irrigating solution, as well as surgical technique, can have deleterious effects on ocular tissues. Since an intraocular irrigating solution comes in contact with the cornea, lens, trabecular meshwork, uvea, vitreous, and retina, and ideal irrigant would be ome that ensures biological function for all of these tissues. In a practical sense, the best irrigant is one that causes the least possible damage to the structural integrity and function of the intraocular environment. This paper summarizes the development, uses, and efficacy of intraocular irrigating solutions as currently used during intraocular surgery.


[Analysis of short-term efficacy of perioperative fecal microbiota transplantation combined with nutritional support in patients with radiation-induced enteritis complicated by intestinal obstruction].
Objective: To explore the short-term efficacy of perioperative fecal microbiota transplantation combined with nutritional support in patients with radiation-induced enteritis complicated by intestinal obstruction. Methods: The cohort of this prospective cohort study comprised 45 patients (nine men and 36 women) with radiation-induced enteritis complicated by intestinal obstruction admitted to Shanghai Tenth People's Hospital Affiliated to Tongji University from January 2022 to October 2022. The median age was 53 (42-65) years. Thirty-five of the patients had gynecological tumors and 10 colorectal malignancies. The patients were randomly allocated to a fecal microbiota transplantation group of 20 patients who underwent fecal microbiota transplantation starting 2 weeks before surgery for 6 days, in addition to receiving conventional perioperative treatment, and a conventional treatment group of 25 patients who only received nutritional support during the perioperative period. There were no significant differences in baseline characteristics (sex, age, preoperative nutritional indices, and surgical procedure) between the two groups (all P>0.05). Postoperative recovery (time to passing flatus or a bowel movement, length of stay) and complications were compared between the two groups. Postoperative complications within 30 days after surgery classified in accordance with the international Clavien-Dindo classification of surgical complications (I-V) were statistically analyzed. Improvement in gastrointestinal symptoms, namely abdominal pain, distension, diarrhea, and rectal bleeding) and gastrointestinal quality of life scores (which include 36 problems rated 0-144 points related to physical, psychological, social activities and family life; the lower the score, the more severe the symptoms) were compared between the two groups. Nutritional recovery was assessed by body mass, body mass index, total protein, albumin, prealbumin, and hemoglobin. Results: Compared with the conventional treatment group, the postoperative hospital stay was shorter in the fecal microbiota transplantation group (8.0±4.3 days vs. 11.2±5.4 days, t=2.157, P=0.037) and the time to passage of flatus or having a bowel movement was earlier (2.2±3.2 days vs. 3.9±2.3 days, t=2.072, P=0.044). There were 26 postoperative complications in the fecal microbiota transplantation group and 59 in the conventional treatment group. There were 20 and 36 Grade I to II complications and no and three Grade III to V complications in the transplantation and conventional treatment group, respectively. The overall grade of complication did not differ significantly between the two groups (P=0.544). However, the incidence of postoperative intestinal inflammatory obstruction was lower in the fecal microbiota transplantation than the conventional treatment group (10.0% [2/20] vs. 40.0% [10/25], P=0.040). One patient in the conventional treatment group died. This patient had complete intestinal obstruction complicated by severe malnutrition preoperatively, and an intestinal fistula complicated by abdominal infection postoperatively, and died despite active treatment. Nineteen and 23 patients in the transplantation and conventional treatment group, respectively, attended for follow-up 1 month after surgery; 19 and 21, respectively, attended for follow-up 3 months after surgery, and 17 and 20, respectively, attended for follow-up 6 months after surgery. There were no significant differences between the two groups in abdominal pain or rectal bleeding 1, 3, or 6 months after surgery (all P>0.05). One month after surgery, the incidence of abdominal distension and diarrhea was lower in the fecal microbiota transplantation than in the conventional treatment group (3/19 vs. 48.0% [11/23], P=0.048; 3/19 vs. 52.2% [12/23], P=0.023). However, at the 3 and 6 month follow-ups the incidence of abdominal distension and diarrhea had gradually decreased in both groups and the differences between the groups were not statistically significant (P>0.05 for all). Scores for gastrointestinal quality of life improved significantly in both treatment groups compared with preoperative values (F=71.250, P<0.001; F=79.130, P<0.001, respectively). Scores for gastrointestinal quality of life were higher in the fecal microbiota transplantation than the conventional treatment group at all follow-up time points (P<0.05). One-way ANOVA showed that body mass, body mass index, and total protein, albumin and hemoglobin concentrations improved in both groups compared with preoperative values (all P<0.05). Prealbumin concentration improved significantly in the transplantation (F=5.514, P=0.002), but not in the conventional, group (F=1.535, P=0.211). The improvements in body mass, body mass index, total protein, and albumin were better in the fecal microbiota transplantation than conventional treatment group at 3 and 6 months of follow-up (all P<0.05). Conclusion: Perioperative fecal microbiota transplantation combined with nutritional support is effective in improving early postoperative nutritional status and quality of life in patients with radiation-induced enteritis complicated by intestinal obstruction.


Thyrotropin-Releasing Hormone Loaded and Chitosan Engineered Polymeric Nanoparticles: Towards Effective Delivery of Neuropeptides.
Thyrotropin-Releasing Hormone (TRH), a tripeptide amide with molecular formula L-pGlu-L-His-L- Pro-NH2, is used in the treatment of brain/spinal injury and certain central nervous system (CNS) disorders, including schizophrenia, Alzheimer's disease, epilepsy, depression, shock and ischemia due to its profound effects on the CNS. However, TRH's therapeutic activity is severely hampered because of instability and hydrophilicity owing to its peptidic nature which results into ineffective penetration into the blood brain barrier. In the present study, we report the synthesis and stability studies of novel chitosan engineered TRH encapsulated poly(lactide-co-glycolide) (PLGA) based nanoformulation. The aim of such an encapsulation is to allow effective delivery of TRH in biological systems as the peptidase degrade naked TRH. The synthesis of TRH was carried out manually in solution phase followed by its encapsulation using PLGA to form polymeric nanoparticles (NPs) via nanoprecipitation technique. Different parameters such as type of organic phase, concentration of stabilizer, ratio of organic phase and aqueous phase, rate of addition of organic phase were optimized, tested and evaluated for particle size, encapsulation efficiency, and stability of NPs. The TRH-PLGA NPs were then surface modified with chitosan to achieve positive surface charge rendering them potential membrane penetrating agents. PLGA, PLGA-TRH, Chitosan-PLGA and Chitosan-PLGA-TRH NPs were characterized and analyzed using Dynamic Light Scattering (DLS), Transmissiom Electron Microscopy (TEM) and Infra-red spectroscopic techniques.


Interferon-alpha therapy for hepatitis C virus infection after liver transplantation.
The aims of this pilot study were to evaluate the safety and efficacy of interferon-alpha 2b for treatment of hepatitis C virus infection in liver transplant recipients, to monitor changes in hepatitis C virus RNA levels with treatment and to determine pretreatment parameters predictive of a complete response. Eighteen patients with documented hepatitis C virus viremia and histological evidence of hepatitis after liver transplantation received 3 million units of alpha interferon three times weekly for at least 4 mo. Pretreatment serum aminotransferase levels were at least 1.5 times the upper limit of normal and no patient had concomitant hepatitis B virus infection. Response to therapy was defined as normalization of both aspartate and alanine aminotransferase at the end of treatment. Five patients (28%) had a complete response, whereas 13 (72%) had persistent elevation of one or both aminotransferases (nonresponders). At the end of therapy, hepatitis C virus RNA levels were reduced in both responders and nonresponders (p = 0.043 and 0.039, respectively by Wilcoxon signed rank test). After cessation of treatment, aminotransferases remained normal in four of five responders but serum hepatitis C virus RNA levels returned to pretreatment levels in responders and nonresponders. There was no significant change in histological score with therapy. Responders were more likely than nonresponders to have low pretreatment hepatitis C virus RNA levels and low serum bilirubin (p = 0.0004 and 0.0077, respectively). Responders tended to have a prolonged interval between transplantation and initiation of therapy (p = 0.10 by rank logistic regression analysis). Side effects resulted in early cessation of therapy in two patients and dose reduction in six.(ABSTRACT TRUNCATED AT 250 WORDS)


MinCD cell division proteins form alternating copolymeric cytomotive filaments.
During bacterial cell division, filaments of the tubulin-like protein FtsZ assemble at midcell to form the cytokinetic Z-ring. Its positioning is regulated by the oscillation of MinCDE proteins. MinC is activated by MinD through an unknown mechanism and prevents Z-ring assembly anywhere but midcell. Here, using X-ray crystallography, electron microscopy and in vivo analyses, we show that MinD activates MinC by forming a new class of alternating copolymeric filaments that show similarity to eukaryotic septin filaments. A non-polymerizing mutation in MinD causes aberrant cell division in Escherichia coli. MinCD copolymers bind to membrane, interact with FtsZ and are disassembled by MinE. Imaging a functional msfGFP-MinC fusion protein in MinE-deleted cells reveals filamentous structures. EM imaging of our reconstitution of the MinCD-FtsZ interaction on liposome surfaces reveals a plausible mechanism for regulation of FtsZ ring assembly by MinCD copolymers.


[Recommendations for protection against electromagnetic interference risk caused by pacemakers and implantable defibrillators in hospitals].
Electromagnetic interference and compatibility are problems that claim an increasing attention of biomedical industries, all over the world. For electromagnetic interference we intend a phenomenon that can occur when an electronic device undergoes the influence of an electromagnetic field, which may cause temporary or definitive malfunctioning of the device itself. Indeed, electromagnetic compatibility is the capacity of an electric device either to operate normally, without generating electromagnetic disturbances that may interfere with other devices or to operate without being influenced by electromagnetic field generated by other electric devices. Pacemaker (PM) and implantable-cardioverter defibrillator (ICD) functioning can be significantly compromised by electromagnetic fields, even though their circuits, nowadays, are well protected from most of electromagnetic wave sources. The basis for electromagnetic interference on PM and ICD lays on different factors even physical such as the power of external signal, the distance between the signal and the PM and ICD, the frequency range, modulation type and immunity level of the PM and ICD. The electromagnetic interference on PM and ICD may result into a temporary or permanent malfunctioning, like pacing inhibition, asynchronous pacing, or the switching of the pacing mode. The purpose of this work is to give useful indications for a correct in-hospital management of patients with PM or ICD, in order to avoid dangerous electromagnetic interference.


[Preparation of carbon fiber reinforced fluid type resin denture (author's transl)].
Transverse strength of cured fluid resins is weaker than that of the heat cured. We have studied to improve the mechanical strength of self-cured acrylic resin by application of carbon fibers as reinforcement and simple methods which must be acceptable for technicians are proposed. A cloth type carbon fiber was the best reinforcement among studied carbon fibers such as chopped or mat. The chopped fibers were difficult to mix homogeneously with fluid resins and effectiveness of the reinforcement was low. Breaking often occurred at the interface between the reinforcement and resin in the cases of mat which gave defects to the test specimens. To prepare reinforced denture, the cloth was trimmed on the master cast after removal of wax and the prepreg was formed with the alginate impression on the cast by Palapress and the cloth. Other steps were same as the usual fluid resin.


Integrated Management of European Cherry Fruit Fly Rhagoletis cerasi (L.): Situation in Switzerland and Europe.
The European cherry fruit fly, Rhagoletis cerasi (L.) (Diptera: Tephritidae), is a highly destructive pest. The low tolerance for damaged fruit requires preventive insecticide treatments for a marketable crop. The phase-out of old insecticides threatens cherry production throughout the European Union (EU). Consequently, new management techniques and tools are needed. With the increasing number of dwarf tree orchards covered against rain to avoid fruit splitting, crop netting has become a viable, cost-effective method of cherry fruit fly control. Recently, a biocontrol method using the entomopathogenic fungus Beauveria bassiana has been developed for organic agriculture. However, for most situations, there is still a lack of efficient and environmentally sound insecticides to control this pest. This review summarizes the literature from over one hundred years of research on R. cerasi with focus on the biology and history of cherry fruit fly control as well as on antagonists and potential biocontrol organisms. We will present the situation of cherry fruit fly regulation in different European countries, give recommendations for cherry fruit fly control, show gaps in knowledge and identify future research opportunities.


Pulmonary delivery of interleukin-7 provides efficient and safe delivery to the aging immune system.
Age-associated atrophy of the thymus with coincident reduction in thymopoeisis, decline in thymic output, and subsequent immune dysfunction has been reversed by the use of interleukin-7 (IL-7). In the earlier studies and in clinical trials, delivery of IL-7 has been by multiple injections over several days to maintain effective activity levels in the tissues. This is unlikely to meet with high compliance rates in future clinical use, and so we tested alternate routes of delivery using a technique involving tagging IL-7 with fluorescent dye that emits in the near-infrared region and whose fluorescence can be visualized within the tissues of live animals. We have shown that intratracheal instillation, enabling transfer through the lungs, provides an effective route for delivering IL-7 into the bloodstream and from there into the tissues in older animals. Delivery is rapid and widespread tissue distribution is seen. Comparison of administration either subcutaneously or by instillation reveals that IL-7 delivery by the pulmonary route provides significantly greater transmission to lymphoid tissues when compared with injection. In functional assessment studies, pulmonary administration led to significantly improved intrathymic T cell development in older animals when compared with IL-7 delivered by injection. Furthermore, in these older animals, delivery of IL-7 by intratracheal instillation was not accompanied by any apparent adverse events when compared with controls receiving saline vehicle by instillation or animals receiving IL-7 by subcutaneous injection.


Remediation of multilayer soils contaminated by heavy chlorinated solvents using biopolymer-surfactant mixtures: Two-dimensional flow experiments and simulations.
To assess the efficiency of remediating dense non-aqueous phase liquids (DNAPLs), here heavy chlorinated solvents, through injection of xanthan solutions with or without surfactant (sodium dodecylbenzenesulfonate: SDBS), we conducted a comprehensive investigation involving rheological measurements, column (1D) and two-dimensional (2D) sandbox experiments, as well as numerical simulations on two-layers sand packs. Sand packs with grain sizes of 0.2-0.3 mm and 0.4-0.6 mm, chosen to represent the low and high permeable soil layers respectively, were selected to be representative of real polluted field. The rheological analysis of xanthan solutions showed that the addition of SDBS to the solution reduced its viscosity due to repulsive electrostatic forces and hydrophobic interactions between the molecules while preserving its shear-thinning behavior. Results of two-phase flow experiments depicted that adding SDBS to the polymer solution led to a reduced differential pressure along the soil and improvements of the DNAPL recovery factor of approximately 0.15 and 0.07 in 1D homogeneous and 2D layered systems, respectively. 2D experiments revealed that the displacement of DNAPL in multilayer zones was affected by permeability difference and density contrast in a heterogeneous soil. Simulation of multiphase flow in a multilayered system was performed by incorporating non-Newtonian properties and coupling the continuity equation with generalized Darcy's law. The results of modeling and experiments are very consistent. Numerical simulations showed that for an unconfined soil, the recovery of DNAPL by injection of xanthan solution can be reduced for more than 50%. In a large 2D experimental system, the combination of injecting xanthan with blocking the contaminated zone led to a promising remediation of DNAPL-contaminated layered zones, with a recovery of 0.87.


Pretreatment Neutrophil-to-Lymphocyte Ratio: A Prognostic Biomarker of Survival in Patients With Epithelial Ovarian Cancer.
Background Inflammation is pathognomonic of all stages of tumor formation, and therefore, there is renewed interest in systemic inflammatory response (SIR) markers including haematological inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR) as prognostic predictors in several cancers. Aim This study was aimed to investigate the effect of pretreatment peripheral blood NLR on the survival prognosis of patients with epithelial ovarian cancer (EOC). Methods We identified 93 patients with a complete clinical record from a cohort of 155 patients who received treatment for EOC between 2009 and 2018. Patients' sociodemographic and clinicopathologic characteristics, and updated three-year follow-up status were extracted from medical records. Pretreatment peripheral blood NLR was calculated by dividing the neutrophil count by the lymphocyte count. We employed the receiver operating characteristic (ROC) curve to identify the optimal cut-off value of the NLR in estimating progression-free survival (PFS) and overall survival (OS). The PFS and OS were assessed using the Kaplan-Meier method, and survival differences were compared using the Log Rank (Mantel-Cox) test. Independent prognostic predictors were determined using Cox regression analysis. Results According to the ROC curves, the optimal cut-off values for the NLR were 2.23 and 1.93 for PFS and OS, respectively. A high NLR was associated with poor PFS (P = 0.033) and OS (P = 0.013) in the univariate analyses. In the multivariate analyses, a high NLR was still an independent predictor of OS (hazard ratio [HR] = 2.23; 95% CI, 1.08 to 4.61) but not PFS (hazard ratio [HR] = 2.43; 95% CI, 0.95 to 6.27). Conclusion The NLR at an optimum cut-off value of 1.93 is an independent prognostic predictor of OS in patients with EOC.


Symptoms or symptom-based scores cannot predict acute otitis media at otitis-prone age.
Acute symptoms are used to diagnose and manage acute otitis media (AOM). We studied whether AOM could be predicted by the reason for parental suspicion of AOM or by the occurrence, duration, and/or severity of symptoms. We also compared scores including or excluding tympanic-membrane examination of children with and without AOM. Children aged 6 to 35 months with parental suspicion of AOM were eligible. Before tympanic-membrane examination, we registered on a structured questionnaire the reason for parental suspicion of AOM, symptoms, and score components. Of 469 children studied, 237 had AOM and 232 had respiratory tract infection without AOM. The most common reason for parental suspicion of AOM, restless sleep, was not predictive for AOM (RR: 1.0 [95% CI: 0.8-1.2]), nor was ear-rubbing (relative risk [RR]: 0.7 [95% confidence interval (CI): 0.5-1.0]). Neither the occurrence of fever (RR: 1.2 [95% CI: 1.0-1.4]) nor the highest mean temperature within 24 hours predicted AOM, nor did the occurrences of ear-related, nonspecific, respiratory, or gastrointestinal symptoms. The duration and severity of symptoms were not predictive for AOM, although rhinitis lasted longer and conjunctivitis was more severe in children with AOM. The clinical/otologic score (median: 4.0 vs 2.0; P = .000) and the AOM total-severity index (11.0 vs 6.0; P = .000), both including symptoms and tympanic-membrane examination, were higher in those with AOM. The AOM severity-of-symptom scale, based solely on symptoms, was equal in children with and without AOM (6.0 vs 6.0; P = .917). AOM cannot be predicted by the occurrence, duration, or severity of symptoms at otitis-prone age. Likewise, solely symptom-based scores do not differentiate between respiratory tract infections with or without AOM. Thus, tympanic-membrane examination is crucial in the diagnosis and severity classification of AOM in clinical practice and research settings.


Length-Dependent Transition from Extended to Folded Shapes in Short Oligomers of an Azetidine-Based α-Amino Acid: The Critical Role of NH···N H-Bonds.
Hydrogen bonds (H-bonds) are ubiquitous in peptides and proteins and are central to the stabilization of their structures. Inter-residue H-bonds between non-adjacent backbone amide NH and C=O motifs lead to the well-known secondary structures of helices, turns and sheets, but it is recognized that other H-bonding modes may be significant, including the weak intra-residue H-bond (called a C5 H-bond) that implicates the NH and C=O motifs of the same amino acid residue. Peptide model compounds that adopt stable C5 H-bonds are not readily available and the so-called 2.05-helix, formed by successive C5 H-bonds, is an elusive secondary structure. Using a combination of theoretical chemistry and spectroscopic studies in both the gas phase and solution phase, we have demonstrated that derivatives of 3-amino-1-methylazetidine-3-carboxylic acid, Aatc(Me) can form sidechain-backbone N-H···N C6γ H-bonds that accompany-and thereby stabilize-C5 H-bonds. In the capped trimer of Aatc(Me), extended C5/C6γ motifs are sufficiently robust to challenge classical 310-helix formation in solution and the fully-extended 2.05-helix conformer has been characterized in the gas phase. Concurrent H-bonding support for successive C5 motifs is a new axiom for stabilizing the extended backbone secondary structure in short peptides.


Single molecule charge transport: from a quantum mechanical to a classical description.
This paper explores charge transport at the single molecule level. The conductive properties of both small organic molecules and conjugated polymers (molecular wires) are considered. In particular, the reasons for the transition from fully coherent to incoherent charge transport and the approaches that can be taken to describe this transition are addressed in some detail. The effects of molecular orbital symmetry, quantum interference, static disorder and molecular vibrations on charge transport are discussed. All of these effects must be taken into account (and may be used in a functional way) in the design of molecular electronic devices. An overview of the theoretical models employed when studying charge transport in small organic molecules and molecular wires is presented.


[Neurohumoral changes in patients with heart failure treated chronically with beta-blockers].
Long-term beta-blocker therapy may be useful in some patients affected by chronic heart failure. In a group of 15 patients with chronic heart failure of different origin we evaluated clinical, hemodynamic and neurohormonal features after 1 year of therapy. All patients were treated with atenolol at dosage of 50 mg/die. We observed a better ejection fraction by radionuclide angiography after 1 year of treatment. There was an increase of exercise time and VO2 max evaluated by cycloergometer test. There was a decrease of mean pulmonary artery pressure, of pulmonary vascular resistance and of right atrial pressure. Plasmatic norepinephrine decreased from 1294 +/- 568 to 574 +/- 33 pg/l. Our results suggest that patients who well tolerated chronic beta-blockade show an improvement of performance parameters.


Bone Regenerative Medicine in Oral and Maxillofacial Region Using a Three-Dimensional Printer<sup/>.
Bone grafts currently used for the treatment of large bone defect or asymmetry in oral and maxillofacial region include autologous, allogeneic, and artificial bones. Although artificial bone is free from the concerns of donor site morbidity, limitation of volume, disease transmission, and ethical issues, it lacks osteogenic and osteoinductive activities. In addition, molding of the artificial bone is an issue especially when it is used for the augmentation of bone as onlay grafts. To solve this problem, additive manufacturing techniques have been applied to fabricate bones which have outer shapes conformed to patients' bones. We developed a custom-made artificial bone called a computed tomography (CT)-bone. Efficacy of CT-bone was proven in a clinical research and clinical trial, showing good manipulability, stability, and patient satisfaction. However, low replacement rate of artificial bones by endogenous bones remain an unsolved issue. Loading of cells and growth factors will improve the bone replacement by inducing osteogenic and osteoinductive activities. In addition, the three-dimensional bioprinting technique will facilitate bone regeneration by placing cells and biological substances into appropriate sites.


Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex.
Plus-strand RNA viruses characteristically replicate their genome in association with altered cellular membranes. In the present study, the capacity of hepatitis C virus (HCV) proteins to elicit intracellular membrane alterations was investigated by expressing, in tetracycline-regulated cell lines, a comprehensive panel of HCV proteins individually as well as in the context of the entire HCV polyprotein. As visualized by electron microscopy (EM), expression of the combined structural proteins core-E1-E2-p7, the NS3-4A complex, and protein NS4B induced distinct membrane alterations. By immunogold EM (IEM), the membrane-altering proteins were always found to localize to the respective altered membranes. NS4B, a protein of hitherto unknown function, induced a tight structure, designated membranous web, consisting of vesicles in a membranous matrix. Expression of the entire HCV polyprotein gave rise to membrane budding into rough endoplasmic reticulum vacuoles, to the membranous web, and to tightly associated vesicles often surrounding the membranous web. By IEM, all HCV proteins were found to be associated with the NS4B-induced membranous web, forming a membrane-associated multiprotein complex. A similar web-like structure in livers of HCV-infected chimpanzees was previously described (Pfeifer et al., Virchows Arch. B., 33:233-243, 1980). In view of this finding and the observation that all HCV proteins accumulate on the membranous web, we propose that the membranous web forms the viral replication complex in HCV-infected cells.


[The evaluation of renal tolerance for roentgen contrast media by determination of urinary kidney-specific proteins].
In the present trial kidney-specific proteins were studied enzymatically or quantitatively in patients' urine after intravascular administration of water-soluble X-ray contrast media, in order to judge about their renal tolerance. 5 clinical trials (phase III), including 198 patients, were carried through, within several radiological examinations. The examined X-ray substance was Iosimide, a new monomeric, nonionic low osmolar c.m. It was compared to the nonionic Iopromide and Iopamidol as well as to the ionic, high osmolar sodium-meglumine-diatrizoate. Enzyme activities of alanine-aminopeptidase (AAP), gamma-glutamyltransferase (GGT), beta-n-acetylglucosaminidase (NAG), kallikrein with creatinine as point of reference were kinetically measured in 4 urine samples (1 before c.m. administration the others as 24 hours urine samples of the following 3 days). Beside the quantitative determination of protein and albumin an electrophoresis was started, when diagnosis was obvious. Kallikrein was brought to the diagnostic palette of this study in order to include the distal segment of the nephron. The specific protein excretion patterns of nonionic c.m. in urine are not different from each other. In contradiction to this, the results of the low osmolar nonionic Iosimide compared to the high osmolar diatrizoate, show evident differences for the benefit of Iosimide.


DNA Polymerase Beta Participates in Mitochondrial DNA Repair.
We have detected DNA polymerase beta (Polβ), known as a key nuclear base excision repair (BER) protein, in mitochondrial protein extracts derived from mammalian tissue and cells. Manipulation of the N-terminal sequence affected the amount of Polβ in the mitochondria. Using Polβ fragments, mitochondrion-specific protein partners were identified, with the interactors functioning mainly in DNA maintenance and mitochondrial import. Of particular interest was the identification of the proteins TWINKLE, SSBP1, and TFAM, all of which are mitochondrion-specific DNA effectors and are known to function in the nucleoid. Polβ directly interacted functionally with the mitochondrial helicase TWINKLE. Human kidney cells with Polβ knockout (KO) had higher endogenous mitochondrial DNA (mtDNA) damage. Mitochondrial extracts derived from heterozygous Polβ mouse tissue and KO cells had lower nucleotide incorporation activity. Mouse-derived Polβ null fibroblasts had severely affected metabolic parameters. Indeed, gene knockout of Polβ caused mitochondrial dysfunction, including reduced membrane potential and mitochondrial content. We show that Polβ is a mitochondrial polymerase involved in mtDNA maintenance and is required for mitochondrial homeostasis.


Hands-on experience: do teachers need it?
Discussion on the efficacy of the clinical involvement and credibility of nurse educators has been ongoing for a considerable time. The author sheds new light on the subject by referring to a survey of nurse education on HIV/AIDS in the UK. She concludes that while a measure of clinical experience is desirable in teaching, it is not always possible to have all the necessary qualities wrapped up in one person, and calls for carefully integrated team effort to take nurse education forward.


Progression of Precancerous Cervical Lesion Predicted by p16 Protein Immunohistochemistry in Rajavithi Hospital.
Objective: To assess the association of p16 immunohistochemical (IHC) staining in cervical squamous intraepithelial lesions (SIL) and progression of cervical intraepithelial neoplasia (CIN) 1 to CIN2+ or recurrence of CIN2+. Material and Methods: A retrospective cohort study of women with newly diagnosed SIL from colposcopy-directed biopsy at Rajavithi Hospital, 2013-2017. Pathologic specimens were reviewed and submitted to p16-IHC staining. Adjusted hazard ratios (HR) of disease-free interval (DFI) and 95% confidence intervals (CI) were carried out using the Cox proportional hazard regression model. Results: A total of 187 women was recruited, 91 cases of positive p16-IHC staining and 96 cases of negative staining. With the median follow-up time of 22 months, women with positive p16-IHC had significantly lower 1-year DFI than those with negative p16-IHC (86.8% vs. 96.6%, p = 0.006). Women with CIN 1 had 22.6% of positive p16-IHC, while those with CIN2-3 had 86.7%. From multivariate analysis, the positive p16-IHC and age > 35 years were the significant prognostic factors of progression/recurrent CIN2+ (adjusted HR 5.33, 95%CI 1.77-16.01, p = 0.003; and adjusted HR 5.80, 95%CI 1.34-25.08, p = 0.019, respectively). From subgroup analysis, the positive p16-IHC was the significant prognostic factor in women with initial CIN1 (HR 5.29, 95%CI 1.18-23.76, p = 0.030), but was not associated with prognosis in women with initial CIN 2-3 (HR 2.13, 95%CI 0.28-16.38, p = 0.468). Conclusion: Overexpression of p16 protein has the prognostic significance of SIL. Using p16-IHC may help stratify patients as low-risk and high-risk groups to progression/recurrence CIN2+.


Expression and prognostic role of orphan receptor GPR110 in glioma.
Glioma is the most common type of malignancy in the central nervous system, which has a poor prognosis due to its rapid progression and diffuse invasion. Identification of novel biomarkers for glioma would be invaluable for studying disease mechanism and improving prognosis. Orphan G protein-coupled receptor 110 (GPR110) belongs to the subfamily VI of adhesion GPCR. The knowledge of the ligand, signaling pathway or physiology function of GPR110 is poorly elucidated. The potential role of GPR110 as an oncogene in mouse has been recently reported by mutagenesis screen. However, its expression and role in human glioma hasn't been identified. Here in the current study, we initially explored the RNA and protein expression of GPR110 in patients with glioma. Statistical analysis proved that GPR110 was highly expressed in some patients, which was correlated with advanced disease stages. Furthermore, univariate and multivariate analyses revealed its role as an independent prognostic biomarker for the overall survival of glioma patients. Interestingly, cellular studies showed that overexpression or knockdown of GPR110 in U87 cells didn't affect cell proliferation and migration. However, the invasion of U87 cells was significantly enhanced by GPR110-overepxression, while inhibited by GPR110-knockdown. The detailed mechanisms remain further investigation although our results suggested the possible participation of STAT3 instead of ERK in the GPR110 signaling pathways.


Assessment of US Food and Drug Administration-Approved Digital Medical Devices for Just-in-Time Interventions: A Systematic Review.
Just-in-time interventions (JITIs) are a type of digital therapeutic intervention that combines remote monitoring tools and algorithms to personalize the delivery of specific interventions at the right time. The US Food and Drug Administration (FDA) regulatory approval documents are often the only available source of information on the effectiveness of therapeutic interventions based on these devices. To systematically review the publicly available information from the FDA on all recently approved medical devices used in JITIs to (1) assess how they operate to deliver JITIs and (2) appraise the evidence supporting their performance and clinical effectiveness. Two reviewers systematically searched the Premarket Notifications (510(k)), Premarket Approvals, De Novo, and Humanitarian Device Exemption databases from January 2019 to December 2021 for all entries associated with devices that monitored patients' data over time to personalize the delivery of interventions to treat, prevent, or mitigate health conditions or events. They assessed whether the product summaries (1) enabled an understanding of how the device operated to deliver a JITI (eg, the nature, type, and frequency of the monitoring, the nature of the decision algorithm, and the nature and intended receiver of the intervention); (2) informed about the performance and effectiveness of the JITI; and (3) included information on data security and ownership. In total, 38 devices were included in this review. These were mainly intended for cardiac conditions (12 [31.6%]), diabetes (10 [26.3%]), and neurological diseases (4 [10.5%]). Monitoring devices ranged from wearable (18 of 28 [64.4%]; eg, smartwatches) to implanted sensors (6 of 28 [21.4%]; eg, inserted electrocardiographic sensors). Only 10 of 38 product summaries (26.3%) allowed a full understanding of how the device operated to deliver a JITI. Similarly, only 12 of 28 (42.9%), 12 of 36 (33.3%), and 5 of 38 (13.2%) reported the assessment of the performance of the monitoring device, assessment of the decision algorithm, and results of clinical studies assessing the effectiveness of the JITI, respectively. Finally, 14 of 36 product summaries (38.9%) included some information on data security, but none included information on data ownership. The results of this systematic review suggest that the information publicly available in the FDA databases on the performance and effectiveness of digital medical devices used in JITIs is heterogeneous.


Cytotoxicity of seputhecarpan D, thonningiol and 12 other phytochemicals from African flora towards human carcinoma cells.
Despite the remarkable progress in cancer therapy in recent years, this disease still remains a serious public health concern. The use of natural products has been and continues to be one of the most effective ways to fight malignancies. The cytotoxicity of 14 compounds from African medicinal plants was evaluated in four human carcinoma cell lines and normal fibroblasts. The tested samples included: β-spinasterol (1), friedelanone (2), 16β-hydroxylupeol (3), β-amyrin acetate (4), lupeol acetate (5), sequoyitol (6), rhamnitrin (7), europetin 3-O-rhamnoside (8), thonningiol (9), glyasperin F (10), seputhecarpan B (11), seputhecarpan C (12), seputhecarpan D (13) and rheediaxanthone A (14). The neutral red uptake (NR) assay was used to evaluate the cytotoxicity of samples; caspase-Glo assay, flow cytometry for cell cycle analysis and mitochondrial membrane potential (MMP) as well as spectrophotometry to measure levels of reactive oxygen species (ROS) were performed to detect the mode of action of compounds 9 and 13 in MCF-7 breast adenocarcinoma cells. Compounds 3, 9-13 displayed cytotoxic effects against the four tested cancer cell lines with IC50 values below 85 μM. Compounds 9 and 13 had IC50 values below 10 μM in 4/4 and 3/4 tested cell lines respectively. The IC50 values varied from 0.36 μM (against MCF7 cells) to 5.65 μM (towards colon carcinoma DLD-1 cells) for 9, from 9.78 μM (against MCF7 cells) to 67.68 μM (against HepG2 cells) for 13 and 0.18 μM (towards HepG2 cells) to 72 μM (towards Caco-2 cells) for the reference drug, doxorubicin. Compounds 9 and 13 induced cell cycle arrest in Go/G1 whilst doxorubicin induced arrest in G2/M. The two molecules (9 and 13) also induced apoptosis in MCF-7 cells through activation of caspases 3/7 and 9 as well as enhanced ROS production. Compounds 9 and 13 are good cytotoxic phytochemicals that should be explored more in future to develop a cytotoxic drug to fight human carcinoma.


[Evaluation of hemoglobin and hematocrit in pregnant women receiving folate and iron supplements].
From week 8 there is a reduction in hemoglobin and hematocrit (owing to the increased plasma volume which exceeds the increased erythrocytic content) that continues to fall steadily until week 16-22, flattening out at a level of 10-11 g/100 ml for hemoglobin and 32-34% for hematocrit. Bone marrow produces red blood cells and hemoglobin in proportion to the increase in plasma volume, provided that there is an adequate iron supply (higher in pregnancy compared to the usual dietary intake). For this reason, the authors examined the systematic supplementation of pregnant women with ferrous gluconate and folic acid, another important element for numerous metabolic reactions which is also lacking in pregnancy owing to increased requirements. The study showed that pregnant patients receiving folic acid and iron supplements from week 5 to 40 presented hematocrit readings and hemoglobin levels from week 12 that were constantly higher compared to the population not receiving supplements, with statistically significant and highly significant differences respectively. The few collateral effects observed in a limited group of patients allow the authors to define the tolerability of the proposed treatment as "excellent". They emphasise, however, the importance of constant supplementation with folic acid and iron throughout pregnancy to avoid sideropenic anemia, with considerable benefits in terms of the physical conditions of the pregnant woman, the supply of O2 to the villi, fetal wellbeing and the need to resort to possible blood transfusions in the event of major blood losses at birth.


Using Epstein-Barr viral load assays to diagnose, monitor, and prevent posttransplant lymphoproliferative disorder.
Epstein-Barr virus (EBV) DNA measurement is being incorporated into routine medical practice to help diagnose, monitor, and predict posttransplant lymphoproliferative disorder (PTLD) in immunocompromised graft recipients. PTLD is an aggressive neoplasm that almost always harbors EBV DNA within the neoplastic lymphocytes, and it is often fatal if not recognized and treated promptly. Validated protocols, commercial reagents, and automated instruments facilitate implementation of EBV load assays by real-time PCR. When applied to either whole blood or plasma, EBV DNA levels reflect clinical status with respect to EBV-related neoplasia. While many healthy transplant recipients have low viral loads, high EBV loads are strongly associated with current or impending PTLD. Complementary laboratory assays as well as histopathologic examination of lesional tissue help in interpreting modest elevations in viral load. Circulating EBV levels in serial samples reflect changes in tumor burden and represent an effective, noninvasive tool for monitoring the efficacy of therapy. In high-risk patients, serial testing permits early clinical intervention to prevent progression toward frank PTLD. Restoring T cell immunity against EBV is a major strategy for overcoming PTLD, and novel EBV-directed therapies are being explored to thwart virus-driven neoplasia.


Microfabrication of an asymmetric, multi-layered microdevice for controlled release of orally delivered therapeutics.
The creation of an oral drug delivery platform to administer chemotherapeutic agents effectively can not only increase patient compliance, but also potentially diminish drug toxicity. A microfabricated device offers advantages over conventional drug delivery technology. Here we describe the development of a multi-layered polymeric drug-loaded microfabricated device (microdevice) for the oral delivery of therapeutics, which offers unidirectional release of multiple therapeutics. The imaging and release of therapeutics from the multi-layered device was performed with three different fluorescently labeled albumins. The release of insulin and chemotherapeutic camptothecin was also observed to be released in a controlled manner over the course of 180 min in vitro. Furthermore, asymmetric delivery was shown to concentrate drug at the device/cell interface, wherein 10 times more drug permeated an intestinal epithelial cell monolayer, compared to unprotected drug-loaded hydrogels. The bioactivity of the released chemotherapeutic was shown with cytostasis of colorectal adenocarcinoma cells. Cytostasis of drug loaded hydrogels was significantly higher than control empty hydrogel laden microdevices. Our results conclude that microfabrication of a hydrogel laden microdevice leads to a viable oral delivery platform for chemotherapeutics.


Clients' perceptions of involuntary hospitalization.
Because involuntary hospitalization involves the restricting of an individual's autonomy and choice, the challenge in nursing practice is to listen to the client's perceptions and then to set "limits in a humane and least restrictive manner to assure the safety of the client and others" (American Nurses' Association, 1982). However, the danger is that limits may be used to enforce socially desired behavior beyond what is necessary for safety (Garritson, 1983). Study results indicate that clients can clearly offer many specific ideas about their health care experience and needs. These perceptions offer an experiential grounding in the process of offering sensitive, relevant, quality care. Because nursing is a client-centered process, studies on clients' perceptions of care experiences are an area in which nurses can make a major research contribution. Implementation of care based on these client-centered studies could offer significant administrative and practice contributions. The client wants to be heard; nurses have an opportunity to take an active role.


Levothyroxine: therapeutic use and regulatory issues related to bioequivalence.
Levothyroxine is the overwhelming choice of clinicians for the treatment of hypothyroidism and for the suppression of goitre and thyroid nodules in selected cases. The monitoring of serum levels of thyroid stimulating hormone is necessary for appropriate dosage adjustment of levothyroxine. Levothyroxine has a narrow therapeutic index: both underdosage (subclinical hypothyroidism) and excessive dosage (subclinical hyperthyroidism) are associated with adverse symptoms and pathophysiological effects and are to be avoided. The consequent necessity for careful titration of doses has had an impact on the issue of switchability, or bioequivalence, of the various marketed levothyroxine products. In this article, the basis for concern about currently accepted standards of the FDA for pharmacological bioequivalence are examined in the context of levothyroxine. The history and status of the recent request by the FDA for a new drug application for all levothyroxine products, and its impact on the market leader Synthroid, is also discussed.


Ultraviolet Quantum Emitters in Hexagonal Boron Nitride from Carbon Clusters.
Ultraviolet (UV) quantum emitters in hexagonal boron nitride (hBN) have generated considerable interest due to their outstanding optical response. Recent experiments have identified a carbon impurity as a possible source of UV single-photon emission. Here, on the basis of first-principles calculations, we systematically evaluate the ability of substitutional carbon defects to develop the UV color centers in hBN. Of 17 defect configurations under consideration, we particularly emphasize the carbon ring defect (6C), for which the calculated zero-phonon line agrees well the experimental 4.1 eV emission signal. We also compare the optical properties of 6C with those of other relevant defects, thereby outlining the key differences in the emission mechanism. Our findings provide new insights into the strong response of this color center to external perturbations and pave the way to a robust identification of the particular carbon substitutional defects by spectroscopic methods.


Television and young Hispanic children's health behaviors.
Television viewing patterns in preschool age Hispanic children were studied in order to explore the role of TV in the establishment of early childhood health behaviors. The television viewing habits and patterns of children and parents and parental coviewing, regulation, and encouragement practices were examined. Using the dimensions of regulation and encouragement, four parental typologies were established: laissez-faire, restrictive, promotive, and selective. Children in this study watched television 3-4 hours a day, half of which consisted of viewing adult shows. This amount of time is significantly higher than the guideline of less than 2 hours a day suggested by the American Academy of Pediatrics (AAP). Relationships between television viewing, injury behaviors, risk taking, and acculturation were established and implications for primary care, school, and community health care nursing are discussed.


In vivo fluorescence imaging in the second near-infrared window with long circulating carbon nanotubes capable of ultrahigh tumor uptake.
Cancer imaging requires selective high accumulation of contrast agents in the tumor region and correspondingly low uptake in healthy tissues. Here, by making use of a novel synthetic polymer to solubilize single-walled carbon nanotubes (SWNTs), we prepared a well-functionalized SWNT formulation with long blood circulation (half-life of ∼30 h) in vivo to achieve ultrahigh accumulation of ∼30% injected dose (ID)/g in 4T1 murine breast tumors in Balb/c mice. Functionalization dependent blood circulation and tumor uptake were investigated through comparisons with phospholipid-PEG solubilized SWNTs. For the first time, we performed video-rate imaging of tumors based on the intrinsic fluorescence of SWNTs in the second near-infrared (NIR-II, 1.1-1.4 μm) window. We carried out dynamic contrast imaging through principal component analysis (PCA) to immediately pinpoint the tumor within ∼20 s after injection. Imaging over time revealed increasing tumor contrast up to 72 h after injection, allowing for its unambiguous identification. The 3D reconstruction of the SWNTs distribution based on their stable photoluminescence inside the tumor revealed a high degree of colocalization of SWNTs and blood vessels, suggesting enhanced permeability and retention (EPR) effect as the main cause of high passive tumor uptake of the nanotubes.


Non-invasive bone competence analysis by high-resolution pQCT: an in vitro reproducibility study on structural and mechanical properties at the human radius.
Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength. Bone strength depends, among others, on bone density, bone geometry and its internal architecture. With the recent introduction of a new generation high-resolution 3D peripheral quantitative computed tomography (HR-pQCT) system, direct quantification of structural bone parameters has become feasible. Furthermore, it has recently been demonstrated that bone mechanical competence can be derived from HR-pQCT based micro-finite element modeling (microFE). However, reproducibility data for HR-pQCT-derived mechanical indices is not well-known. Therefore, the aim of this study was to quantify reproducibility of HR-pQCT-derived indices. We measured 14 distal formalin-fixed cadaveric forearms three times and analyzed three different regions for each measurement. For each region cortical and trabecular parameters were determined. Reproducibility was assessed with respect to precision error (PE) and intraclass correlation coefficient (ICC). Reproducibility values were found to be best in all three regions for the full bone compartment with an average PE of 0.79%, followed by the cortical compartment (PE=1.19%) and the trabecular compartment with an average PE of 2.31%. The mechanical parameters showed similar reproducibility (PE=0.48%-2.93% for bone strength and stiffness, respectively). ICC showed a very high reproducibility of subject-specific measurements, ranging from 0.982 to 1.000, allowing secure identification of individual donors ranging from healthy to severely osteoporotic subjects. From these in vitro results we conclude that HR-pQCT derived morphometric and mechanical parameters are highly reproducible such that differences in bone structure and strength can be detected with a reproducibility error smaller than 3%; hence, the technique has a high potential to become a tool for detecting bone quality and bone competence of individual subjects.


Improvement in immune parameters and human immunodeficiency virus-1 viral response in individuals treated with 16alpha-bromoepiandrosterone (HE2000).
A randomised, double-blind, placebo-controlled study examined the safety, tolerance, immunological effect and anti-human immunodeficiency virus (HIV) activity of sub-cutaneously administered HE2000 (16alpha-bromoepiandrosterone) as monotherapy in treatment-naïve patients with HIV-1. Twenty-four patients received five sequential daily doses of 50 or 100 mg of HE2000 or placebo every 6 weeks for up to three courses, and were followed thereafter for 3 months. HE2000 was safe, with transient injection site reactions being the main side-effect. Peripheral blood samples, collected serially, were analysed for changes in immune cell phenotypes. Significant increases were observed in the numbers of circulating dendritic cells, early activated (CD69+ CD25-) CD8 T-cells and T-NK cells after administration of 50-mg doses of HE2000 (p < 0.05). Gene expression in peripheral blood mononuclear cells was analysed by real-time RT-PCR. Before treatment, HIV-1-infected patients had significantly elevated transcripts for a number of inflammatory mediators (p < 0.012). After 50 mg or 100 mg HE2000, but not after placebo, there were significant sustained decreases in IL-1beta, TNF-alpha, IL-6 and Cox-2 transcripts (p < 0.05). There were no significant differences in CD4 cell numbers, although patients receiving 50-mg doses demonstrated a significant decrease in viral load (- 0.6 log; p < 0.01). Anti-HIV-1 T-cell responses were analysed serially using GAG-peptides to stimulate cytoplasmic IFN-gamma responses. After three courses, the 50-mg dose group demonstrated a significant increase in CD8 T-cell response against two distinct GAG peptide pools (p < 0.03). These findings suggest that immune-based therapies may be able to impact viral load by decreasing inflammation and/or stimulating CD8 T-cells.


Changes in hepatic lipoperoxide concentration in endotoxemic rats.
Wistar strain rats were treated with E. coli endotoxin by intraperitoneal injection (1 mg/100g body weight). Three hours after injection, the livers were excised to determine lipoperoxide concentration and superoxide dismutase activity. A significant elevation of lipoperoxide concentration and a marked reduction of superoxide dismutase activity were observed. Treatment with xanthine oxidase inhibitor were observed. Treatment with xanthine oxidase inhibitor allopurinol (10 mg/100g) 20 minutes prior the injection of endotoxin inhibited the elevation of lipoperoxide and the reduction of superoxide dismutase induced by endotoxin. Pretreatment of free radical scavengers such as reduced glutathione and alpha-tocopherol prevented the accumulation of lipoperoxide in the liver. Reduced glutathione protected the hepatic superoxide dismutase from decrease by endotoxin treatment. However, alpha-tocopherol did not maintain liver superoxide dismutase activity following the injection of endotoxin. These results indicate that endotoxemia gives rise to the accumulation of hepatic lipoperoxide by the activation of a production system and impairment of an elimination system of superoxide radicals.


Liver fat content and hepatic insulin sensitivity in overweight patients with type 1 diabetes.
Patients with type 1 diabetes mellitus (T1DM) lack the portal/peripheral insulin gradient, which might diminish insulin stimulation of hepatic lipogenesis and protect against development of nonalcoholic fatty liver disease (NAFLD). We compared liver fat content and insulin sensitivity of hepatic glucose production and lipolysis between overweight T1DM patients and nondiabetic subjects. We compared 32 overweight adult T1DM patients and 32 nondiabetic subjects matched for age, body mass index (BMI), and gender. Liver fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS), body composition by magnetic resonance imaging, and insulin sensitivity using the euglycemic-hyperinsulinemic clamp technique (insulin 0.4 mU/kg · min combined with infusion of D-[3-(3)H]glucose). We also hypothesized that low liver fat might protect from obesity-associated increases in insulin requirements and, therefore, determined insulin requirements across BMI categories in 3164 T1DM patients. Liver fat content was significantly lower in T1DM patients than in nondiabetic subjects (0.6% [25th-75th quartiles, 0.3%-1.1%] vs 9.0% [3.0%-18.0%]; P < .001). The endogenous rate of glucose production (R(a)) during euglycemic hyperinsulinemia was significantly lower (0.4 [-0.7 to 0.8] mg/kg fat-free mass · min vs 0.9 [0.2-1.6] fat-free mass · min; P = .012) and the percent suppression of endogenous Ra by insulin was significantly greater (89% [78%-112%] vs 77% [50%-94%]; p = .009) in T1DM patients than in nondiabetic subjects. Serum nonesterified fatty acid concentrations during euglycemic hyperinsulinemia were significantly lower (78.5 [33.0-155.0] vs 306 [200.0-438.0] μmol/L; P < .001) and the percent suppression of nonesterified fatty acids significantly higher (89.1% [78.6%-93.3%] vs 51.4% [36.5%-71.1%]; P < .001) in T1DM patients than in nondiabetic subjects. Insulin doses were similar across BMI categories. T1DM patients might be protected from steatosis and hepatic insulin resistance. Obesity may not increase insulin requirements in T1DM.


Invasive fungal infections: managing the continuum of risk in HCT patients.
43rd Annual Meeting of the EBMT, 26-29 March 2017, Marseille, France The European Society for Blood and Marrow Transplantation (EBMT) was established in 1974 to enable scientists and physicians to share their experience and develop studies in clinical bone marrow transplantation. Despite advances in treatment, invasive fungal infections (IFI), especially those caused by moulds such as Aspergillus, remain a leading cause of morbidity and mortality in patients with hematological malignancies. There is a continuum of risk of IFI during induction and consolidation therapy, and after hematopoietic cell transplantation. New, evidence-based approaches to the prevention, diagnosis and treatment of IFI were, therefore, of major interest to the over 5000 delegates from 85 countries attending the 43rd EBMT Annual Meeting (EBMT 2017).


Transcriptional regulation of ataxia-telangiectasia and Rad3-related protein by activated p21-activated kinase-1 protects keratinocytes in UV-B-induced premalignant skin lesions.
Sun-induced skin lesions, in particular actinic keratosis, are generally considered as premalignant skin lesions that can progress into squamous cell carcinoma (SCC) and invasive SCC if left untreated. Therefore, understanding the molecular mechanisms by which the ultraviolet-B (UV-B)-exposed cells are being protected and the signaling pathways that promote the progression of certain premalignant skin lesions to malignant lesions will permit us to prevent or cure skin cancers. In the current study, we found that phospho-p21-activated kinase-1 (Pak1) and Pak1 expression was high in clinical samples of sunlight-induced premalignant skin lesions assessed by immunohistochemistry. Further, we observed that phospho-Pak1 and Pak1 levels are high in UV-B-exposed hairless SKH mouse model skin samples as compared with unexposed skin tissue. Our results from cell line and animal models showed that Pak1 is activated in response to UV-B radiation, and this activated Pak1 translocates from the cytoplasm to the nucleus. Inside the nucleus, Pak1 via C-Fos binds to a specific promoter region of DNA repair kinase ATR (ataxia-telangiectasia and Rad3-related protein) and acts as a transcriptional regulator of ATR. Results from our analysis showed that Pak1 overexpression, knockdown and Pak1 knockout cell line models showed that Pak1 confers protection to keratinocytes from UV-B-induced apoptosis and DNA damage via ATR. To our knowledge, this is the first study that evaluates the functional and clinical significance of a signaling molecule, Pak1, in sun-induced premalignant skin lesions and indicates that increased Pak1 activation and expression could serve as an early warning sign of progression toward non-melanoma skin cancer, if ignored.


Genome-wide identification of FK506-binding domain protein gene family, its characterization, and expression analysis in tomato (Solanum lycopersicum L.).
FK506-protein also called FKBP protein belongs to PPIase (peptidylprolylcis-trans isomerase) super family of immune suppressive drugs that act as molecular protein chaperones. In plants, FKBPs are ubiquitous and involved in various biological and physiological processes like plant germination, development, stress response and hormonal signaling. Here, we identified 24 FKBP family genes in tomato by using different tools and bioinformatic approaches. The specific structure, domain organisation, cis-regulatory elements, phylogenetic analysis, multiple sequence alignment, tissue-specific expression patterns and expression under abiotic and phytohormone stresses of all genes were investigated. The genes are clustered on ten tomato chromosomes and are categorised into two sub-classes; single and multiple domains protein gene. One of the main features of tomato FKBPs is their large fractions localized in chloroplast (in silico analysis) and clustered together phylogenetically. Tissue-specific expression analysis using available RNA-seq data revealed the spatiotemporal expression of the FKBPs, but few genes were observed with relatively high expressions in certain developmental stages. However, the quantitative expression profile of all genes under hormone stress provided a supporting evidence for their potential role in hormone signal pathways. Our prediction not only providing the foundation for better understanding the complex physiological regulation of FKBP gene family in tomato but also providing the potential aids to accelerate tolerance and survival in tomato under stressful condition.


The dilemma of the gender assignment in a Portuguese adolescent with disorder of sex development due to 17β-hydroxysteroid-dehydrogenase type 3 enzyme deficiency.
The development of male internal and external genitalia in an XY fetus requires a complex interplay of many critical genes, enzymes, and cofactors. The enzyme 17β-hydroxysteroid-dehydrogenase type 3 (17βHSD3) is present almost exclusively in the testicles and converts Delta 4-androstenodione (Δ4) to testosterone. A deficiency in this enzyme is rare and is a frequently misdiagnosed autosomal recessive cause of 46,XY, disorder of sex development. The case report is of a 15-year-old adolescent, who was raised according to female gender. At puberty, the adolescent had a severe virilization and primary amenorrhea. The physical examination showed a male phenotype with micropenis and blind vagina. The Tanner stage was A3B1P4, nonpalpable gonads. The karyotype revealed 46,XY. The endocrinology study revealed: testosterone=2.38 ng/ml, Δ4>10.00 ng/ml, and low testosterone/Δ4 ratio=0.23. Magnetic resonance imaging of the abdominal-pelvic showed the presence of testicles in inguinal canal, seminal vesicle, prostate, micropenis, and absence of uterus and vagina. The genetic study confirmed the mutation p.Glu215Asp on HSD17B3 gene in homozygosity. The dilemma of sex reassignment was seriously considered when the diagnosis was made. During all procedures the patient was accompanied by a child psychiatrist/psychologist. The teenager desired to continue being a female, so gonadectomy was performed. Estrogen therapy and surgical procedure to change external genitalia was carried out. In this case, there was a severe virilization at puberty. It is speculated to be due to a partial activity of 17βHSD3 in the testicles and/or extratesticular ability to convert Δ4 to testosterone by 17βHSD5. Prenatal exposure of the brain to androgens has increasingly been put forward as a critical factor in gender identity development, but in this case the social factor was more important for the gender assignment. In this case, we highlight the late diagnosis, probably because the patient belongs to a poor family without proper primary medical care.We emphasize the psychological and social aspects in the sex assignment decision.


Lateral ankle instability - repair/ reconstruct what's new.
Lateral ankle instability is a common condition which responds well to non-surgical management. However, the chronic symptomatic instability may require surgical intervention. The acceptable and practiced procedure is the Brostom Gould modification and it has a high patient satisfaction score. However, the current understanding and newer techniques for stabilising the lateral ligament complex has resulted in arthroscopic repairs, augmentation and tendon graft reconstructions. The literature does not provide an answer to the efficacy of these new techniques but there is some preliminary information favouring some of the latest procedures. It is now accepted practise to include ankle arthroscopy as a pre repair step. Augmentation of anatomical repair is also favoured in a select group of patients. This article provides an up to date account of the newer techniques for lateral ankle stabilisation.


Poly-N-Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect.
Poly-N-acetylglucosamine (PNAG) is a major component of the Staphylococcus epidermidis biofilm extracellular matrix. However, it is not yet clear how this polysaccharide impacts the host immune response and infection-associated pathology. Faster neutrophil recruitment and bacterial clearance were observed in mice challenged intraperitoneally with S. epidermidis biofilm cells of the PNAG-producing 9142 strain than in mice similarly challenged with the isogenic PNAG-defective M10 mutant. Moreover, intraperitoneal priming with 9142 cells exacerbated liver inflammatory pathology induced by a subsequent intravenous S. epidermidis challenge, compared to priming with M10 cells. The 9142-primed mice had elevated splenic CD4(+) T cells producing gamma interferon and interleukin-17A, indicating that PNAG promoted cell-mediated immunity. Curiously, despite having more marked liver tissue pathology, 9142-primed mice also had splenic T regulatory cells with greater suppressive activity than those of their M10-primed counterparts. By showing that PNAG production by S. epidermidis biofilm cells exacerbates host inflammatory pathology, these results together suggest that this polysaccharide contributes to the clinical features associated with biofilm-derived infections.


Acellular dermal matrix seeded with autologous gingival fibroblasts for the treatment of gingival recession: a proof-of-concept study.
One of the most common esthetic concerns associated with periodontal tissues is gingival recession. There are multiple periodontal plastic surgery approaches documented in the literature for the treatment of such defects. With the tremendous advances being made in periodontal science and technology, tissue engineering could be considered among the latest exciting techniques for recession management. In this split-mouth, controlled, double-masked clinical case series, 20 sites from 10 patients with Miller Class I or II recessions affecting canines or premolars in the maxillary arch were selected. One tooth in each patient was randomized to receive either a subepithelial connective tissue graft (SCTG) (control group) or an acellular dermal matrix allograft (ADMA) seeded with autologous gingival fibroblasts (test group) under a coronally positioned flap. Clinical parameters, including recession depth, probing depth, clinical attachment level, width of keratinized tissue, attached gingiva, and plaque scores, were recorded by a calibrated examiner at baseline and 3 and 6 months. The inflammation of grafted sites was scored, and the healing time was calculated. The final esthetic outcome of treated sites was assessed by the root coverage esthetic score at the end of 6 months. There were no significant differences between test and control sites for all measured clinical parameters. However, the test sites demonstrated less inflammation in the early postoperative period. Within the limits of this case series, the results indicate that an ADMA seeded with autologous gingival fibroblasts by tissue-engineering technology may be explored as a substitute to an SCTG for the treatment of Miller Class I and II recession defects.


Surgical treatment of conjunctival hemangioma and hemangiosarcoma: A retrospective study of 52 dogs.
To review cases of canine conjunctival hemangioma (HA) and hemangiosarcoma (HSA) treated surgically at a referral center to establish success of surgical management, recurrence rates, and long-term outcomes for patients. Retrospective record review of dogs that underwent surgery to remove histologically diagnosed conjunctival HA or HSA between April 2004 and April 2020 to collect data on signalment, tumor location, interval between initial presentation and surgery, tumor diagnosis, surgical dose, surgical margins, tumor size, recurrence and survival times. A total of 52 dogs (60 tumors) were included. The mean age of affected dogs was 8.69 years; the most affected breed was the Border collie (n = 13, 25%). 28 tumors were HA (46.67%) and 32 HSA (53.33%). Tumors occurred in three locations: the lateral bulbar conjunctiva (n = 37, 61.67%), the third eyelid margin (n = 19, 31.67%), and the ventral conjunctival fornix (n = 4, 6.67%). There was no site predilection for HA versus HSA. 97% of tumors occurred in non-pigmented tissue. Corneal invasion was more likely to be a feature of malignant tumors. Five tumors were incompletely excised, one of which recurred. There was no statistical difference in likelihood of incomplete excision between HSA and HA. Six tumors (10%) recurred. HSA was not statistically more likely to recur than HA. Recurrence times ranged from 5 weeks to 1 year. Surgical treatment of conjunctival HA and HSA is likely to be curative. There is a recurrence rate of 10% regardless of tumor type, and recurrence may be late in the course of the disease.


Targeted metagenomics unveils the molecular basis for adaptive evolution of enzymes to their environment.
Microorganisms have a wonderful ability to adapt rapidly to new or altered environmental conditions. Enzymes are the basis of metabolism in all living organisms and, therefore, enzyme adaptation plays a crucial role in the adaptation of microorganisms. Comparisons of homology and parallel beneficial mutations in an enzyme family provide valuable hints of how an enzyme adapted to an ecological system; consequently, a series of enzyme collections is required to investigate enzyme evolution. Targeted metagenomics is a promising tool for the construction of enzyme pools and for studying the adaptive evolution of enzymes. This perspective article presents a summary of targeted metagenomic approaches useful for this purpose.


[A successful surgical case report of impending rupture of the true thoraco-abdominal aortic aneurysm induced by thrombosed-type acute aortic dissection (Stanford type A)].
Impending rupture of the true aneurysm of the thoraco-abdominal aorta induced by acute aortic dissection (Stanford type A) is very rare, and decision making of the therapeutic plain is difficult. A 88-year-old woman manifested severe back pain with hypotension. Chest computed tomographic examination revealed a true aneurysm of the thoraco-abdominal aorta and acute thrombosed-type aortic dissection (Stanford type A) with cardiac tamponade. Under the diagnosis of impending rupture of the thoraco-abdominal aortic aneurysm induced by acute aortic dissection (Stanford type A), graft replacement of the thoraco-abdominal aortic aneurysm and pericardial drainage were successfully performed. Two months later, computed tomographic examination revealed disappearance of the thrombosed false lumen in the ascending aorta.


Mechanism study on a plague outbreak driven by the construction of a large reservoir in southwest china (surveillance from 2000-2015).
Plague, a Yersinia pestis infection, is a fatal disease with tremendous transmission capacity. However, the mechanism of how the pathogen stays in a reservoir, circulates and then re-emerges is an enigma. We studied a plague outbreak caused by the construction of a large reservoir in southwest China followed 16-years' surveillance. The results show the prevalence of plague within the natural plague focus is closely related to the stability of local ecology. Before and during the decade of construction the reservoir on the Nanpan River, no confirmed plague has ever emerged. With the impoundment of reservoir and destruction of drowned farmland and vegetation, the infected rodent population previously dispersed was concentrated together in a flood-free area and turned a rest focus alive. Human plague broke out after the enzootic plague via the flea bite. With the construction completed and ecology gradually of human residential environment, animal population and type of vegetation settling down to a new balance, the natural plague foci returned to a rest period. With the rodent density decreased as some of them died, the flea density increased as the rodents lived near or in local farm houses where had more domestic animals, and human has a more concentrated population. In contrast, in the Himalayan marmot foci of the Qinghai-Tibet Plateau in the Qilian Mountains. There are few human inhabitants and the local ecology is relatively stable; plague is prevalence, showing no rest period. Thus the plague can be significantly affected by ecological shifts.


Dating of fossil human teeth and shells from Toca do Enoque site at Serra das Confusões National Park, Brazil.
This work reports the dating of a fossil human tooth and shell found at the archaeological site Toca do Enoque located in Serra das Confusões National Park (Piauí, Brazil). Many prehistoric paintings have been found at this site. An archaeological excavation unearthed three sepulchers with human skeletons and some shells. Two Brazilian laboratories, in Ribeirão Preto (USP) and Recife (UFPE), independently performed Electron Spin Resonance (ESR) measurements to date the tooth and the shell and obtain the equivalent dose received by each sample. The laboratories determined similar ages for the tooth and the shell (~4.8 kyBP). The results agreed with C-14 dating of the shell and other samples (charcoal) collected in the same sepulcher. Therefore, this work provides a valid inter-comparison of results by two independent ESR-dating laboratories and between two dating methods; i.e., C-14 and ESR, showing the validity of ESR dating for this range of ages.