A microfluidic electrochemical detection technique for assessing stability of thin films and emulsions.
An experimental technique is developed for assessing stability of thin liquid films by application of electric potential to compress the liquid film and to simultaneously measure the electrical properties of the system. The concept involves creating a thin film at the intersection of two microchannels etched onto a glass substrate. A ramped DC potential difference is applied across the film, which develops an electrical stress across the film. Increasing the potential to a critical value leads to the rupture of the film. The critical potential is used to assess the stability of the liquid film. Small channel dimensions in this microfluidic platform allow characterization of thin films formed between micron-sized droplets representing systems with high capillary pressures, analysis of which are typically beyond the scope of conventional thin film characterization techniques. The results of DC potential breakdown of films show that critical potential can be considered as a measure of thin film stability.


Dual atrioventricular nodal pathways associated with a gap phenomenon in atrioventricular nodal conduction.
A 67 year old man underwent electrophysiologic study for evaluation of syncope. During atrial pacing at a basic cycle length of 600 ms, atrial premature stimuli were introduced at progressively shorter coupling intervals. The graph of atrial coupling intervals versus corresponding His bundle responses revealed an abrupt increase in atrioventricular (AV) nodal conduction time with coupling intervals from 320 to 340 ms. In an atrial coupling interval of less than 320 ms, conduction was again rapid until the effective refractory period of the atrium was reached. These unique findings are compatible with dual pathways and a gap phenomenon within the AV node.


Osborn waves during therapeutic hypothermia and recurrence of fatal arrhythmia in patients resuscitated following sudden cardiac arrest.
This study investigates the impact of the occurrence of Osborn waves during therapeutic hypothermia (TH) on the recurrence of future fatal arrhythmias in patients resuscitated after sudden cardiac arrest (SCA). Of all survivors of out-of-hospital SCA, 100 consecutive patients (mean age, 52 ± 15 years; 80% men) who received TH were included in this study. The most common first documented arrhythmia was ventricular fibrillation (VF) (77%), and ischemic heart disease (44%) and idiopathic VF (22%) were the most common causes of SCA in resuscitated patients. During TH, Osborn waves developed in 29 patients (29%). Osborn waves occurred more frequently in patients with Brugada syndrome. Patients with Osborn waves had lower in-hospital (10.3% vs 26.8%; P = .072) and 1-year death rates (20.7% vs 39.4%; P = .073) and better cerebral function (cerebral performance category scale, 2.0 ± 1.5 vs 2.7 ± 1.8; P = .053) than those without Osborn waves, although there was no statistical significance. Among 78 in-hospital survivors, 31 (40%) underwent implantable cardioverter-defibrillator (ICD) implantation. Appropriate ICD shocks from fatal arrhythmias were more frequent in patients who had Osborn waves than in those without Osborn waves (43% vs 6%; P = .032). Osborn waves during TH had no significant effect on the survival and cerebral function of patients resuscitated SCA. However, appropriate ICD shocks due to the recurrence of VF were more frequent in patients with Osborn waves during long-term follow-up.


Transient-phase kinetics of enzyme inactivation induced by suicide substrates.
This paper deals with the kinetic study of reaction mechanisms with enzyme inactivation induced by a suicide substrate in the presence or absence of an auxiliary substrate and in conditions of excess of substrates in relation to the enzyme concentration and vice versa. A transient-phase approach has been developed that enables explicit equations with one or two significant exponentials to be obtained, thereby showing the dependence of product concentration on time. The validity of these equations has been checked, and a comparison made with those previously obtained by other authors. We propose an experimental design to determine the corresponding parameters and kinetic constants. The simplicity of our method allows a systematic application to more complex mechanisms.


Travelling home for treatment and EU patients' rights to care abroad: results of a survey among German students at Maastricht University.
Empirical evidence on patient mobility in Europe is lacking despite widespread legal, policy and media attention which the phenomenon attracts. This paper presents quantitative data on the health care seeking behaviour of German students at Maastricht University in the Netherlands. A cross-sectional survey design was applied with a mixed-methods approach including open and closed questions. Questionnaire items were based on a theoretical model of patient mobility and input from focus group discussions with German students living in Maastricht. 235 valid surveys were completed, representing ca. 8% of the target population. Data collection took place in Oct-Dec 2010. Of respondents who received medical care over the last two years, 97% returned to Germany; of these, 76% travelled to their home city for medical treatment. 72% received care only in Germany, i.e. not even once in Maastricht. Distance partly influenced whether students travelled to Germany, returned home or stayed in Maastricht, and the type of care accessed. Key motivations were familiarity with home providers/system, and reimbursement issues. In the context of the new EU Directive on patients' rights, the findings call into question whether Europeans use entitlements to cross-border care and what the real potential of patient mobility is. The results demonstrate the existence and magnitude of return movements as a sub-group of patient mobility.


Management and outcomes of postpancreatectomy fistula, leak, and abscess: results of 908 patients resected at a single institution between 2000 and 2005.
Anastomotic fistula, leak, and abscess are common complications of pancreatectomy. The goal of this study was to describe our current management and outcomes of clinically significant postpancreatectomy fistula, leak, and abscess. Review of a prospectively maintained database identified 908 patients who underwent pancreatectomy between January 2000 and August 2005. Complication data were prospectively entered into a validated postoperative complication database. Patients were included if they were identified as having a clinically significant (>/=grade 2) pancreatic fistula, leak, or abscess. Multivariate analyses were performed to identify factors predictive of prolonged drainage (> 30 days). Clinically significant postoperative fistula, leak, or abscess occurred in 158 of 908 resected patients (17%) and included 63 culture-positive pancreatic fistulas, 29 noninfected pancreatic fistulas, 42 abscesses, and 24 other collections (biliary fistula, culture-negative collection). Surgical drains were placed at the time of initial resection in 88 of these 158 patients (56%). Adequate drainage was obtained by prolonged use of surgical drains in 16 patients (16 of 88 [18%]). Reoperation was required in 26 of the 158 patients (16%). ICU admission was required in 22%. Within this group of 158 patients the mortality rate was 5% (8 of 158; 90 days). At the time of discharge a home health aide was required in 56% of patients, 8% were discharged to a rehabilitation facility, and readmission was required in 50% of patients. Mean drainage time was 38 days (range 3 to 228). Predictors of prolonged drainage included drain output > 200 mL during the first 48 hours (odds ratio = 2.88; p = 0.02) and distal (versus proximal) pancreatectomy (odds ratio = 4.29; p = 0.01). Although mortality after pancreatectomy has decreased to approximately 2%, the morbidity associated with pancreatic fistula, leak, and abscess remains substantial.


Structural, optical and antibacterial activity of pure and co-doped (Fe & Ni) tin oxide nanoparticles.
In this investigation, ferric (Fe) and nickel (Ni) co-doped tin oxide (SnO2) nanoparticles structural, optical, morphological, and antibacterial characteristics were synthesised, characterised, and examined. By employing SnCl2·2H2O and the transition metal precursors FeCl3 and NiCl2·6H2O with various Fe/Ni molar ratios, thermal annealing was carried out at a high temperature (700 °C). X-ray diffraction (XRD), UV-Visible spectroscopy, Photoluminescence (PL), FT-IR, and scanning electron microscopy (SEM) with energy dispersive X-ray techniques (EDX) were used to examine the materials' structural, chemical, optical, morphological, and anti-microbial capabilities. The average particle size of pure and co-doped SnO2 nanoparticles was determined to be around 52 nm and 15 nm, and SnO2 crystallites were observed to present tetragonal rutile structure with space group P42/mmm (No.136). Metal ions were replaced in the Sn lattice, as shown by Fe and Ni co-doped SnO2 nanoparticles. Pure and co-doped samples have capsule and sphere-like features in their SEM morphology. Using UV-visible diffuse reflectance spectroscopy, the optical property was examined, and it was observed that the band gaps for pure and co-doped SnO2 were 3.73 eV and 3.53 eV, respectively. The functional groups and incorporation of Fe and Ni in the prepared powder were also validated by FT-IR and EDX studies. By utilising the agar well diffusion technique and Nutrient agar, the antibacterial properties of pure, Ni-Fe co-doped SnO2 nanoparticles annealed at 700 °C were assessed. They were evaluated against various Gram-positive bacteria (Staphylococcus pheumoniae) and Gram-negative bacteria (Shigella dysenteria). The zone of incubation was found against the Gram +Ve and Gram -Ve bacterial strains.


Impact of Gabapentin on PACU Length of Stay and Perioperative Intravenous Opioid Use for ERAS Hysterectomy Patients.
We investigated the impact of preoperative gabapentin on perioperative intravenous opioid requirements and post anesthesia care unit length of stay (PACU LOS) for patients undergoing laparoscopic and vaginal hysterectomies within an Enhanced Recovery After Surgery (ERAS) pathway. A multidisciplinary team retrospectively examined 2,015 patients who underwent laparoscopic or vaginal hysterectomies between October 2016 and January 2020 at a single academic institution. The average PACU LOS was 168 min among patients who did not receive gabapentin vs. 180 min both among patients who received ≤ 300 mg of gabapentin and patients who received > 300 mg of gabapentin. After adjusting for demographics and medical comorbidities, PACU LOS for patients given ≤ 300 mg gabapentin was 6% longer (rate ratio (RR) = 1.06, 95% CI = 1.01-1.11) than for patients who were not given gabapentin, and for patients who received > 300 mg of gabapentin was 7% longer (RR = 1.07, 95%CI = 1.01-1.13) than for those who did not receive gabapentin. Patients who received ≤ 300 mg gabapentin received 9% less perioperative intravenous hydromorphone than patients who did not receive gabapentin (RR = 0.91, 95% CI = 0.86 - 0.97); patients who received > 300 mg of gabapentin received 12% less perioperative intravenous hydromorphone than patients who did not receive gabapentin (RR = 0.88, 95% CI = 0.82 - 0.95). These findings represent an absolute difference of 0.09 mg intravenous hydromorphone. There were no statistically significant differences in total intravenous fentanyl received. Preoperative gabapentin given as part of an ERAS pathway is associated with statistically but not clinically significant increases in PACU LOS and decreases in total perioperative intravenous opioid use.


Antihypertensive effect of Melothria maderaspatana leaf fractions on DOCA-salt-induced hypertensive rats and identification of compounds by GC-MS analysis.
The present study was designed to investigate the antihypertensive effect of Melothria maderaspatana leaf fractions on deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats and to identify compounds from the active fraction by GC-MS analysis. Administration of DOCA salt significantly increased the systolic and diastolic blood pressure compared to sham-operated control rats. When treated with chloroform (CFM), ethyl acetate (EAFM) or methanol fractions of M. maderaspatana (MFM), EAFM alone significantly lowered the systolic and diastolic blood pressure. The levels of magnesium and copper significantly increased in plasma and decreased in tissues while the zinc level significantly increased in plasma and tissues, and administration of EAFM brought these parameters back to sham-operated control levels. By GC-MS analysis, phytochemicals such as coumarin, vallinic acid, p-coumaric acid, gallic acid, caffeic acid, and ferulic acid were identified in EAFM. In conclusion, the EAFM controls blood pressure in DOCA-salt hypertensive rats and reverts the metabolic alterations in magnesium, copper and zinc.


Fine needle aspiration cytology of penile tumors.
Penile tumors are unusual and can represent neoplastic or inflammatory processes. We report a series of penile tumors diagnosed by fine needle aspiration (FNA) cytology. Files from the Division of Clinical Cytology, Karolinska Hospital, were searched, and cases of FNA cytology of the penis selected. Clinical information and cytologic diagnoses were recorded and observations from aspiration smears made. Eleven patients had presented to Karolinska Hospital for FNA cytology of the penis. They ranged from 46 to 89 years of age; all were uncircumcised. Tumors were present in various locations, including the glans and shaft. Five patients had squamous cell carcinoma (SCCA) of the penis; three were primary, one locally recurrent and one metastatic from primary lung SCCA. There were three carcinomas metastatic from primary colon, prostate and bladder tumors. There was one each of locally recurrent malignant melanoma, locally metastatic testicular mesothelioma and Peyronie's disease. Discomfort associated with the procedure was tolerable, there were no complications, and each biopsy provided sufficient material for a cytologic diagnosis. FNA cytology of penile tumors is a successful, well-tolerated procedure capable of providing a cytologic diagnosis and useful information for patient management.


Commentary on Classification of patients with incident non-specific low back pain: implications for research.
Norton G, McDonough CM, Cabral HJ, Shwartz M, Burgess JF Jr. Classification of patients with incident non-specific low back pain: implications for research. Spine J 2016;16:567-76 (in this issue).


Cardiac Affection in Type 1 Diabetic Patients in Relation to Omentin.
To evaluate cardiac affection in type 1 diabetes in relation to Omentin. Sixty two diabetics and 30 volunteer of the same age and sex were included as a control group. Blood sample was taken for assessment of omentin and oxidized low density lipoprotein (OxLDL), glycosylated hemoglobin (HbA1) and lipid profile. Urine sample was taken for assessment of albumin/creatinine ratio. 24 hour holter was also done. T-test, simple correlation followed by stepwise multiple regression analysis was used for analysis of data. Parameters of 24 hour holter were significantly lower in diabetics. Omentin was significantly lower, while OxLDL were significantly higher than controls. RMSSD, ST deviation and OxLDL were the parameters related to omentin by stepwise multiple regression analysis in diabetics. Diabetic patients had a cardiac autonomic neuropathy. A significant reduction of omentin and elevation OxLDL imply that they influence glucose metabolism in type 1 diabetes. Omentin had a significant relation to 24 hr holter which may reflect its role in cardiac affection. Omentin and OxLDL had a role in renal affection.


GTP-induced membrane binding and ion channel activity of annexin VI: is annexin VI a GTP biosensor?
Annexin VI (AnxVI) formed ion channels in planar lipid bilayers that were induced by the addition of millimolar guanosine 5'-triphosphate (GTP) at pH 7.4 and that were not accompanied by a penetration of the protein into the membrane hydrophobic region. GTP-influenced interactions of AnxVI with Ca2+/liposomes produced small structural alterations as revealed by circular dichroism and infrared spectroscopies. Guanosine 5'-3-O-(thio)-triphosphate (GTPgammaS) binding to AnxVI, promoted by the photorelease of GTPgammaS from GTPgammaS[1-(4,5-dimethoxy-2-nitrophenyl)-ethyl] (caged-GTPgammaS), affected three to four amino acid residues of AnxVI in the presence of Ca2+/liposomes, while about eight or nine amino acid residues were altered in their absence. This suggested that the nucleotide-binding site overlapped the lipid-binding domain of AnxVI. The binding of the fluorescent GTP analog, 2'-(or 3')-O-(2,4,6-trinitrophenyl)guanosine 5'-triphosphate (TNP-GTP) to AnxVI was optimal in the presence of Ca2+/liposomes, with a dissociation constant (K(d)) of 1 microM and stoichiometry of 1. TNP-GTP promoted fluorescence resonance energy transfer from tryptophan residues to the nucleotide. Ion conductance and fluorescence measurements of the C- and N-terminal fragments of AnxVI indicated distinct GTP-binding properties, suggesting that the existence of the GTP-induced ion channel activity of AnxVI is associated with the flexibility of the two halves of the protein. Such structural flexibility could contribute to a molecular mechanism of AnxVI acting as a GTP biosensor.


Pearls for Working with People Who Have Personality Disorder Diagnoses.
Personality disorders are a group of diagnostic categories applicable when people show personality traits that are so extreme they cause clear difficulties in their lives and relationships. More widespread agreement is found on sorting by three broad categories (odd/eccentric, dramatic/emotional/erratic, and anxious/fearful) than by more specific subtypes. Primary care physicians need to recognize when extreme personality traits are causing difficulties in their relationships with patients and to have a way to approach these difficulties when they arise. This article reviews current thinking on the diagnosis and treatment of personality disorders, focusing especially on dramatic/emotional/erratic disorders, which are those most often problematic in clinical settings.


Differential immunoreactivity of epidermal growth factor receptor in benign, dysplastic and malignant prostatic tissues.
To investigate epidermal growth factor receptor (EGFr) presence in the prostate, monoclonal antibody (clone EGFR1) immunohistochemical examination of radical prostatectomy specimens was performed (n = 37). All prostatic specimens contained benign prostatic hyperplasia (BPH) and/or dysplasia (prostatic intraepithelial neoplasia or PIN), as well as prostatic carcinoma (CaP). Areas of dysplasia were further categorized as to the basal cell layer and the luminal cell area. BPH, PIN, and CaP tissues in each specimen were analyzed by a single observer and graded on a scale from 0-4+. Fifteen samples were also analyzed for EGFr content utilizing a Cell Analysis Systems (CAS 200) image cytometer. EGFr immunoreactivity of BPH basal cells was significantly higher than EGFr immunoreactivity in areas of CaP (p < 0.001). EGFr staining of BPH basal cells was also significantly higher than that seen in PIN luminal cells (p < 0.001). Immunoreactivity of EGFr in PIN basal cells was significantly higher than in PIN luminal cells (p < 0.001). EGFr staining of basal cells in BPH tissues was higher than that seen in the PIN basal cell layer but the difference was not statistically significant (p = 0.06). The amount of staining present in PIN luminal cells was also significantly greater than in CaP tissues (p = 0.002). Quantitative image analysis utilizing the CAS 200 image cytometer was performed on BPH and CaP areas exclusively. EGFr immunoreactivity in basal cells of the BPH tissues was significantly greater than that seen in CaP tissues (p < 0.001). The decreased EGFr immunoreactivity in CaP may reflect a differentiating role for EGFr in normal tissues. Loss of EGFr influence may be associated with an increased proliferative state in PIN and CaP. Destruction or alteration of the epidermal grwoth factor receptor by a protease, such as prostatic specific antigen, may also explain our findings. At the present time the meaning of the different amounts of EGFr in the various types of prostate tissues is unknown.


Assessment of multi-trophic changes in a shallow boreal lake simultaneously exposed to climate change and aerial deposition of contaminants from the Athabasca Oil Sands Region, Canada.
The Athabasca Oil Sands Region (AOSR) has been intensely developed for industrial bitumen extraction and upgrading since the 1980s. A paucity of environmental monitoring prior to development raises questions about baseline conditions in freshwater systems in the region and ecological responses to industrial activities. Further, climatic changes prompt questions about the relative roles of climate and industry in shaping aquatic ecosystems through time. We use aquatic bioindicators from multiple trophic levels, concentrations of petrogenic contaminants (dibenzothiophenes), and spectrally-inferred chlorophyll-a preserved in well-dated sediments of a closed-basin, shallow lake ~50km away from the main area of industry, in conjunction with climate observations, to assess how the biotic assemblages of a typical AOSR lake have changed during the past ~75years. We examine the contributions of the area's stressors in structuring aquatic communities. Increases in sedimentary measures of petrogenic contaminants provide clear evidence of aerial contaminant deposition from local industry since its establishment, while climate records demonstrate consistent warming and a recent period of reduced precipitation. Quantitative comparisons of biological assemblages from before and after the establishment of regional industry find significant (p<0.05) differences; however, the magnitude and overall timing of the changes are not consistent with a threshold-type shift in response to the onset of regional industry. Rather, biotic assemblages from multiple trophic levels suggest transitions to an increasingly complex benthic environment and relatively warmer waters, which, like the increasing trends in inferred primary production, are consistent with a changing climate. These findings highlight the important role of climate conditions in regulating primary production and structuring aquatic communities in these shallow systems.


Pitfalls in the use of laparoscopic staplers to perform subtotal cholecystectomy.
Laparoscopic subtotal cholecystectomy (LSC) is considered to be a safe option in severe cholecystitis with non-discernible anatomy within the Calot's triangle where there is a potential risk of causing injury to the common bile duct. Here we present two cases of gallstone pancreatitis associated with use of an endoscopic stapler during LSC.


The impact of geographic proximity to transplant center on outcomes after allogeneic hematopoietic stem cell transplantation.
Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) need access to specialized care. We hypothesized that access to the transplant center after HSCT may be challenging for patients living in geographically distant areas, and that this would have an adverse effect on their outcome. We analyzed 1912 adult patients who underwent allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) between 1996 and 2009 and who resided within 6 hours driving time of the institution. Driving time from primary residence to DF/BWCC based on zipcode was determined using geographic information systems. The median driving time (range) to DF/BWCC was 72 (2-358) minutes. When patients were stratified by driving time quartile, overall survival (OS) after HSCT was similar in the first year but worse after 1 year in patients in the top quartile (≥ 160 minutes driving time). In a landmark analysis of the 909 patients alive and free of disease at 1 year, 5-year OS was 76% and 65% for patients in the first (≤ 40 minutes) and fourth (≥ 160 minutes) quartiles, respectively (P = .027). This was confirmed in a multivariable analysis. The difference appeared to be mostly because of an increase in nonrelapse mortality. The number of visits to the transplant center between day 100 and 365 after HSCT declined significantly with increasing driving time to the transplant center, which was independently associated with worse survival. Long driving time to the transplant center is associated with worse OS in patients alive and disease-free 1 year after HSCT, independently of other patient-, disease-, and HSCT-related variables. This may be in part related to the lower frequency of post-HSCT visits in patients living farther away.


Effects of counter-ions and volume on the simulated dynamics of solvated proteins. Application to the activation domain of procarboxypeptidase B.
Molecular dynamics (MD) simulations of the globular activation domain of porcine procarboxypeptidase B (ADBp) and its isolated alpha-helix 1 were performed in order to understand the effects of adding salts and using periodic boundary conditions (this being reflected in the box size) along the simulations. alpha-Helix 1 was chosen because it is the most charged element of the secondary structure within ADBp. Different types of MD simulations with the GROMOS package were performed, studying either the whole activation domain or the isolated alpha-helix 1 with different water box sizes and counter-ionic shells. The analyses of the trajectories show that simulations of solvated proteins are highly sensitive to the presence of counter-ions and less sensitive to the volume of the water box. The differences in protein potential energies, r.m.s. deviations and radius of gyration between the simulations with and without counter-ions demonstrate that during such studies secondary structures of proteins are more stable when their charges are carefully neutralized. This stresses the need for such a procedure when analysing significantly charged proteins. The results also showed that the enlargement of the water box helps in the stabilization of the system.


Isolated working heart: description of models relevant to radioisotopic and pharmacological assessments.
Isolated heart preparations are used to study physiological and metabolic parameters of the heart independently of its environment. Several preparations of isolated perfused heart are currently used, mainly the retrograde perfusion system and the working heart model. Both models allow investigations of the metabolic regulation of the heart in various physiological conditions (changes in workload, hormonal influences, substrate competition). These systems may also reproduce different pathological conditions, such as ischemia, reperfusion and hypoxia. Quantitation of metabolic activity can be performed with specific radioactive tracers. Finally, the effects of various drugs on cardiac performance and resistance to ischemia can be studied as well. Heart perfusion also revealed efficient methods to determine the tracer/tracee relation for radioisotopic analogues used with Positron Emission Tomography.


DRD4 VNTR polymorphism and age at onset of severe mental illnesses.
A large number of studies has investigated the hypothesis that DRD4 48 bp variable number of tandem repeat (VNTR) polymorphism is involved in the etiology of schizophrenia and bipolar disorder. However, the results are inconsistent likely due to genetic and phenotypic heterogeneity. Age at onset (AAO) is considered an important alternate phenotype for genetic investigations of psychiatric disorders. In the present study, the DRD4 VNTR 7 repeat allele (7R) was examined in 477 patients with major psychoses. Age at onset was defined as the age of first psychotic episode for schizophrenia and the age at appearance of first clinically recognized symptoms for the bipolar sample. Our results showed an interaction between sex and DRD4 genotypes among schizophrenia patients (n=203, β=.213, p=.017). On comparing AAO between carriers and non-carriers of the 7R, we observed that females with 7R present had later onset (p=.021). The effect was not observed for males. In the sample with bipolar disorder, we observed significant association between DRD4 7R-genotype and AAO (n=274, β=-.148, p=.012). No interaction was observed between sex and genotypic groups of the bipolar sample. The 7R was associated with early onset of the bipolar illness (p=.028). In summary, our results suggest that the 7R is associated with AAO in both schizophrenia and bipolar disorders. The effect was observed across both sexes in bipolar disorder, but specifically in females for schizophrenia.


RNA-seq analysis of Lgr6+ stem cells and identification of an Lgr6 isoform.
We studied Lgr6+ stem cells in experimental UV carcinogenesis in hairless mice. For further characterization through RNA-seq, these stem cells were isolated by FACS from transgenic hairless mice bearing an EGFP-Ires-CreERT2 reporter cassette inserted into exon 1 of the Lgr6 gene (purity confirmed by human ERT2 expression). Between Lgr6/EGFP+ and Lgr6/EGFP- basal cells (Tg/wt), 682 RNAs were differentially expressed, indicating stemness and expression of cancer-related pathways in Lgr6/EGFP+ cells. We discovered that suspected "Lgr6 null" mice (Tg/Tg) expressed RNA of an Lgr6 isoform (delta-Lgr6, lacking 74 N-terminal aa) which could be functional and explain the lack of a phenotype.


Experimental phasing of serial femtosecond crystallography data.
A synopsis of and prospects for de novo phasing using diffraction data collected at X-ray free-electron lasers are given.


Extended Time Window Mechanical Thrombectomy for Acute Stroke in Brazil.
Mechanical thrombectomy (MT) is the standard of care for acute ischemic stroke (AIS) caused by large vessel occlusion of the anterior circulation within 6 hours of symptoms onset and can be performed with an extended window up to 24 hours in selected patients. Nevertheless, the outcomes of MT with extended window are unknown in developing countries. Explore the safety and efficacy of MT for AIS performed beyond 6 hours from symptoms onset in Brazil. We reviewed data from AIS patients treated with MT beyond 6 hours of stroke onset, from 2015 to 2018 in a Brazilian public hospital. Patients had an occlusion of the intracranial internal carotid artery and/or proximal segment of the middle cerebral artery. CT Perfusion mismatch was evaluated using the RAPID® software. We evaluated the modified Rankin scale (mRS) and mortality at 90 days, and rate of symptomatic intracranial hemorrhage (sICH). Fifty-four patients were included, with a mean age of 65.6 ± 16.1 years, 55.6% were male, and the median NIHSS score at presentation was 17. Successful recanalization (TICI 2b to 3) was obtained in 92.6% of patients and sICH rate was 11.1%. Overall, 34% of the patients had a good outcome (mRS ≤2) at 90 days and the mortality rate was 20.3%. Our study, the first series of MT for AIS treated with extended window reported in Latin America, shows that MT can be performed with safety and lead to adequate functional outcomes in this context. Further studies should explore the barriers to broad implementation of MT for AIS in Latin America.


The biphasic expression of IMP/Vg1-RBP is conserved between vertebrates and Drosophila.
The human IGF-II mRNA-binding proteins (IMPs) 1-3, and their Xenopus homologue Vg1 RNA-binding protein (Vg1-RBP) are RNA-binding proteins implicated in mRNA localization and translational control in vertebrate development. We have sequenced the Drosophila homologue (dIMP) of these genes, and examined its expression pattern in Drosophila embryos by in situ hybridization. The study shows that dIMP exhibits a biphasic expression pattern. In the early stages of development, a maternal pool of dIMP mRNA is evenly distributed in the embryo and degraded by the end of stage 4. Expression reappears in the developing central nervous system, where dIMP is expressed throughout neurogenesis. In addition, dIMP is present in the pole cells.


Variation of the brachial artery emerging through an opening in the median nerve: a case report.
The median nerve maintains a close relationship with the brachial artery in the upper limb. Variability in the formation and distribution of upper extremity vessels is frequently encountered during donor body dissections or surgical procedures. This case presents a rare anatomical variation of the brachial artery emerging through an opening in the median nerve. The median nerve formed a small opening without the contribution from additional nerve roots and the remaining vasculature of the upper limb was otherwise normal. An abnormal arrangement of a neurovascular bundle in the arm can cause sensory and motor issues, as well as vascular implications. This variation has clinical significance in surgical interventions and potentially daily functioning. To our knowledge, this is the first report of a small median nerve opening pierced by the brachial artery.


Perioperative coagulation assessment of patients undergoing major elective orthopedic surgery.
Traditional coagulative parameters are of limited use in identifying perioperative coagulopathy occurring in patients undergoing major elective orthopedic surgery (MEOS). The aim of our study was to evaluate the coagulation changes in patients undergoing MEOS and to facilitate an early detection of perioperative coagulopathy in patients experiencing major intraoperative bleeding. We enrolled 40 consecutive patients (M/F 10/30, age range 34-90 years) who underwent MEOS at the Orthopedic Unit of the Padua University Hospital, Italy, between January 2014 and January 2015. Blood samples were obtained at the following time points: T0-pre: 30 min before surgery; T0-post: 30 min after the end of the procedure; T1: morning of the first postoperative day; T2: 7 ± 2 days after surgery. Patients who experienced an intraoperative blood loss ≥250 mL/h were considered as cases. Routine coagulative parameters, thromboelastometry and thrombin generation (TG) profiles were evaluated. At baseline, a significantly lower platelet count and FIBTEM MCF/AUC were observed in patents with excessive bleeding (p < 0.05 and 0.02/0.01, respectively). At T0-post and T1 intervals, cases showed hypocoagulation characterized by a significantly low platelet count (p = 0.001), prolonged CFT INTEM/EXTEM, reduction of alpha-angle and MaxV INTEM/EXTEM, MCF and AUC INTEM/EXTEM/FIBTEM (p < 0.05 in all comparisons). The only TG parameter standing out between study groups was time to peak at T0-pre. A low platelet count and fibrinogen activity were associated with significant intraoperative bleeding in patients undergoing MEOS. Thromboelastometry performed by ROTEM(®) identifies patients with coagulopathy.


Mechanism of action of gonadotropin releasing hormone upon gonadotropin secretion: involvement of protein kinase C as revealed by staurosporine inhibition and enzyme depletion.
The role of protein kinase C (PKC) in the mechanism of action of gonadotropin-releasing hormone (GnRH) upon gonadotropin secretion is controversial and therefore was investigated in primary cultures of rat anterior pituitary cells. A relatively selective PKC inhibitor, staurosporine, inhibited both GnRH- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced luteinizing hormone (LH) release with half-maximal inhibition (IC50) of about 80 nM. Inhibition of GnRH action was not complete suggesting also a PKC-insensitive component in GnRH-induced gonadotropin release. Staurosporine had no effect on basal LH release, or on cellular LH content, neither did the drug interfere with the binding of [125I]iodo-[D-Ser(t-Bu)6]des-Gly10-GnRH N-ethylamide to its receptor in pituitary cells. When cultured pituitary cells were incubated with TPA (1 microM) for 24-48 h no measurable cellular PKC activity could be detected. The decrease in total PKC activity was accompanied by an increase in Ca2+, phosphatidylserine (PS), diacylglycerol (DG)-insensitive activity suggesting the release of a portion of the catalytic domain of PKC (M-kinase) by the phorbol ester treatment. TPA-induced LH release was nearly abolished in PKC-depleted cells and the response to GnRH was markedly reduced (40%). The stimulatory effect of the Ca2+ ionophore, ionomycin, was not impaired in PKC-depleted cells. Impaired responses to GnRH in PKC-depleted cells were only noticed at a later phase (2-4 h) of the exocytotic response of the neurohormone. The data strongly suggest a role for PKC during the second phase of GnRH-induced gonadotropin secretion.


Vanadium(IV)-stimulated hydrolysis of 2,3-diphosphoglycerate.
Vanadium(IV) stimulates the hydrolysis of 2,3-diphosphoglycerate at 23 degrees C. The pH optimum is 5.0. Reactions were analyzed by enzymatic and phosphate release assays. The products of 2,3-diphosphoglycerate hydrolysis are inorganic phosphate and 3-phosphoglycerate. The reaction is inhibited by high concentrations of 2,3-diphosphoglycerate and an equation has been formulated that describes the kinetic constants for this reaction at pH 7. The possible relevance of the reaction to the therapeutic lowering by vanadium(IV) of red cell 2,3-diphosphoglycerate in sickle-cell disease is discussed.


Thoracic vagal efferent nerve stimulation evokes substance P-induced early airway bronchonstriction and late proinflammatory and oxidative injury in the rat respiratory tract.
Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-kappaB (NF-kappaB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O (2)(-) and H(2)O(2) ROS amount. L-732138 (NK(1) receptor antagonist), SR-48968 (NK(2) receptor antagonist), dimethylthiourea (H(2)O(2) scavenger) or catechins (O (2)(-) and H(2)O(2) scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-kappaB (NF-kappaB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-kappaB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-kappaB mediated ICAM-1 expression and O (2)(-) and H(2)O(2) ROS production in the respiratory tract.


A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth.
Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. We have developed a thermally responsive polypeptide, based on the sequence of Elastin-like polypeptide (ELP), that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. Following systemic administration, the ELP - delivered c-Myc inhibitory peptide was targeted to tumors using focused hyperthermia, and significantly reduced tumor growth in an orthotopic mouse model of breast cancer. This work provides a new modality for targeted delivery of a specific oncogene inhibitory peptide, and this strategy may be expanded for delivery of other therapeutic peptides or small molecule drugs.


Epileptic spasms in individuals with Down syndrome: A review of the current literature.
Epilepsy can occur in individuals with Down syndrome (DS), with epileptic spasms representing the most frequent seizure type in this population. Epileptic spasms can have devastating consequences on the development of individuals with the condition. This review sought to explore the lifetime prevalence and underlying mechanism of epileptic spasms in this population. We also aimed to review the response rate to various treatments, the relapse rate, and the development of subsequent epilepsy or autism in this population. A comprehensive literature search was conducted for articles discussing the lifetime prevalence, diagnosis, treatment, outcomes, or underlying etiology of epileptic spasms in animal models or individuals with DS. According to available literature, the global clinic-based lifetime prevalence of epilepsy in individuals with DS ranged from 1.6% to 23.1%, with epileptic spasms representing 6.7%-66.7% of these cases. Response rate to treatment with adrenocorticotropic hormone/corticosteroids was highest (81%) and has the most literature supporting its use, with other regimens, including vigabatrin and other antiepileptic drugs, having lower response rates. Epileptic spasms occur more frequently in children with DS than in the general population, though more studies are needed to determine the true lifetime prevalence of epileptic spasms in this population. Generally, children with DS and epileptic spasms tend to be more responsive to treatment and have better outcomes than children with epileptic spasms of unknown etiology (ie, without DS), in terms of response and relapse rates as well as the development of intractable epilepsy (eg, Lennox-Gastaut syndrome).


Translational physiologically-based pharmacokinetic model for ocular disposition of monoclonal antibodies.
We have previously published a PBPK model comprising the ocular compartment to characterize the disposition of monoclonal antibodies (mAbs) in rabbits. While rabbits are commonly used preclinical species in ocular research, non-human primates (NHPs) have the most phylogenetic resemblance to humans including the presence of macula in the eyes as well as higher sequence homology. However, their use in ocular research is limited due to the strict ethical guidelines. Similarly, in humans the ocular samples cannot be collected except for the tapping of aqueous humor (AH). Therefore, we have translated this rabbit model to monkeys and human species using literature-reported datasets. Parameters describing the tissue volumes, physiological flows, and FcRn-binding were obtained from the literature, or estimated by fitting the model to the data. In the monkey model, the values for the rate of lysosomal degradation for antibodies (Kdeg), intraocular reflection coefficients (σaq, σret, σcho), bidirectional rate of fluid circulation between the vitreous chamber and the aqueous chamber (QVA), and permeability-surface area product of lens (PSlens) were estimated; and were found to be 31.5 h-1, 0.7629, 0.6982, 0.9999, 1.64 × 10-5 L/h, and 4.62 × 10-7 L/h, respectively. The monkey model could capture the data in plasma, aqueous humor, vitreous humor and retina reasonably well with the predictions being within twofold of the observed values. For the human model, only the value of Kdeg was estimated to fit the model to the plasma pharmacokinetics (PK) of mAbs and was found to be 24.4 h-1 (4.14%). The human model could also capture the ocular PK data reasonably well with the predictions being within two- to threefold of observed values for the plasma, aqueous and vitreous humor. Thus, the proposed framework can be used to characterize and predict the PK of mAbs in the eye of monkey and human species following systemic and intravitreal administration. The model can also facilitate the development of new antibody-based therapeutics for the treatment of ocular diseases as well as predict ocular toxicities of such molecules following systemic administration.


Synthesis of α-1,2- and α-1,3-linked di-rhamnolipids for biological studies.
For a detailed examination of the interaction of rhamnose containing derivatives with recombinant horseshoe crab plasma lectin (rHPL), two di-rhamno-di-lipids (an α-1,2- and an α-1,3-linked) were synthesized via a new simple method. The N-iodosuccinimide/triflic acid mediated glycosylation of the methyl (R)-3-hydroxydecanoate with phenyl-1-thio-rhamnobioside donors afforded the mono-lipid disaccharides. Removal of the methyl ester group followed by esterification of the mono-lipids with a second (R)-3-hydroxydecanoate unit resulted in fully protected di-lipid derivatives, transformation of which into the target compounds was accomplished in two steps. This method allows the synthesis of both regioisomers in only 6 steps starting from the corresponding free disaccharides. Both synthetic di-rhamnolipids were biologically active for lectin binding differential binding preference between two isomeric di-rhamno-di-lipids. The rHPL lectin favours the α-1,3-linked di-rhamno-di-lipids over its α-1,2-linked regioisomer.


Nonrigid connection of tooth with implants in the esthetic zone with a ceramic restoration: a clinical report.
Restoring edentulous areas with fixed prostheses can be challenging, especially when key abutment teeth are missing and implant placement is not an option. Sometimes, clinicians are faced with situations where teeth have to be connected with implants even though long-term prognosis of those connections may be questionable. This clinical report presents a connection of 2 implants with 1 tooth in the esthetic zone with a nonrigid connection. Two zirconia custom abutments and 1 zirconia coping definitively cemented on the tooth were used. A zirconia superstructure, veneered with porcelain, was cemented with provisional cement on the abutments and the coping.


Molecular design of two sterol 14alpha-demethylase homology models and their interactions with the azole antifungals ketoconazole and bifonazole.
Sterol 14alpha-demethylase (CYP51) is one of the known major targets for azole antifungals. Therapeutic side effects of these antifungals are based on interactions of the azoles with the human analogue enzyme. This study describes for the first time a comparison of a human CYP51 (HU-CYP51) homology model with a homology model of the fungal CYP51 of Candida albicans (CA-CYP51). Both models are constructed by using the crystal structure of Mycobacterium tuberculosis MT-CYP51 (PDB code: 1EA1). The binding mode of the azole ketoconazole is investigated in molecular dynamics simulations with the GROMACS force field. The usage of special parameters for the iron azole complex binding is necessary to obtain the correct complex geometry in the active site of the enzyme models. Based on the dynamics simulations it is possible to explain the enantioselectivity of the human enzyme and also to predict the binding mode of the isomers of ketoconazole in the active site of the fungal model.


Paramagnetic rim lesions are associated with greater incidence of relapse and worse cognitive recovery following relapse.
Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing-remitting multiple sclerosis (pwRRMS). To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL-). Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL (p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS (n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL - pwRRMS (n = 7; p = 0.027). These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.


Prevalence of Self-Reported Lifetime History of Traumatic Brain Injury and Associated Disability: A Statewide Population-Based Survey.
To investigate the prevalence of all severities of traumatic brain injury (TBI), regardless of treatment setting, and their associated negative outcomes. A total of 2701 adult Coloradoans. A statewide, population-based, random digit-dialed telephone survey. The lifetime history of TBI was assessed by a modification of the Ohio State University TBI Identification Method; activity limitation and life satisfaction were also assessed. The distribution of self-reported lifetime injury was as follows: 19.8%, no injury; 37.7%, injury but no TBI; 36.4%, mild TBI; and 6.0%, moderate-severe TBI. Of those reporting a TBI, 23.1% were hospitalized, 38.5% were treated in an emergency department, 9.8% were treated in a physician's office, and 27.5% did not seek medical care. A clear gradient of activity limitations and low life satisfaction was seen, with the highest proportions of these negative outcomes occurring in people reporting more severe TBI and the lowest proportions in those not reporting a TBI. Approximately twice as many people reported activity limitations and low life satisfaction after nonhospitalized TBI compared with hospitalized TBI. This investigation highlights the seriousness of TBI as a public health problem and the importance of including all severities of TBI, no matter where, or if treated, in estimating the prevalence of disability co-occurring with TBI.


The temporal contiguity effect predicts episodic memory performance.
One way to study the associative processes at work during episodic memory is to examine the order of participant responses, which reveal the strong tendency to transition between temporally contiguous or semantically proximal items on the study list. Here, we assessed the correlation between participants' recall performance and their use of semantic and temporal associations to guide retrieval across nine delayed free recall studies. The size of the participants' temporal contiguity effects predicted their recall performance. When interpreted in terms of two models of episodic memory, these results suggest that participants who more effectively form and retrieve associations between items that occur nearby in time perform better on episodic recall tasks. Sample code may be downloaded as a supplement for this article from http://mc.psychonomic-journals.org/content/supplemental.


Typing of canine parvovirus isolates using mini-sequencing based single nucleotide polymorphism analysis.
The antigenic types of canine parvovirus (CPV) are defined based on differences in the amino acids of the major capsid protein VP2. Type specificity is conferred by a limited number of amino acid changes and in particular by few nucleotide substitutions. PCR based methods are not particularly suitable for typing circulating variants which differ in a few specific nucleotide substitutions. Assays for determining SNPs can detect efficiently nucleotide substitutions and can thus be adapted to identify CPV types. In the present study, CPV typing was performed by single nucleotide extension using the mini-sequencing technique. A mini-sequencing signature was established for all the four CPV types (CPV2, 2a, 2b and 2c) and feline panleukopenia virus. The CPV typing using the mini-sequencing reaction was performed for 13 CPV field isolates and the two vaccine strains available in our repository. All the isolates had been typed earlier by full-length sequencing of the VP2 gene. The typing results obtained from mini-sequencing matched completely with that of sequencing. Typing could be achieved with less than 100 copies of standard plasmid DNA constructs or ≤10¹ FAID₅₀ of virus by mini-sequencing technique. The technique was also efficient for detecting multiple types in mixed infections.


Mapping of RNase P Ribozyme Regions in Proximity with a Human RNase P Subunit Protein Using Fe(II)-EDTA Cleavage and Nuclease Footprint Analyses.
Ribonuclease P (RNase P), which may consist of both protein subunits and a catalytic RNA part, is responsible for 5' maturation of tRNA by cleaving the 5'-leader sequence. In Escherichia coli, RNase P contains a catalytic RNA subunit (M1 RNA) and a protein factor (C5 protein). In human cells, RNase P holoenzyme consists of an RNA subunit (H1 RNA) and multiple protein subunits that include human RPP29 protein. M1GS, a sequence specific targeting ribozyme derived from M1 RNA, can be constructed to target a specific mRNA to degrade it in vitro. Recent studies have shown that M1GS ribozymes are efficient in blocking the expression of viral mRNAs in cultured cells and in animals. These results suggest that RNase P ribozymes have the potential to be useful in basic research and in clinical applications. It has been shown that RNase P binding proteins, such as C5 protein and RPP29, can enhance the activities of M1GS RNA in processing a natural tRNA substrate and a target mRNA. Understanding how RPP29 binds to M1GS RNA and enhances the enzyme's catalytic activity will provide great insight into developing more robust gene-targeting ribozymes for in vivo application. In this chapter, we describe the methods of using Fe(II)-ethylenediaminetetraacetic acid (EDTA) cleavage and nuclease footprint analyses to determine the regions of a M1GS ribozyme that are in proximity to RPP29 protein.


Effects of Probiotic Supplementation on Inflammatory Markers and Glucose Homeostasis in Adults With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.
Background: Several studies have revealed the effect of probiotic supplementation in patients with type 2 diabetes (T2DM) on the amelioration of low-grade inflammation, which plays an important role in the pathogenesis of T2DM. However, the effects of the clinical application of probiotics on inflammation in individuals with T2DM remain inconsistent. This study aims to investigate the comprehensive effects of probiotics on inflammatory markers in adults with T2DM. Methods: PubMed, Embase, Cochrane Library, and the Web of Science were searched to identify randomized controlled trials (RCTs) exploring the effect of probiotic supplementation on inflammatory markers in individuals with T2DM through March 11, 2021. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias of the included studies. We used a random-effects model to calculate the standardized mean difference (SMD) between the probiotic supplementation and control groups. Results: Seventeen eligible studies were selected with a total of 836 participants, including 423 participants in probiotic supplementation groups and 413 participants in control groups. Our study demonstrated that compared with the control condition, probiotic intake produced a beneficial effect in reducing the levels of plasma inflammation markers, including tumour necrosis factor-α (TNF-α) (SMD [95% CI]; -0.37 [-0.56, -0.19], p < 0.0001) and C-reactive protein (CRP) (SMD [95% CI]; -0.21 [-0.42, -0.01], p = 0.040), while it had no effect on the plasma interleukin-6 (IL-6) level (SMD [95% CI]; -0.07 [-0.27, 0.13], p = 0.520). In addition, our results support the notion that probiotic supplementation improves glycaemic control, as evidenced by a significant reduction in fasting blood glucose (FPG), HbA1c and HOMA-IR (SMD [95% CI]: -0.24 [-0.42, -0.05], p = 0.010; -0.19 [-0.37, -0.00], p = 0.040; -0.36 [-0.62, -0.10], p = 0.006, respectively). Conclusion: Our study revealed some beneficial effects of probiotic supplementation on improving inflammatory markers and glucose homeostasis in individuals with T2DM. Probiotics might be a potential adjuvant therapeutic approach for T2DM.


Cortical pattern of complex but not simple movements is affected in writer's cramp: a parametric event-related fMRI study.
Patients with writer's cramp (WC) were studied for differences in cortical activation during movements likely to induce WC (complex movements) and movements which rarely lead to dystonia (simple movements). Eleven WC patients (10F, 1M, mean age 41.5 ± (SD)7.2 years) and eleven age matched controls were examined for Blood oxygenation-level dependent (BOLD) 1.5 T fMRI. The complex task consisted of writing a single letter or random drawing using an especially adapted joystick with the line of trajectory visualized or hidden. The simple task consisted of self-initiated fingers flexion/extension using the affected hand. Unlike the controls, WC patients performing complex movements exhibited a lower BOLD signal in the primary sensorimotor cortex and in the posterior parietal cortex bilaterally. A hypoactivation was also observed in the right secondary somatosensory area, in the right anterior insula and in the left premotor cortex (p < 0.05 corrected). No significant inter-group differences were found for simple movements. Although WC patients' complex movements during fMRI were never associated with dystonic cramp, they exhibited an abnormally low cortical activity. This phenomenon was not observed in simple movements and was unrelated to the character of handwriting or to visual feedback. Our results support the dualistic behavior in the sensorimotor system in WC.


[Studies on chemical constituents from bark of Morus nigra].
To investigate the chemical constituents in the barks of Morus nigra. The nine compounds were isolated and purified by column chromatography over silica gel, LH -20 and preparative HPLC and their structures were identified by various spectroscopic methods. The nine compounds were isolated and identified as olcancolic acid , apigenin, cyclocommunol, morusin, cyclomorusin, kuwanon C, daucosterol, ursolic acid, 63-sitosterol. Olcancolic acid, apingenin, cyclocommunol, morusin, cyclomorusin, kuwanon C, daucosterol were firstly isolated from the M. nigra.


The burden of geriatric traumatic brain injury on trauma systems: Analysis of 348,800 Medicare inpatient claims.
Traumatic brain injury (TBI) is a leading cause of death and disability in older adults. The aim of this study was to characterize the burden of TBI in older adults by describing demographics, care location, diagnoses, outcomes, and payments in this high-risk group. Using 2016-2019 Centers for Medicare & Medicaid Services (CMS) Inpatient Standard Analytical Files (IPSAF), patients >65 years with TBI (>1 injury ICD-10 starting with "S06") were selected. Trauma center levels were linked to the IPSAF file via American Hospital Association Hospital Provider ID and fuzzy-string matching. Patient variables were compared across trauma center levels. Three hundred forty-eight thousand eight hundred inpatients (50.4% female; 87.1% white) from 2963 US hospitals were included. Level I/II trauma centers treated 66.9% of patients; non-trauma centers treated 21.5%. Overall inter-facility transfer rate was 19.2%; in Level I/II trauma centers transfers-in represented 23.3% of admissions. Significant TBI (Head AIS ≥3) was present in 70.0%. Most frequent diagnoses were subdural hemorrhage (56.6%) and subarachnoid hemorrhage (30.6%). Neurosurgical operations were performed in 10.9% of patients and operative rates were similar regardless of center level. Total unadjusted mortality for the sample was 13.9%, with a mortality of 8.1% for those who expired in-hospital, and an additional 5.8% for those discharged to hospice. Medicare payments totaled $4.91B, with the majority (73.4%) going to Level I/II trauma centers. This study fills a gap in TBI research by demonstrating that although the majority of older adult TBI patients in the United States receive care at Level I/II trauma centers, a substantial percentage are managed at other facilities, despite 1 in 10 requiring neurosurgical operation regardless of level of trauma center. This analysis provides preliminary data on the function of regionalized trauma care for older adult TBI care. Future studies assessing the efficacy of early care guidelines in this population are warranted.


Circadian variation in tolerance to the hypothermic action of CNS drugs.
Male SAF mice (30-35 g) or male Sprague-Dawley rats (180-250 g) were used to study the circadian variation in tolerance to the hypothermic action of ethanol, apomorphine, and nicotine. Animals were treated for 2 or 3 consecutive days during the light phase (1000, 1400, or 1800 h) or the dark phase (2200, 0200, or 0600 h) and hypothermia produced measured. In one experiment, repeated injections of 20% ethanol (3 g/kg, IP) to mice resulted in varying degrees of hypothermia depending upon the time of injection. Tolerance to hypothermic action was observed only in animals treated during the light phase. On the contrary, the hypothermic response in animals treated during the dark phase increased. In another experiment, apomorphine (15 mg/kg, IP) was used and tolerance to apomorphine-induced hypothermia observed following repeated injections during the light phase with maximum tolerance noticed at 1400 h. In the third experiment, nicotine (2 mg/kg, IP) was repeatedly administered and resulted in tolerance development when given during the light phase. These results indicate that the rapid development of tolerance to CNS drugs studied is a diurnally controlled phenomenon.


Synthesis and characterization of nanoheterostructures based on oligothiophene functionalized Ru nanoparticles.
Monodisperse ruthenium nanoparticles functionalized by electroactive oligothiophenes have been prepared and characterized. Using TEM, UV-visible and FTIR we established that the organization of these nanoparticles into nanospheres can be directly controlled via modulation of the pi-pi interaction between the organic components adsorbed on the surface. This finding also shows that the self-assembled nanoheterostructures may be switched from monodisperse nanoparticles to ordered nanospheres by tuning the pH.


Diffuse axonal injury without direct head trauma and with delayed onset of coma.
A 16-year-old female was involved in a jet ski (water craft) accident resulting in bilateral lower extremity fractures but no loss of consciousness or any other evidence of head trauma. Thirty hours later she became comatose. Magnetic resonance imaging was consistent with diffuse axonal injury. She recovered after several weeks without any clinical sequelae. This patient demonstrates an unusual example of diffuse axonal injury without direct head trauma and with delayed onset of symptoms. The authors recommend that patients involved in high-velocity accidents, even without immediate evidence of head injury, be observed for signs of diffuse axonal injury.


The comparison of glycosphingolipids isolated from an epithelial ovarian cancer cell line and a nontumorigenic epithelial ovarian cell line using MALDI-MS and MALDI-MS/MS.
Glycosphingolipids (GSLs) are important biomolecules, which are linked to many diseases such as GSL storage disorders and cancer. Consequently, the expression of GSLs may be altered in ovarian cancer cell lines in comparison to apparently healthy cell lines. Here, differential expressions of GSLs in an epithelial ovarian cancer cell line SKOV3 and a nontumorigenic epithelial ovarian cell line T29 were studied using matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) and MALDI-MS/MS. The isolation of GSLs from SKOV3 and T29 cell lines was carried out using Folch partition. GSLs were successfully detected by MALDI-MS, and structurally assigned by a comparison of their MALDI-MS/MS fragmentation patterns with MS/MS data found in SimLipid database. Additionally, LIPID MAPS was used to assign GSL ion masses in MALDI-MS spectra. Seventeen neutral GSLs were identified in Folch partition lower (chloroform/methanol) phases originating from both cell lines, while five globo series neutral GSLs were identified only in the Folch partition lower phase of SKOV3 cell line. Several different sialylated GSLs were detected in Folch partition upper (water/methanol) phases of SKOV3 and T29 cell lines. Overall, this study demonstrates the alteration and increased glycosylation of GSLs in an epithelial ovarian cancer cell line in comparison to a nontumorigenic epithelial ovarian cell line.


[Evaluation of radiotherapy treatment planes in terms of iso-TDF curves (author's transl)].
The usefulness of working out radiotherapy treatment planes using radiobiological iso-effect curves instead of only iso-dose curves is explained. Examples of the application of iso-TDF curves are presented with reference to the method of Ellis.


BnA10.RCO, a homeobox gene, positively regulates leaf lobe formation in Brassica napus L.
BnA10.RCO positively regulates the development of leaf lobes in Brassica napus, and cis-regulatory divergences cause the different allele effects. The functional importance of lobed leaves in rapeseed (Brassica napus L.) has been identified with potential advantages for high-density planting and hybrid production. Our previous studies indicated that the tandemly duplicated LMI1-like genes BnA10. RCO and BnA10.LMI1 are candidate genes of an incompletely dominant locus, which is responsible for the lobed-leaf shape in rapeseed. We provided strong evidence that BnA10.LMI1 positively regulates leaf lobe formation. Here, we show that BnA10.RCO is a nucleus-specific protein, encoding an HD-ZIP I transcription factor, which is responsible for the lobed-leaf shape in rapeseed. Sequence analysis of parental alleles revealed that no vital sequence variation was detected in the coding sequence of BnA10.RCO, whereas abundant variations were identified in the regulatory regions. Consistent with this finding, the expression level of BnRCO was substantially elevated in the lobed-leaved parent HY compared with its near-isogenic line. Moreover, the altered expression of BnA10.RCO in transgenic lines showed a positive connection with leaf complexity without a substantial change in BnLMI1 transcript level. Furthermore, CRISPR/Cas9-induced null mutations of BnA10.RCO in the lobed-leaved parent HY were sufficient to produce an unlobed leaf without alteration in BnLMI1 transcript level. Our results indicate that BnA10.RCO functions together with BnA10.LMI1 to positively determine the lobed-leaf development, providing a fundamental basis for crop improvement by targeting leaf shape in rapeseed.


Experimental and Computational Studies on the Basic Transmission Properties of Electromagnetic Waves in Softmaterial Waveguides.
Conventional waveguides are usually made of metallic materials, and they are effective pathways for the transmission of electromagnetic waves. A "Softmaterial waveguide", by contrast, is supposed to be made of dielectric material and ionic fluids. In this work, by means of both experiment and computational simulation we examined one kind of softmaterial waveguide, which has the configuration of ionic fluids filled in and out of a dielectric tube. We investigated configurations with varied parameters, i.e., tube thickness from 0.2 mm to 5.0 mm, tube length of 2.0-12.0 cm, ionic concentration covering 4 orders of magnitude from 0.0002-2.0 mol/L, frequency of 10 Hz to 100 MHz for sine wave excitations, pulse duration of 5 ns to 100 ms for excitation pulses. We also mimicked the myelin sheath structure in myelinated axons in simulation. Both experimental and simulation results consistently showed a clear confinement effect for the energy flux of transmitting electromagnetic waves inside the dielectric tube, strongly supporting the model of softmaterail waveguide. The results revealed that the softmaterial waveguide had a low-pass nature, where the intensity of transmitted signals saturated at a duration of 10-100 μs for pulses, or cut off at frequency of 10-100 kHz for sine waves. And, the transmission efficiency increased with the thickness of the dielectric layer, as well as ion concentration of the solution. The results may help for a better understanding various electrical communication behaviors observed in biosystems, where a natural lipid membrane with bilateral fluids was suggested as the efficient pathway for pulsed neural impulses in a way similar to soliton-like electromagnetic pulses transmitting in a softmaterial waveguide.


Hematological cancer in 2011: New therapeutic targets and treatment strategies.
2011 saw improvements in our understanding of B-cell malignancies: insights into the genomic basis of chronic lymphocytic leukemia were achieved; reduced treatment intensity caused fewer toxic effects in early-stage Hodgkin lymphoma; first-line rituximab maintenance therapy improved outcome in follicular lymphoma; and selected patients with diffuse large-cell lymphoma benefited from the addition of bortezomib.


Perioperative do-not-resuscitate orders--doing 'nothing' when 'something' can be done.
Cardiopulmonary resuscitation (CPR) has the ability to reverse premature death. It can also prolong terminal illness, increase discomfort and consume enormous resources. Despite the desire to respect patient autonomy, there are many reasons why withholding CPR may be complicated in the perioperative setting. This review outlines these factors in order to offer practical suggestions and to provoke discussion among perioperative care providers. Although originally described for witnessed intraoperative arrests, closed chest cardiac massage quickly became universal practice, and a legal imperative in many hospitals. Concerns were raised by both health care workers and patient groups; this eventually led to the creation of the do-not-resuscitate (DNR) order. However, legal precedents and ethical interpretations dictated that patients were expected to receive full resuscitation unless there was explicit documentation to the contrary. In short, CPR became the only medical intervention that required an order to prevent it from being performed. Before the 1990s, patients routinely had pre-existing DNR orders suspended during the perioperative period. Several articles criticized this widespread practice, and the policy of 'required reconsideration' was proposed. Despite this, many practical issues have hindered widespread observance of DNR orders for surgical patients, including concerns related to the DNR order itself and difficulties related to the nature of the operating room environment. This review outlines the origins of the DNR order, and how it currently affects the patient presenting for surgery with a pre-existing DNR order. There are many obstacles yet to overcome, but several practical strategies exist to aid health care workers and patients alike.


Evaluating motor neuron death in neonatal rats subjected to sciatic nerve lesion.
Neonatal sciatic nerve lesion is a useful experimental model for the study of neuronal cell death. Sciatic nerve transection or crush is the most frequently used approach to evaluate motoneuron loss in the lumbar enlargement of the spinal cord. Here we describe and illustrate the surgical procedures performed in our laboratory to assess motoneuron cell death and the related cellular mechanisms.


Caution against simultaneous integrated boost radiotherapy for upper thoracic esophageal squamous cell carcinoma: results from a single-arm phase II trial.
To explore the feasibility and safety of simultaneous integrated boost technology (SIB) with elective nodal irradiation (ENI) to the cervical and upper mediastinal lymph node (LN) regions in upper thoracic esophageal squamous cell carcinoma (ESCC). Patients with pathologically proven unresectable upper thoracic ESCC were assigned 50.4 Gy/28 fractions (F) to the clinical target volume (encompassing the ENI area of cervical and upper mediastinal LN regions) and a boost of 63 Gy/28 F to the gross tumor volume. Chemotherapy consisted of courses of concurrent cisplatin (20 mg/m2) and docetaxel (20 mg/m2) weekly for 6 weeks. The primary endpoint was toxicity. Between Jan 2017 and Dec 2019, 28 patients were included. The median follow-up time for all patients was 24.6 months (range 1.9-53.5). Radiation-related acute toxicity included esophagitis, pneumonia and radiodermatitis, all of which were well managed and reversed. Late morbidity included esophageal ulcer, stenosis, fistula and pulmonary fibrosis. Grade III esophageal stenosis and fistula was seen in 11% (3/28) and 14% (4/28) patients, respectively. The cumulative incidence rate of late esophageal toxicity was 7.7%, 19.2% and 24.6% at 6, 12 and 18 months, respectively. There was significant difference of the occurrence of severe late esophageal toxicity among the different volume levels of the esophagus, and cervical and upper mediastinal LNs which received ≥ 63 Gy stratified by the tertiles (p = 0.014). Despite the acceptably tolerated acute toxicity of SIB in concurrent CRT with ENI to the cervical and upper mediastinal LN regions for upper thoracic ESCC, the incidence of severe late esophageal toxicity was relatively high. Cautions are provided against easy clinical application of SIB (50.4 Gy/28F to the CTV, 63 Gy/28F to the GTV) in upper thoracic ESCC. Further exploration on dose optimization is warranted.


Insulin receptors in mouse brain: Reversibility of age-related impairments by a thymic extract.
Recently, we have shown that insulin receptors (InsRs) in the brain undergo impairments with aging. Interestingly, age-related alterations of brain InsRs, are not irreparable as thymus grafts are able to recover them. With the present study we verified the possibility that an aqueous extract from calf thymus (TME) can mimic the restoring action of age-related impairments induced by thymus graft. InsR characteristics were assayed in a group of 25 months old BALB/c-nu mice treated with TME: 2μg/g body weight every third day, for total five subcutaneous injections. The last dose was injected the day before animals were killed. Other two groups of young (4 months) and old (25 months) mice received saline solution with the same schedule. A two-sites model analysis of receptor data confirms the age-dependent decrease of InsR number and kd previously observed in the high affinity population. Furthermore, a statistically significant recovery of number impairment is shown in TME-treated animals. On the contrary, the characteristics of the low affinity receptor subset show no statistically significant differences among the three animal models studied. TME induced recovery of the age-related changes found in brain InsRs, together with previously observed regulatory action of the same thymic extract on the adrenergic system, suggest that thymic gland does not necessarily have to mutually interact with other controlling systems for maintaining or recoving homeostasis of the complex neuroendocrine network during development and aging.


Mice lacking GPR3 receptors display late-onset obese phenotype due to impaired thermogenic function in brown adipose tissue.
We report an unexpected link between aging, thermogenesis and weight gain via the orphan G protein-coupled receptor GPR3. Mice lacking GPR3 and maintained on normal chow had similar body weights during their first 5 months of life, but gained considerably more weight thereafter and displayed reduced total energy expenditure and lower core body temperature. By the age of 5 months GPR3 KO mice already had lower thermogenic gene expression and uncoupling protein 1 protein level and showed impaired glucose uptake into interscapular brown adipose tissue (iBAT) relative to WT littermates. These molecular deviations in iBAT of GPR3 KO mice preceded measurable differences in body weight and core body temperature at ambient conditions, but were coupled to a failure to maintain thermal homeostasis during acute cold challenge. At the same time, the same cold challenge caused a 17-fold increase in Gpr3 expression in iBAT of WT mice. Thus, GPR3 appears to have a key role in the thermogenic response of iBAT and may represent a new therapeutic target in age-related obesity.


Systematic characterization of small RNAs associated with C. elegans Argonautes.
Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs (sRNAs). An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans. Canonical sRNAs in C. elegans are miRNAs, small interfering RNAs including 22G-RNAs and 26G-RNAs, and 21U-RNAs, which are C. elegans piRNAs. Previous studies have only covered some of these Argonautes for their sRNA partners, and thus, a systematic study is needed to reveal the comprehensive regulatory networks formed by C. elegans Argonautes and their associated sRNAs. We obtained in situ knockin (KI) strains of all C. elegans Argonautes with fusion tags by CRISPR/Cas9 technology. RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the sRNA profiles of individual Argonautes. The sRNA partners for each Argonaute were then analyzed. We found that there were 10 Argonautes enriched miRNAs, 17 Argonautes bound to 22G-RNAs, 8 Argonautes bound to 26G-RNAs, and 1 Argonaute PRG-1 bound to piRNAs. Uridylated 22G-RNAs were bound by four Argonautes HRDE-1, WAGO-4, CSR-1, and PPW-2. We found that all four Argonautes played a role in transgenerational epigenetic inheritance. Regulatory roles of the corresponding Argonaute-sRNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated. In this study, we portrayed the sRNAs bound to each functional Argonaute in C. elegans. Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C. elegans Argonautes and sRNAs. The sRNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.


Exploratory study of Australian aged care staff knowledge and attitudes of later life sexuality.
To explore aged care staff knowledge and attitudes towards later life sexuality and attitudes about intimacy in people with dementia. Fifty-two care staff working in two aged care facilities with secure dementia care units were recruited. Knowledge and attitudes on later life sexuality and attitudes towards later life sexuality in people with dementia were surveyed using the Aging Sexual Knowledge and Attitudes Scale and the selected eight items of the Staff Attitudes about Intimacy and Dementia, respectively. The results indicated that aged care staff knowledge of later life sexuality is inadequate, but attitudes towards later life sexuality and about intimacy and dementia were relatively permissive. Improving aged care staff knowledge of later life sexuality is needed. Continuing education and training should provide to support the expression of later life sexuality including those with dementia.


Comparative study of the N-linked oligosaccharides released from normal human esophageal epithelium and esophageal squamous carcinoma.
N-Linked sugar chains of normal human esophageal epithelium and esophageal squamous carcinoma were quantitatively released as oligosaccharides from their membrane preparations by hydrazinolysis. After being fractionated by serial lectin column chromatography using concanavalin A-Sepharose and Datura stramonium agglutinin-Sepharose, their structures were elucidated by exoglycosidase digestion in combination with methylation analysis. Both normal epithelium and esophageal carcinoma contained bi-, tri- and tetraantennary oligosaccharides as well as high mannose-type oligosaccharides. Interestingly, carcinoma had about 1.6 times larger amounts of tri- and tetraantennary oligosaccharides with the GlcNAc beta 1----4Man alpha 1----and/or the GlcNAc beta 1----6Man alpha 1----linkages than normal epithelium. Tri- and tetraantennary oligosaccharides with N-acetyllactosamine repeating units (the Gal beta 1----4GlcNAc beta 1----3Gal beta 1----4GlcNAc group) were also increased in carcinoma. These data indicated that the altered glycosylation of proteins previously found in transformed rodent cells also occurs widely in human esophageal carcinoma.


High content chitosan-based materials with high performance properties.
Chitosan is a valuable biopolymer with a great potential to be used in the design of sustainable materials. Its use typically requires converting the solid powder into a quite dilute solution by disrupting the hydrogen bonding between primary amine and hydroxyl groups. In this work we show that chitosan can be reacted with a tris-aromatic tris-epoxy monomer, generating thermoset materials. The design of the new structures adopted a strategy where the chitosan was mixed in its solid form, to avoid the use of solvents and additional processing steps. A combined polymerization mechanism was proposed, including growth chain polymerization and polyaddition. The obtained materials containing different epoxy/chitosan weight percentage ratios show outstanding properties: high glass transition ~230 °C, high Young's modulus ~2116 and 1716 MPa, tensile strength of ~35 MPa and T5% ~ 300 °C.


Cancer in an incarcerated population.
The challenge posed to prison health systems in the U.S. by an immense incarcerated population is significant. However, the patterns of presentation and associated mortality of cancer among the incarcerated population is unknown. An historical cohort of cancers diagnosed among inmates of the Texas Department of Criminal Justice over the course of 20 years who were followed at the University of Texas Medical Branch in Galveston, Texas was identified. There were 1807 inmates who were diagnosed with cancer. Two cohorts were chosen for comparison: a random sample of 179,757 patients from the Surveillance, Epidemiology, and End Results (SEER) registry, and an age-matched, gender-matched, race-matched SEER population comprised of 6124 patients (MSEER). Disease sites and associated mortality of the inmate cancer patients were determined and compared with SEER cohorts. A marked rise in cancer diagnoses among inmates paralleled the rise in the inmate population. The leading cancers were lung carcinoma, non-Hodgkin lymphoma (NHL), and carcinomas of the oral cavity and pharynx. Among women, cervical carcinoma was the most common. Lung carcinoma, NHL, and hepatic carcinoma accounted for more cancer deaths among inmates than in the SEER cohort (P < 0.0001 for all comparisons). Lung carcinoma, hepatic carcinoma, and NHL were significantly more common in the inmate cohort than in the MSEER cohort (P < 0.001 for all comparisons). The median survival was inferior in the inmate cohort (21 mos) compared with the SEER cohort (55 mos) and the MSEER cohort (54 mos) (P < 0.0001 for both comparisons). Cancers with unique epidemiology and high associated mortality have emerged among the incarcerated. This has significant implications for prison health systems.


The prevalence and factors associated with obesity and hypertension in university academic staff: a cross-sectional study in Bangladesh.
Obesity is a major risk factor for hypertension, type 2 diabetes and other morbidities. On the other hand, hypertension is a leading cause of cardiovascular disease. The presence of obesity in hypertensive persons increases cardiovascular risk and related mortality. Data on the prevalence of obesity and hypertension in academic staff in Bangladesh are scarce. This study aimed to determine the prevalence and factors associated with obesity and hypertension among university academic staff in Bangladesh. In total, 352 academic staff were enrolled in this study from two universities in Bangladesh. A pre-structured questionnaire was used to obtain data on anthropometric, demographic and lifestyle-related factors. Bivariate and multivariate logistic regression analyses were performed to assess the factors associated with obesity and hypertension. Overall, the prevalence of general and abdominal obesity and hypertension was 26.7%, 46.9% and 33.7%, respectively. Female staff had a significantly higher prevalence of both general and abdominal obesity (41% and 64.1%, respectively) than male staff (21.5% and 34.9%, respectively) (p < 0.001). In contrast, male staff had a higher prevalence of hypertension (36.9%) than female staff (25.6%)(p < 0.001). An increased prevalence of hypertension was found in the higher BMI and WC groups of the participants. The prevalence of general obesity, abdominal obesity and hypertension was higher in the 30-40 years, > 50 years and 41-50 years age groups, respectively. According to the regression analysis, female gender and inadequate physical activity were independently associated with general and abdominal obesity. On the other hand, increased age, BMI, WC, presence of diabetes and smoking showed a significant association with hypertension. In conclusion, the prevalence of obesity and hypertension was higher among university academic staff members in Bangladesh. Our findings suggest that comprehensive screening programs are needed to facilitate the diagnosis, control, and prevention of obesity and hypertension in high-risk population groups.


Integration of modern data in W.H.O. categorisation of lymphosarcomas. Its value for prognosis prediction and therapeutic adaptation to prognosis.
The categorisation of lymphosarcomas with immune markers has enriched the prognostic value of W.H.O. classification. The prolymphocytic (centrofollicular B type and the null lymphoblastic subtype have a good prognosis while the (T or B) immunoblastic type and the T-lymphoblastic subtype have a poor prognosis.


Assessment of foetal risk associated with 93 non-US-FDA approved medications during pregnancy.
Health care practitioners utilize the United States-Food and Drug Administration (US-FDA) pregnancy categorization (A, B, C, D, X) for making decision on the appropriateness of certain medications during pregnancy. Many non US-FDA approved medications are registered and marketed in Saudi Arabia. However, these medications do not have an assigned pregnancy risk categorization like those approved in the US. The objective of this review is to evaluate, report, and categorize the foetal risk associated with non-US-FDA approved medications registered by the Saudi Food and Drug Authority (S-FDA) according to the US-FDA pregnancy risk categorization system. We identified 109 non-US-FDA approved medications in the Saudi National Formulary (SNF) as of October 2007. We searched for data on functional or anatomical birth defects or embryocidal-associated risk using different databases and references. An algorithm for risk assessment was used to determine a pregnancy risk category for each medication. Out of 93 eligible medications, 73% were assigned category risk C, 10 medications (11%) were assigned category risk D, and 12 medications (13%) were assigned category risk B. Only three medications were judged to be safe during pregnancy based on the available evidence and were assigned category risk A. Inconsistencies in defining and reporting the foetal risk category among different drug regulatory authorities could create confusion and affect prescribing. We believe that standardization and inclusion of this information in the medication package insert is extremely important to all health care practitioners.


Does previous history of cancer or atypia predict histologic upgrade for pure intraductal papillomas diagnosed via core biopsy? A study of 490 cases at a single institution.
Management of pure intraductal papillomas (IDP) without atypia diagnosed on core needle biopsy (CNB) remains controversial given highly variable rates of upgrade in the literature. We sought to identify clinical and histologic factors that predict upgrade to atypia or malignancy in a large population. A retrospective review was performed of all cases of pure IDP diagnosed on CNB and then surgically excised at a single institution from 2008 to 2018. Clinical, radiologic, and pathologic factors were compared in the no upgrade, upgrade to atypia, or upgrade to cancer groups. Univariate analysis was performed comparing no upgrade and upgrade to cancer or atypia. Four hundred and thirty nine patients were identified with a total of 490 IDP and a median age of 50 years (range 16-85). Of these patients, 54 (12.3%) were upgraded to atypia after surgical excision and five (1.1%) were upgraded to cancer. The presence of multiple papillomas in a single patient was a significant predictor of upgrade to cancer or atypia (p < .01), as well as age over ≥55 years (p < .01) and a prior history of cancer (p < .01). No other clinical, radiologic and histologic factors were found to be significant predictors of upgrade. 40/439 (9.1%) patients in the total cohort had prior history of cancer, and of these, 2/40 (5%) were found to have a new cancer after excision. In patients with pure IDP on CNB, the upgrade rate to malignancy was 1.1%, while 12.3% were upgraded to atypia. The clinical significance of identifying atypia in a papilloma is unknown, especially in a patient with a prior history of atypia or cancer. However, the majority of patients who were upgraded to either atypia or cancer had no prior history of high-risk or malignant breast disease and are therefore considered true clinical upgrades. As such excision for IDP should be considered.


Polypeptide from Moschus Suppresses Lipopolysaccharide-Induced Inflammation by Inhibiting NF-κ B-ROS/NLRP3 Pathway.
To examine the anti-inflammatory effects and potential mechanisms of polypeptide from Moschus (PPM) in lipopolysaccharide (LPS)-induced THP-1 macrophages and BALB/c mice. The polypeptide was extracted from Moschus and analyzed by high-performance liquid chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Subsequently, LPS was used to induce inflammation in THP-1 macrophages and BALB/c mice. In LPS-treated or untreated THP-1 macrophages, cell viability was observed by cell counting kit 8 and lactate dehydrogenase release assays; the proinflammatory cytokines and reactive oxygen species (ROS) were measured by enzyme-linked immunosorbent assay and flow cytometry, respectively; and protein and mRNA levels were measured by Western blot and real-time quantitative polymerase chain reaction (qRT-PCR), respectively. In LPS-induced BALB/c mice, the proinflammatory cytokines were measured, and lung histology and cytokines were observed by hematoxylin and eosin (HE) and immunohistochemical (IHC) staining, respectively. The SDS-PAGE results suggested that the molecular weight of purified PPM was in the range of 10-26 kD. In vitro, PPM reduced the production of interleukin 1β (IL-1β), IL-18, tumor necrosis factor α (TNF-α), IL-6 and ROS in LPS-induced THP-1 macrophages (P<0.01). Western blot analysis demonstrated that PPM inhibited LPS-induced nuclear factor κB (NF-κB) pathway and thioredoxin interacting protein (TXNIP)/nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome pathway by reducing protein expression of phospho-NF-κB p65, phospho-inhibitors of NF-κB (Iκ Bs) kinase α/β (IKKα/β), TXNIP, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1 (P<0.05 or P<0.01). In addition, qRT-PCR revealed the inhibitory effects of PPM on the mRNA levels of TXNIP, NLRP3, ASC, and caspase-1 (P<0.05 or P<0.01). Furthermore, in LPS-induced BALB/c mice, PPM reduced TNF-α and IL-6 levels in serum (P<0.05 or P<0.01), decreased IL-1β and IL-18 levels in the lungs (P<0.01) and alleviated pathological injury to the lungs. PPM could attenuate LPS-induced inflammation by inhibiting the NF-κB-ROS/NLRP3 pathway, and may be a novel potential candidate drug for treating inflammation and inflammation-related diseases.


Inactivation of biologically active DNA by gamma-ray-induced superoxide radicals and their dismutation products singlet molecular oxygen and hydrogen peroxide.
Since superoxide radicals are involved in many metabolically important as well as in some other, detrimental cellular processes, the reactivity of gamma-ray-induced superoxide radicals and its dismutation products singlet molecular oxygen and hydrogen peroxide with DNA have been studied. Superoxide dismutase which removes superoxide radicals and inhibits the formation of singlet oxygen in the solution protects the biologically active replicative form of DNA (from bacteriophage theta X174) against inactivation by ionizing radiation. Catalase which removes hydrogen peroxide also protects the DNA. Attempts with various chemical sources of singlet oxygen to determine whether this species inactivates DNA did not give an unequivocal answer. It is concluded from the presented experiments that a combination of the protonated form of the superoxide radical (HO-2) and H2O2 do inactivate DNA.


Total Abdominal Wall Reconstruction with Component Separation, Reinforcement, and Vertical Abdominoplasty in Patients with Complex Ventral Hernias.
Large complex ventral hernias act as tissue expanders for skin and subcutaneous fat. The purpose of this study is to evaluate outcomes of total abdominal wall reconstruction with component separation, posterior reinforcement, and vertical abdominoplasty in patients with large complex ventral hernias. Between 2010 and 2014, 58 patients underwent total abdominal wall reconstruction with component separation, intra-abdominal reinforcement, and vertical abdominoplasty. Between 2010 and 2012, patients underwent the conventional technique of component separation, while a perforator-preserving technique was performed during 2013 and 2014. Reinforcement material used was either synthetic mesh in clean cases or biologic mesh if contamination was present. All of the excessive skin and subcutaneous fat was removed in a vertical fashion. Data were analyzed with Mann-Whitney's U test or Fisher's exact test, as indicated. There were 27 moderately complex and 31 majorly complex hernias. Mean hernia size was 16 × 12 cm. The mean size of the removed skin island was 21 × 12 cm. Patients with contamination during the repair had longer in-hospital stays. Overall the local wound complication rate was 24 %, and was lower with the perforator-preserving technique compared to the conventional technique of component separation (11 vs. 48 %; OR 0.13, CI 0.03-0.5; p = 0.003). The overall postoperative morbidity rate was higher in the presence of contamination, and in patients with lower preoperative serum albumin levels. Mean total follow-up was 14 months with a 1-year recurrence-free survival of 96 %. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Pharmacodynamic modeling of digoxin-induced bradycardia.
Digoxin-induced bradycardia in dogs was used to evaluate several pharmacodynamic models. Digoxin plasma concentrations and response were monitored in beagle dogs administered either 0.05 or 0.025 mg/kg of digoxin iv as an infusion over 5 min. The models investigated were the linking model, the linear model, the effect compartment model, and the inhibitory model. Regression procedures for investigating the effect compartment model were conducted with Emax (the maximal response, where response was the percentage decrease in heart rate) as a variable with an upper bound of 100%, with a constant value of 100%, or alternately with a constant value equal to the maximal observed response. Based on statistical criteria the effect model using Emax as a variable was found to be the best model for describing digoxin-induced bradycardia. For the effect compartment model, CPss(50) (concentration at steady state that will produce 50% of the maximal response) ranged from 3.8-9.8 ng/ml; delta (exponent describing the steepness of the concentration-response relationship) ranged from 0.6-7.1. The implication of these models in understanding concentration-effect relationships are discussed.


Improving the risk-to-benefit ratio of inhaled corticosteroids through delivery and dose: current progress and future directions.
Inhaled corticosteroids (ICS) are known to increase the risk of systemic and local adverse effects, especially with high doses and long-term use. Hence, considerable resources are invested to improve pharmacokinetic/pharmacodynamic (PK/PD) properties of ICS, effective delivery systems and novel combination therapies to enhance the risk-to-benefit ratio of ICS. There is an unmet need for new solutions to achieve optimal clinical outcomes with minimal dose of ICS. This paper gives an overview of novel treatment strategies regarding the safety of ICS therapy on the basis of the three most recent molecules introduced to our everyday clinical practice - ciclesonide, mometasone furoate, and fluticasone furoate. Advances in aerosol devices and new areas of inhalation therapy are also discussed. Current progress in improving the risk-to-benefit ratio of ICS through dose and delivery probably established pathways for further developments. This applies both to the improvement of the PK/PD properties of ICS molecules but also includes technical aspects that lead to simplified applicability of the device with simultaneous optimal drug deposition in the lungs. Indubitably, the future of medicine lies not only in the development of new molecules but also in technology and digital revolution.