Association of Patient, Physician, and Practice-Level Factors with Uptake of Payer-Led Oncology Clinical Pathways.
Payers use oncology clinical pathways programs to increase evidence-based drug prescribing and control drug spending. However, compliance with these programs has been low, which may decrease their efficacy, and factors associated with pathway compliance are unknown. To determine extent of pathway compliance and identify factors associated with pathway compliance using characteristics of patients, practices, and the companies that develop cancer treatment pathways. This cohort study comprised patients with claims and administrative data from a national insurer and a pathways health care professional between July 1, 2018, and October 31, 2021. Adult patients with metastatic breast, lung, colorectal, pancreatic, melanoma, kidney, bladder, gastric, and uterine cancer being treated in the first line were included. Six months of continuous insurance coverage prior to the date of treatment initiation was required for determination of baseline characteristics. Stepwise logistic regression was used to identify factors associated with pathway compliance. Use of a pathway program-endorsed treatment regimen in the first-line setting for metastatic cancer. Among 17 293 patients (mean [SD] age, 60.7 [11.2] years; 9183 [53.1%] women; mean [SD] Black patients per census block, 0.10 [0.20]), 11 071 patients (64.0%) were on-pathway, and 6222 (36.0%) were off-pathway. Factors associated with increased pathway compliance were higher health care utilization during the 6-month baseline period (measured in inpatient visits and emergency department visits) (5220 on-pathway inpatient visits [47.2%] vs 2797 off-pathway [45.0%]; emergency department visits, 3304 [27.1%] vs 1503 [24.2%]; adjusted odds ratio [aOR] for inpatient visits, 1.32; 95% CI, 1.22-1.43; P < .001), volume of patients with this insurance provider per physician (mean [SD] visits: on-pathway, 128.0 [258.3] vs off-pathway, 121.8 [161.4]; aOR, 1.12; 95% CI, 1.04-1.20; P = .002), and practice participation in the Oncology Care Model (on-pathway participation, 2601 [23.5%] vs 1305 [21.0%]; aOR, 1.13; 95% CI, 1.04-1.23; P = .004). Higher total medical cost during the 6-month baseline period were associated with decreased pathway compliance (mean [SD] costs: on-pathway, $55 990 [$69 706] vs $65 955 [$74 678]; aOR, 0.86; 95% CI, 0.83-0.88; P < .001). There was heterogeneity in odds of pathway compliance between different malignancies. Pathway compliance rates trended down from the reference year of 2018. In this cohort study, despite generous financial incentives, compliance with payer-led pathways remained at historically reported low rates. Factors such as increasing exposure to the program due to the number of patients impacted and participation in other value-based payment programs, such as the Oncology Care Model, were positively associated with compliance; factors such as the type of cancer and patient complexity may have played a role, but the directionality of potential effects was unclear.


Osmotic parameters of red blood cells from umbilical cord blood.
The transfusion of red blood cells from umbilical cord blood (cord RBCs) is gathering significant interest for the treatment of fetal and neonatal anemia, due to its high content of fetal hemoglobin as well as numerous other potential benefits to fetuses and neonates. However, in order to establish a stable supply of cord RBCs for clinical use, a cryopreservation method must be developed. This, in turn, requires knowledge of the osmotic parameters of cord RBCs. Thus, the objective of this study was to characterize the osmotic parameters of cord RBCs: osmotically inactive fraction (b), hydraulic conductivity (Lp), permeability to cryoprotectant glycerol (Pglycerol), and corresponding Arrhenius activation energies (Ea). For Lp and Pglycerol determination, RBCs were analyzed using a stopped-flow system to monitor osmotically-induced RBC volume changes via intrinsic RBC hemoglobin fluorescence. Lp and Pglycerol were characterized at 4°C, 20°C, and 35°C using Jacobs and Stewart equations with the Ea calculated from the Arrhenius plot. Results indicate that cord RBCs have a larger osmotically inactive fraction compared to adult RBCs. Hydraulic conductivity and osmotic permeability to glycerol of cord RBCs differed compared to those of adult RBCs with the differences dependent on experimental conditions, such as temperature and osmolality. Compared to adult RBCs, cord RBCs had a higher Ea for Lp and a lower Ea for Pglycerol. This information regarding osmotic parameters will be used in future work to develop a protocol for cryopreserving cord RBCs.


Spontaneous Chest Wall Herniation in Centrally Obese Patients: A Single-Center Experience of a Rare Problem.
Spontaneous rib fractures, especially in association with chest wall herniation, represent an uncommon pathology. As such, there are little data analyzing approaches to treatment or regarding the success of intervention. The goal of this study was to analyze our cumulative experience with this unusual condition. A case series of 12 patients was gathered from a single institution based on outpatient visits between February 2015 and October 2018. Each chart was retrospectively reviewed with particular attention to age, gender, BMI, area of injury, and smoking history. Patients presented with complaints of dyspnea or pain related to rib fractures with or without intercostal neuralgia. Each of these patients was noted to have rib fractures with lung herniation either on imaging, outside hospital records, or physical exam. A thorough medical history was obtained with attempts to find common predisposing factors as well as data regarding any previous surgical intervention for their herniation. Nine of the 12 patients reviewed had recent or prior surgical intervention. Every patient seen in the clinic with a spontaneous fracture and herniation incidentally had a BMI >30 and was therefore classified as obese. Additionally, every patient who had a recurrence after their first surgical attempt at repair had a BMI greater than or equal to 35. All 12 patients seen at our institution were males. The failure rate of operative intervention was 66%. Obesity was a prevalent comorbidity in the patient population we reviewed. Given the role obesity plays in abdominal and hiatal hernia repair success rates, it should be considered that obesity is a significant contributor to chest wall herniation if rib fractures occur. With 66% chest wall repair failure, patient selection is critical in the success of surgical intervention. Perhaps additional patient optimization, especially weight loss, should be considered prior to surgery.


The application of polyethylene glycol to radioimmunoassays used in haemostasis.
Use of polyethylene glycol 6000 in the second stages of double antibody radioimmunoassays for fibrinopeptide A, B-thromboglobulin and platelet factor 4 facilitates the more rapid separation of free from bound antigen, and allows precipitating antiserum to be used in greater dilution. At a final PEG 6000 concentration of 5%, separation of free from bound antigen was complete within 1 hour, and antisera could be used in dilutions 3-9 times greater than those recommended by the manufacturers. PEG 6000 had a negligible effect on the affinity of first stage antibodies for their respective antigens. Radioimmunoassays using PEG 6000 were sensitive to protein concentration, failure to adjust standards to similar protein concentrations as those of test samples causing artefactually low results.


Effect of treatment interruption monitored by CD4 cell count on mitochondrial DNA content in HIV-infected patients: a prospective study.
HIV infection per se and HAART can alter mitochondrial functionality, leading to a decrease in mitochondrial DNA content. To evaluate whether treatment interruption monitored by CD4 cell count can restore mitochondrial DNA content in peripheral blood lymphocytes. Mitochondrial DNA content was measured in platelet-free CD4 and CD8 T cells by real-time polymerase chain reaction; flow cytometry was used to identify and quantify activated CD4 and CD8 T lymphocytes. The 30 patients had been treated for a mean of 107 months (range, 27-197). Median CD4 cell count at discontinuation was 702 cells/microl (range, 547-798). Median observational time from HAART discontinuation was 11.3 months (range, 4-26). Discontinuation of treatment provoked significant increases in mitochondrial DNA in CD8 T cells, which started only 6 months after therapy discontinuation [5.12 copies/cell per month from 0 to 6 months (P = 0.37) and 26.96 copies/cell per month from 6 to 12 months (P < 0.0001)]. This study is the first showing that mitochondrial DNA content can increase in peripheral blood lymphocytes during treatment interruption, but only after at least 6 months of interruption. Consequently, interruptions of shorter periods, whether by clinician or patient decision, are unlikely to allow restoration of mitochondrial DNA and so decrease HAART-related toxicity.


Voltage-dependent modulation of calcium current by GTP gamma S and dopamine in cultured frog pituitary melanotrophs.
Dopamine (1 microM) reversibly scaled down barium current through high-voltage activated (HVA) calcium channels but had little effect on the time course of current activation in cultured frog melanotrophs. Intracellular perfusion with guanosine-5'-O-(3-thiotriphosphate) (GTP gamma S; 100 microM) sustained the effect of dopamine. Moreover, GTP gamma S drastically slowed down the current activation kinetics. The latter effect was in part reversed by dopamine. A conditioning prepulse to +70 mV facilitated the current in GTP gamma S-dialyzed cells but not in cells exposed to dopamine. These results suggest the existence of a dual G protein-mediated mechanism for reducing HVA calcium current.


Zero fluoroscopy ablation for atrioventricular nodal reentrant tachycardia and typical atrial flutter is equally safe and effective with EnSite NavX, Carto3, and Rhythmia mapping systems.
Our purpose was to compare the procedural characteristics, success rate, and complication rate of the conventional fluoroscopic (CF) and the zero-fluoroscopic (ZF) approach in patients undergoing catheter ablation of AVNRT or typical atrial flutter (Aflu). 186 consecutive patients with an indication for AVNRT or Aflu ablation were enrolled. Based on the operator's preference, the patients were assigned to either CF or ZF group. In the ZF group EnSite NavX, Carto3, or Rhythmia EAMS were used for catheter guidance. The median age was 56 (IQR = 42-68) years, 144 patients had AVNRT, and 42 had Aflu ablation. CF approach was chosen in 123 cases, while ZF in 63 cases. ZF approach was used more often in case of AVNRT patients [56 (39%) vs. 7 (17%), p = 0.006] and in the case of female patients [43 (68%) vs. 20 (32%), p = 0.008]. Acute procedural success was obtained in all cases. There was no difference in the complication rate (1 vs. 1, p > 0.99) between the two groups. No difference was found regarding the procedure time between the CF and ZF groups [CF: 55 (46-60) min, ZF 60 (47-65) min; p = 0.487] or in the procedure time for the different EAMS [EnSite NavX: 58 (50-63) min, Carto3: 60 (44.5-66.3) min, Rhythmia: 55 (35-69) min; p = 0.887]. A similar success rate was seen at the 3-month follow-up in the two groups [41 (100%) vs. 96 (97%); p = 0.55]. The ZF approach demonstrated non-inferiority in safety and efficacy compared with CF for the AVNRT and Aflu ablations.


Lipid domain formation and membrane shaping by C24-ceramide.
Ceramides are an important group of sphingolipids that modulate several cellular events. The mechanisms underlying biological actions of ceramides are not fully known, but evidence suggests that ceramides can act through regulation of the biophysical properties of the membrane. However, ceramide-induced changes on membrane properties are complex and depend on several factors. To gain further insight into this subject, we characterized the biophysical impact of very-long acyl chain C24-ceramide in a fluid model membrane under thermodynamic equilibrium and non-equilibrium conditions. Our results show that C24-ceramide readily forms two types of gel domains with distinct properties, likely corresponding to different interdigitated metastable gel phases. Upon reaching thermodynamic equilibrium, only partially interdigitated gel phase coexists with the fluid phase. In addition, C24-ceramide promotes strong changes in the shape of the vesicles, including domains with sharp edges and tubule-like structures. The results suggest that the formation of very long acyl chain ceramides in response to stress stimuli will initially induce a multitude of changes in the organization and fluidity of biological membranes that might be responsible for the activation of different cellular processes.


Differential immune response of mallard duck peripheral blood mononuclear cells to two highly pathogenic avian influenza H5N1 viruses with distinct pathogenicity in mallard ducks.
CK10 and GS10 are two H5N1 highly pathogenic influenza viruses of similar genetic background but differ in their pathogenicity in mallard ducks. CK10 is highly pathogenic whereas GS10 is low pathogenic. In this study, strong inflammatory response in terms of the expression level of several cytokines was observed in mallard duck peripheral blood mononuclear cells (PBMC) infected with CK10 while mild response was triggered in those by GS10 infection. Two remarkable and intense peaks of immune response were induced by CK10 infection within 24 hours (at 8 and 24 hours post infection, respectively) without reducing the virus replication. Our observations indicated that sustained and intense innate immune responses may be central to the high pathogenicity caused by CK10 in ducks.


Structure of WNT inhibitor adenomatosis polyposis coli down-regulated 1 (APCDD1), a cell-surface lipid-binding protein.
Diverse extracellular proteins negatively regulate WNT signaling. One such regulator is adenomatosis polyposis coli down-regulated 1 (APCDD1), a conserved single-span transmembrane protein. In response to WNT signaling in a variety of tissues, APCDD1 transcripts are highly up-regulated. We have determined the three-dimensional structure of the extracellular domain of APCDD1, and this structure reveals an unusual architecture consisting of two closely apposed β-barrel domains (ABD1 and ABD2). ABD2, but not ABD1, has a large hydrophobic pocket that accommodates a bound lipid. The APCDD1 ECD can also bind to WNT7A, presumably via its covalently bound palmitoleate, a modification that is common to all WNTs and is essential for signaling. This work suggests that APCDD1 functions as a negative feedback regulator by titrating WNT ligands at the surface of responding cells.


Characterization of integrated prophages within diverse species of clinical nontuberculous mycobacteria.
Nontuberculous mycobacterial (NTM) infections are increasing in prevalence, with current estimates suggesting that over 100,000 people in the United States are affected each year. It is unclear how certain species of mycobacteria transition from environmental bacteria to clinical pathogens, or what genetic elements influence the differences in virulence among strains of the same species. A potential mechanism of genetic evolution and diversity within mycobacteria is the presence of integrated viruses called prophages in the host genome. Prophages may act as carriers of bacterial genes, with the potential of altering bacterial fitness through horizontal gene transfer. In this study, we quantify the frequency and composition of prophages within mycobacteria isolated from clinical samples and compare them against the composition of PhagesDB, an environmental mycobacteriophage database. Prophages were predicted by agreement between two discovery tools, VirSorter and Phaster, and the frequencies of integrated prophages were compared by growth rate. Prophages were assigned to PhagesDB lettered clusters. Bacterial virulence gene frequency was calculated using a combination of the Virulence Factor Database (VFDB) and the Pathosystems Resource Integration Center virulence database (Patric-VF) within the gene annotation software Prokka. CRISPR elements were discovered using CRT. ARAGORN was used to quantify tRNAs. Rapidly growing mycobacteria (RGM) were more likely to contain prophage than slowly growing mycobacteria (SGM). CRISPR elements were not associated with prophage abundance in mycobacteria. The abundance of tRNAs was enriched in SGM compared to RGM. We compared the abundance of bacterial virulence genes within prophage genomes from clinical isolates to mycobacteriophages from PhagesDB. Our data suggests that prophages from clinical mycobacteria are enriched for bacterial virulence genes relative to environmental mycobacteriophage from PhagesDB. Prophages are present in clinical NTM isolates. Prophages are more likely to be present in RGM compared to SGM genomes. The mechanism and selective advantage of this enrichment by growth rate remain unclear. In addition, the frequency of bacterial virulence genes in prophages from clinical NTM is enriched relative to the PhagesDB environmental proxy. This suggests prophages may act as a reservoir of genetic elements bacteria could use to thrive within a clinical environment.


Convection-enhanced delivery of therapeutic agents into the brain.
CED of therapeutic agents remains a promising strategy for treating malignant gliomas and non-neoplastic neurological diseases. Although initial clinical trials have failed to show survival benefit for new agents delivered via this approach, multiple earlier stage trials have addressed only a fraction of the myriad of technical and technological issues that surround this novel approach. Development of CED has been limited by the fact that both new technologies and novel therapeutic agents are being developed simultaneously.New trials are being planned to investigate agents that can be coinfused with radiographic tracers, as well as novel catheters that avoid problems with backflow and potentially will provide more reliable drug distribution.


Reactivity of Cyclic (Alkyl)(amino)germylene towards Copper(I) and Gold(I) Complexes.
The reactions of cyclic (alkyl)(amino)germylenes (CAAGe) with copper(I) and gold(I) complexes were investigated. CAAGe (1) reacts with CuBr(SMe2 ) leading to a tetrameric germylene complex [CAAGeCuBr]4 (2), whereas CAAGe (3) undergoes Au-Cl bond insertion with LAuCl (L=phosphine or N-heterocyclic carbene) to afford germanium gold(I) complexes (5 and 6). Chlorine abstraction of 6 gives the cationic germylene gold(I) complex 7.


Spirostanol saponins from Tacca vietnamensis and their anti-inflammatory activity.
Using various chromatographic methods, five new steroidal saponins named taccavietnamosides A-E (1-5) and three known, (24S,25R)-spirost-5-en-3β,24-diol 3-O-α-l-rhamnopyranosyl-(1→2)-[α-l-rhamnopyranosyl-(1→3)]-β-d-glucopyranoside (6), (24S,25R)-spirost-5-en-3β,24-diol 3-O-α-l-rhamnopyranosyl-(1→2)-[β-d-glucopyranosyl-(1→4)-α-l-rhamnopyranosyl-(1→3)]-β-d-glucopyranoside (7), and chantrieroside A (8) were isolated from the rhizomes of Tacca vietnamensis Thin et Hoat. Their chemical structures were elucidated by physical and chemical methods. All compounds were evaluated for the inhibitory activities of nitric oxide production in LPS-stimulated RAW 264.7 macrophages and BV2 cells. As the results, compounds 3-5 showed moderate inhibition on NO production in LPS-stimulated BV2 cells and RAW 264.7 macrophages with the IC50 values ranging from 37.0 to 60.7μM.


Preoperative predictors of vascular invasion in hepatocellular carcinoma.
Vascular invasion is an established adverse prognostic factor in hepatocellular carcinoma (HCC). The aim of the current study was to identify the preoperative predictors of vascular invasion in patients undergoing partial hepatectomy for HCC. A retrospective analysis of 227 consecutive patients who underwent partial hepatectomy for HCC was conducted. Vascular invasion was defined as gross or microscopic involvement of the vessels (portal vein or hepatic vein) within the peritumoral liver tissue. Seventy-six (33%) patients had vascular invasion. Among the preoperative factors, only the tumour size (relative risk, 16.78; p<0.01) and the serum alpha-fetoprotein (AFP) level (relative risk, 3.57; p<0.01) independently predicted vascular invasion. As the tumour size increased, the incidence of vascular invasion increased: < or =2 cm, 3%; 2.1-3 cm, 20%; 3.1-5 cm, 38%; and > 5 cm, 65%. The incidence of vascular invasion was 32% in patients with serum AFP levels < or =1000 ng/mL, compared to 61% in patients with higher serum AFP levels (p<0.01). Patients with both tumours >5 cm and serum AFP levels >1000 ng/mL had an 82% incidence of vascular invasion. The tumour size and serum AFP level, alone or in combination, are useful in predicting the presence or absence of vascular invasion before hepatectomy for HCC.


Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial.
Cytomegalovirus is a common congenital infection, with high morbidity after an early primary maternal infection. No effective means exist to prevent viral transmission to the fetus. We aimed to investigate whether valaciclovir can prevent vertical transmission of cytomegalovirus to the fetus in pregnant women with a primary infection acquired early in pregnancy. This prospective, randomised, double-blind, placebo-controlled trial was done at the Infectious Feto-Maternal Clinic of Rabin Medical Center (Petach Tikvah, Israel). Pregnant women aged 18 years or older, with serological evidence of a primary cytomegalovirus infection acquired either periconceptionally or during the first trimester of pregnancy, were randomly assigned to oral valaciclovir (8 g per day, twice daily) or placebo from enrolment until amniocentesis at 21 or 22 gestational weeks. Randomisation was done separately for participants infected periconceptionally or during the first trimester and was done in blocks of four. Patients and researchers were masked to participant allocation throughout the entire study period. The primary endpoint was the rate of vertical transmission of cytomegalovirus. Statistical analyses were done according to per-protocol principles. The study was registered at ClinicalTrials.gov, NCT02351102. Between Nov 15, 2015, and Oct 8, 2018, we enrolled and randomly assigned 100 patients to receive valaciclovir or placebo. Ten patients were excluded, five from each study group; therefore, the final analysis included 45 patients (all singletons) in the valaciclovir group and 45 patients (43 singletons and two sets of twins) in the placebo group. In the valaciclovir group, including both first trimester and periconceptional infections, five (11%) of 45 amniocenteses were positive for cytomegalovirus, compared with 14 (30%) of 47 amniocenteses in the placebo group (p=0·027; odds ratio 0·29, 95% CI 0·09-0·90 for vertical cytomegalovirus transmission). Among participants with a primary cytomegalovirus infection during the first trimester, a positive amniocentesis for cytomegalovirus was significantly less likely in the valaciclovir group (two [11%] of 19 amniocenteses) compared with the placebo group (11 [48%] of 23 amniocenteses; p=0·020. No clinically significant adverse events were reported. Valaciclovir is effective in reducing the rate of fetal cytomegalovirus infection after maternal primary infection acquired early in pregnancy. Early treatment of pregnant women with primary infection might prevent termination of pregnancies or delivery of infants with congenital cytomegalovirus. None.


The acetyltransferase BmCBP changes the acetylation modification of BmSP3 and affects its protein expression in silkworm, Bombyx mori.
Protein acetylation is an important post-translational modification (PTM) that widely exists in organisms. As a reversible PTM, acetylation modification can regulate the function of proteins with high efficiency. In the previous study, the acetylation sites of silkworm proteins were identified on a large scale by nano-HPLC/MS/MS (nanoscale high performance liquid chromatography-tandem secondary mass spectrometry), and a total of 11 acetylation sites were discovered on Bombyx mori nutrient-storage protein SP3 (BmSP3). The purpose of this study was to investigate the effect of acetylation level on BmSP3. In this study, the acetylation of BmSP3 was further verified by immunoprecipitation (IP) and Western blotting. Then, it was confirmed that acetylation could up-regulate the expression of BmSP3 by improving its protein stability in BmN cells. Co-IP and RNAi experiments showed acetyltransferase BmCBP could bind to BmSP3 and catalyze its acetylation modification, then regulate the expression of BmSP3. Furthermore, the knock-down of BmCBP could improve the ubiquitination level of BmSP3. Both acetylation and ubiquitination occur on the side chain of lysine residues, therefore, we speculated that the acetylation of BmSP3 catalyzed by BmCBP could competitively inhibit its ubiquitination modification and improve its protein stability by inhibiting ubiquitin-mediated proteasome degradation pathway, and thereby increase the expression and intracellular accumulation. BmCBP catalyzes the acetylation of BmSP3 and may improve the stability of BmSP3 by competitive ubiquitination. This conclusion provides a new functional basis for the extensive involvement of acetylation in the regulation of nutrient storage and utilization in silkworm, Bombyx mori.


Astrocytic and microglial nicotinic acetylcholine receptors: an overlooked issue in Alzheimer's disease.
It is increasingly recognized that astrocytes and microglia-associated dysfunction contribute to AD pathology. In addition, glial nicotinic acetylcholine receptors (nAChRs) play a role in AD-related phenomena, such as neuron survival, synaptic plasticity, and memory. From mechanistic point of view, the glial regulation of pro-inflammatory cytokines, as common contributors in AD, is modulated by nAChRs. Astrocytic and microglial nAChRs contribute to Aβ metabolism, including Aβ phagocytosis and degradation as well as Aβ-related oxidative stress and neurotoxicity. These receptors are also involved in neurotransmission and gliotransmission through indirect interaction with N-Methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptors as well as gamma-aminobutyric acid (GABA) and intracellular calcium regulation. In addition, glial nAChRs participate in trophic factors-induced neuroprotection. This review gathers the most recent advances along with the previous data on astrocytic and microglial nAChRs role in AD pathogenesis.


An internet survey of the characteristics and physical activity of community-dwelling Australian adults with acquired brain injury: Exploring interest in an internet-delivered self-management program focused on physical activity.
Individuals with acquired brain injury (ABI) are more likely to be physically inactive and experience barriers to accessing services to address inactivity. This study was designed to guide the development of an internet-delivered self-management program to increase physical activity after ABI. The aims of this study were to examine the current physical activity status of community-dwelling Australian adults with ABI, the barriers to physical activity they experience and to explore interest an internet-delivered self-management program aimed at increasing physical activity. An online survey of Australian adults with ABI was used to collect information about demographic characteristics; general health; emotional well-being; mobility and physical activity status, and satisfaction; barriers to physical activity; confidence in overcoming barriers, and; interest in an internet self-management program. Data were analyzed descriptively and correlational analyses examined relationships between variables. Data were analyzed from 59 respondents. Over half were not satisfied with their current physical activity status. The most frequently reported barriers were pain/discomfort, fatigue and fear, and confidence to overcome these barriers was very low. Interest in an internet-delivered self-management program was high (74%) and not related to the amount of physical activity, satisfaction with physical activity and mobility status or total number of barriers. Australian adults with ABI are not satisfied with their activity levels and experience barriers in maintaining their physical activity levels. Participants were interested in accessing an internet-delivered self-management program aimed at improving physical activity levels. Therefore such a program warrants development and evaluation.


Hotson's syndrome--the "all-or-nothing" rule.
Whenever a plaintiff has lost a chance of a better medical result, which might have been achieved by prompt diagnosis and correct treatment, he or she must recover 100% of the award of damages provided that the plaintiff can prove that he or she had a better than 50% chance of an improved result.


Results of combined resection-recession on a single rectus muscle for incomitant deviations-an alternative to the posterior fixation suture.
To compare outcomes of combined resection and recession on previously unoperated single horizontal or vertical rectus muscles in consecutive adult patients with acquired incomitant deviations minimal in primary gaze and maximal in an eccentric gaze position. The surgical goal was to decrease the incomitance by 50%, expand the field of binocular single vision, and relieve diplopia. Recessions for the maximal deviations were combined with smaller resections using hang-back, nonadjustable sutures. Pre- and postoperative incomitance was compared using the paired t test. A total of 16 adults were studied (mean age at surgery, 49.3 ± 17.5 years), 12 with incomitant vertical deviations and 4 with incomitant horizontal deviations. Eight patients had preoperative deviations of <2Δ in primary gaze (mean, 9.2Δ ± 10.5Δ; range, 1Δ-35Δ). The mean maximum eccentric gaze deviation was 21.4Δ ± 9.9Δ (range, 10Δ-48Δ). Postoperatively, 12 patients (75%) had a decrease in incomitance of >50%, and all had expansion of the field of binocular single vision. Improvement in postoperative incomitance was highly statistically significant in the vertical incomitant group (P < 0.0001) but not statistically significant in the horizontal group (P = 0.39). The technique corrected downgaze deviations in 4 patients with canine tooth syndrome (93% ± 3.3, P < 0.0001) without worsening the hypotropia in upgaze. Combined resection-recession single muscle surgery significantly reduces incomitance with minimal effect on primary gaze. It is most effective for treating vertical deviations worse on downgaze with primary gaze deviations of <2Δ and for canine tooth syndrome; the technique was less successful in reducing horizontal incomitance and in cases involving gaze palsies and nystagmus.


Murine graft-versus-host disease induced using interferon-gamma-deficient grafts features antibodies to double-stranded DNA, T helper 2-type cytokines and hypereosinophilia.
Acute, lethal graft-versus-host disease (GvHD) develops in B6D2F1 hybrid recipients of wild-type, C57BL/6, parental strain grafts; however, when interferon-gamma (IFN-gamma) gene knockout (gko) donors are used, the disease is prolonged and associated with a higher level of engraftment, particularly of T cells. Lesions containing large, mixed cellular infiltrates develop in the skin, liver, pancreas, salivary gland, lung and kidney. In our current study, we wished to determine whether GvHD features a preponderance of T helper 2 (Th2) cytokines in the absence of donor-derived IFN-gamma, and whether autoantibody production, commonly associated with chronic GvHD, also occurs. Because mitogen responsiveness is consistently suppressed in mice with acute GvHD, we wished to measure this response in recipients of IFN-gamma gko grafts. Our findings indicate that spleen cells from the latter produce interleukin (IL)-4, IL-5 and IL-13 in culture, but respond poorly to concanavalin A (Con A) and lipopolysaccharide (LPS). Their sera contain anti-nuclear antibodies (ANA), some of which are specific for double-stranded (ds)DNA and are predominantly immunoglobulin (Ig)M and IgG1. We also noted the presence of numerous eosinophils in the infiltrates developing within the target organs. In some respects, this syndrome bears resemblance to both systemic lupus erythematosus (SLE) and chronic GvHD. However, histological evidence of glomerulonephritis is lacking and proteinuria fails to develop in recipients of IFN-gamma gko grafts, suggesting that IFN-gamma may be necessary for the development of lupus nephritis. On a broader scope, our findings underscore the importance of IFN-gamma in the pathogenetic mechanism of GvHD, and demonstrate that the absence of this cytokine promotes the development of chronic GvHD and autoimmunity.


Trends and predictions to 2020 in breast cancer mortality in Europe.
We analyzed trends in mortality from breast cancer in women in 36 European countries and the European Union (EU) over the period 1970-2014, and predicted numbers of deaths and rates to 2020. We derived breast cancer death certification data and population figures from the World Health Organization and Eurostat databases. We obtained 2020 estimates using a joinpoint regression model. Overall, EU breast cancer mortality rates (world standard) declined from 17.9/100,000 in 2002 to 15.2 in 2012. The predicted 2020 rate is 13.4/100,000. The falls were largest in young women (20-49 years, -22% between 2002 and 2012). Within the EU, declines were larger in the United Kingdom (UK) and other northern and western European countries than in most central and eastern Europe. The UK has the second lowest predicted breast cancer mortality rate in 2020 (after Spain), starting from the highest one in 1970. Breast cancer mortality is predicted to rise in Poland, where the predicted 2020 rate is 15.3/100,000. We estimated that about 32,500 breast cancer deaths will be avoided in 2020 in the EU as compared to the peak rate of 1989, and a total of 475,000 breast cancer deaths over the period 1990-2020. The overall favourable breast cancer mortality trends are mainly due to a succession of improvements in the management and treatment of breast cancer, though early diagnosis and screening played a role, too. Improving breast cancer management in central and eastern Europe is a priority.


Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma.
CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC. The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed. Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P < .001), lymph node metastasis (pN factor; P = .001), pathologic stage (P < .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and <.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P < .001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS. Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.


Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts.
EML4-ALK is a fusion-type protein tyrosine kinase that is generated by inv(2)(p21p23) in the genome of non-small cell lung cancer (NSCLC). To allow sensitive detection of EML4-ALK fusion transcripts, we have now developed a multiplex reverse transcription-PCR (RT-PCR) system that captures all in-frame fusions between the two genes. Primers were designed to detect all possible in-frame fusions of EML4 to exon 20 of ALK, and a single-tube multiplex RT-PCR assay was done with total RNA from 656 solid tumors of the lung (n = 364) and 10 other organs. From consecutive lung adenocarcinoma cases (n = 253), we identified 11 specimens (4.35%) positive for fusion transcripts, 9 of which were positive for the previously identified variants 1, 2, and 3. The remaining two specimens harbored novel transcript isoforms in which exon 14 (variant 4) or exon 2 (variant 5) of EML4 was connected to exon 20 of ALK. No fusion transcripts were detected for other types of lung cancer (n = 111) or for tumors from 10 other organs (n = 292). Genomic rearrangements responsible for the fusion events in NSCLC cells were confirmed by genomic PCR analysis and fluorescence in situ hybridization. The novel isoforms of EML4-ALK manifested marked oncogenic activity, and they yielded a pattern of cytoplasmic staining with fine granular foci in immunohistochemical analysis of NSCLC specimens. These data reinforce the importance of accurate diagnosis of EML4-ALK-positive tumors for the optimization of treatment strategies.


Fracture dislocation of the trapezio-scaphoid joint--the missing link?
Fracture-dislocation of the trapezio-scaphoid joint is an extremely rare injury. We report a case treated using Herbert's compression screw technique.


Corpses against science death: new Italian law titled 'Rules relating to the directives of one's body and tissues post-mortem for study, training, and scientific research purposes'.
The new Italian Law no. 10 of 2020, titled 'Rules relating to the directives of one's body and tissues post-mortem for study, training, and scientific research purposes' (10 February, 2020), has opened the doors to a new and clearer regimentation on body donation to science, according to the procedure already introduced by Law no. 219/2017 on the 'Rules relating to informed consent and advance directives of treatment'. The authors exposed some concerning regarding the application of the law, such as donation mistrust, also linked to our cultural heritage; the incomplete protection of minor and incompetent people; the complexity of an adequate information, which could undermine the informed consent; and finally, the fees overload for research institutes, with already exiguous budgets. Next, the authors analysed some positive aspects of the law and in primis the central role of corpses in scientifical knowledge and medical training. Moreover, a simple mechanism based on a conscious and pre-stated consent, registered in a database that follows European data protection Regulation, is discussed. Further, the procedure of the restitution of the bodies to their families, which represents a way to guarantee the relatives' commemoration, is also elucidated. In conclusion, the authors proposed a format of informed consent, to try a direct application of the law, thereby fastening the process of standardisation and centralisation of all the living wills. The authors optimistically investigated the opportunities offered by the law and encouraged a conscientious participation by citizens.


Traumatic rosette cataract.
One of the clinical presentations of traumatic cataracts is a rosette-shaped posterior capsular opacity. The severity of vision loss, the patient's age, and the cornea, macula, and optic nerve states are major determinants of the therapeutic approach.


Anxiety and Depression Symptoms in At-Risk Pregnancy: Influence on Maternal-Fetal Attachment in Tunisia.
To investigate maternal prenatal anxiety and depression in high-risk pregnancies and examine their influence on maternal-fetal attachment. We included 95 hospitalized high-risk pregnant women. The Hospital Anxiety and Depression Scale (HADS) and the Prenatal Attachment Inventory (PAI) were used to assess the primary objective. Internal consistency and construct validity of the PAI were investigated. The average age was 31 years and gestational age ranged from 26 to 41 weeks. Prevalence of depressive symptoms was 20% and anxiety symptoms 39%. Cronbach alpha coefficient of the PAI Tunisian version was 0.8 and the construct validity in favour of one factor model. PAI scores correlated negatively and significatively with the HADS total score (r = - 0.218, p = 0.034) and was attributed to the depression dimension only (r = - 0.205, p = 0.046). Emotional wellbeing of pregnant women especially in high-risk pregnancies should be explored in order to prevent consequences on women, their growing fetus, and prenatal attachment.


A phase I study of SAR405838, a novel human double minute 2 (HDM2) antagonist, in patients with solid tumours.
In tumours with wild-type TP53, the tumour-suppressive function of p53 is frequently inhibited by HDM2. This phase I, dose-escalating study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and pharmacodynamics of SAR405838, an HDM2 inhibitor, in patients with advanced solid tumours (NCT01636479). In dose escalation, patients with any locally advanced/metastatic solid tumour with TP53 mutation prevalence below 40%, or documented as TP53 wild-type, were eligible. In the MTD expansion cohort, only patients with de-differentiated liposarcoma were included. Primary end-points were MTD and efficacy in the MTD expansion cohort. Secondary end-points included safety, pharmacokinetics and pharmacodynamics biomarkers. Seventy-four patients were treated with SAR405838 (50-800 mg once daily [QD], 800-1800 mg weekly and 1800 mg twice weekly). Two patients treated with SAR405838 400 mg QD had thrombocytopaenia as a dose-limiting toxicity (DLT). The MTD for the QD schedule of SAR405838 was 300 mg QD. No DLTs were observed with the weekly schedule; one patient had a DLT of nausea with the 1800 mg twice-weekly dose. Treatment with SAR405838 was associated with increased plasma MIC-1, reflecting p53 pathway activation. In the de-differentiated liposarcoma MTD cohort, 89% of the patients had HDM2 amplification at baseline and no TP53 mutations were observed; best response was stable disease in 56% and progression-free rate at 3 months was 32%. SAR405838 had an acceptable safety profile with limited activity in patients with advanced solid tumours. The MTD of SAR405838 was 300 mg QD; MTD was not reached with the weekly schedule.


The role of dopamine and noradrenaline in temperature control of normal and reserpine-pretreated mice.
Drugs with the common property of stimulating dopamine receptors, have been tested for their effects on core temperature in control and reserpine-pretreated mice. Apomorphine, amantadine, amphetamine, L-dopa and atropine all produced a fall in mouse oesophageal temperature, their efficacy correlating with their ability to activate central dopamine receptors. Amphetamine and L-dopa had a biphasic effect the initial fall being followed by a rise. In reserpine-pretreated mice only amphetamine, apomorphine, L-dopa and D.L-threo-dihydroxyphenyl-serine effectively reversed hypothermia. Amphetamine had the highest efficacy of all the drugs tested. The sum of the effects of apomorphine and D.L-threo-dihydroxyphenylserine was equivalent to the effect of amphetamine alone. It is suggested that in control mice dopaminergic mechanisms mediate the hypothermia and noradrenergic mechanisms the hyperthermia. In reserpine-pretreated mice both systems are involved in the mechanisms restoring body temperature to normal.


An endodermal sinus tumor diagnosed in pregnancy: case report and review of the literature.
The use of chemotherapeutic drugs in pregnancy is a rare occurrence. Experience and results need to be shared. At 23 weeks gestational age, a patient was diagnosed with an endodermal sinus tumor of the ovary. She received one course of postoperative bleomycin, cisplatin, and etoposide. One week later, the patient was investigated for increasing abdominal pain and the fetus was noted to have ventriculomegaly. The baby was delivered, and the patient was surgically staged and completed chemotherapy. Although the patient is alive and well 16 months after delivery, the infant has developed significant ventriculomegaly with cerebral atrophy. The etiology of this infant's significant cerebral atrophy is not clear. Tumor-specific, perioperative, or drug-related events must be considered.


An evaluation of the efficacy of injectable microencapsulated vitamin B12 in increasing and maintaining the serum and liver vitamin B12 concentrations of lambs.
To develop a long-acting Vitamin B12 injection to prevent Co deficiency in sheep. Formulations of microencapsulated Vitamin B12 in lactide-glycolide polymers were injected intramuscularly or subcutaneously into the anterior neck region of groups of 10 lambs and their efficacy determined from changes in serum and liver Vitamin B12 concentrations. The 95:5 lactide glycolide and the 100 lactide formulations containing more than 12.5% Vitamin B12 w/w significantly increased and maintained serum Vitamin B12 concentrations for at least 210 days as well as liver Vitamin B12 concentrations in treated lambs when compared with untreated controls. Injections of microencapsulated Vitamin B12 in lactide/glycolide copolymers are able to increase and maintain the Vitamin B12 status of lambs for at least 210 days. Another option for the prevention of Co deficiency in sheep is now available using a long acting injectable Vitamin B12.


Delayed Cutaneous Hypersensitivity Reactions to Antibiotics: Management with Desensitization.
Successful desensitization to mild to moderate delayed cutaneous adverse reaction to antibiotics has been described in a limited number of antibiotics and found to be safe. However, there are ample opportunities to standardize protocols for delayed cutaneous adverse reactions to antibiotics.


Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia.
Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.


Use of symptom-focused oncological cancer therapies in hospices: a retrospective analysis.
There is controversy regarding the practical implementation of symptom-focused oncological cancer therapies to hospice residents. In this study, we aim to analyse the use and indication of supportive-oncological cancer therapies in hospices. We conducted a retrospective survey of all residents of two hospice centres in the government district of Lower Bavaria, Germany. Hospice 1 (H1) was a member of an oncological-palliative medical network, and hospice 2 (H2) was independently organized. The evaluation period was the first 40 months after the opening of the respective hospice care centre. Demographical and epidemiological data as well as indications and type of supportive-oncological cancer therapies were recorded. A descriptive analysis and statistical tests were performed. Of the 706 residents, 645 had an underlying malignant disease. The average age was 72 years and the mean residence time was 28 days. The most frequent cancer types were gastrointestinal cancers, gynaecological cancers and bronchial carcinomas. Overall 39 residents (33 in H1 and 6 in H2, p < 0.01) received symptom-focused oncological cancer therapy. The average age of these residents was 68 years, and the mean residence time was 55 days. The most common therapeutic indications were dyspnoea and pain. The most common symptom-focused oncological cancer therapies were bisphosphonates, transfusions (erythrocyte- and platelet- concentrates), radiotherapy and anti-proliferative drugs (chemotherapy, anti-hormonal- and targeted- therapies). Patients with therapy lived significantly longer than patients without therapy (p < 0.01). Symptom-focused oncological cancer therapies can be implemented in hospices; however, their implementation seems to require certain structural and organizational prerequisites as well as careful patient selection. As a palliative medical approach, the focus is to ameliorate the symptoms and not prolong life. Symptom-focused oncology treatment could be a further and important part for the therapy of hospice patients in the future.


Action of some non-steroid anti-inflammatory drugs on skin anaphylaxis due to ovalbumin in the rat and the guinea pig.
Six non-steroidal anti-inflammatory drugs, metiazinic and niflumic acids, iburofen, indometacin, ketoprofen and phenylbutazone, were tested on two anaphylactic skin reactions to ovalbumin: the passive reaction in the rat and active anaphylaxis in the guinea pig. In the rat, only niflumic and metiazinic acids reduced very slightly the reaction. In the guinea pig, ibuprofen, phenylbutazone, metiazinic acid and ketoprofen had good activity. The results are discussed.


Impact of Trypanosoma cruzi on antimicrobial peptide gene expression and activity in the fat body and midgut of Rhodnius prolixus.
Rhodnius prolixus is a major vector of Trypanosoma cruzi, the causative agent of Chagas disease in Latin America. In natural habitats, these insects are in contact with a variety of bacteria, fungi, virus and parasites that they acquire from both their environments and the blood of their hosts. Microorganism ingestion may trigger the synthesis of humoral immune factors, including antimicrobial peptides (AMPs). The objective of this study was to compare the expression levels of AMPs (defensins and prolixicin) in the different midgut compartments and the fat body of R. prolixus infected with different T. cruzi strains. The T. cruzi Dm 28c clone (TcI) successfully develops whereas Y strain (TcII) does not complete its life- cycle in R. prolixus. The relative AMP gene expressions were evaluated in the insect midgut and fat body infected on different days with the T. cruzi Dm 28c clone and the Y strain. The influence of the antibacterial activity on the intestinal microbiota was taken into account. The presence of T. cruzi in the midgut of R. prolixus was analysed by optical microscope. The relative expression of the antimicrobial peptides encoding genes defensin (defA, defB, defC) and prolixicin (prol) was quantified by RT-qPCR. The antimicrobial activity of the AMPs against Staphylococcus aureus, Escherichia coli and Serratia marcescens were evaluated in vitro using turbidimetric tests with haemolymph, anterior and posterior midgut samples. Midgut bacteria were quantified using colony forming unit (CFU) assays and real time quantitative polymerase chain reaction (RT-qPCR). Our results showed that the infection of R. prolixus by the two different T. cruzi strains exhibited different temporal AMP induction profiles in the anterior and posterior midgut. Insects infected with T. cruzi Dm 28c exhibited an increase in defC and prol transcripts and a simultaneous reduction in the midgut cultivable bacteria population, Serratia marcescens and Rhodococcus rhodnii. In contrast, the T. cruzi Y strain neither induced AMP gene expression in the gut nor reduced the number of colony formation units in the anterior midgut. Beside the induction of a local immune response in the midgut after feeding R. prolixus with T. cruzi, a simultaneous systemic response was also detected in the fat body. R. prolixus AMP gene expressions and the cultivable midgut bacterial microbiota were modulated in distinct patterns, which depend on the T. cruzi genotype used for infection.


Multiple Evanescent White Dot Syndrome: A Multimodal Imaging Study of Foveal Granularity.
To describe multiple evanescent white dot syndrome (MEWDS)-related foveal granularity features on different imaging modalities. Clinical and multi-imaging files from five patients affected by MEWDS were reviewed. Each image set included: blue fundus autofluorescence (BAF), near-infrared fundus autofluorescence (NIR-FAF), spectral-domain optical coherence tomography (SD-OCT), fluorescein (FA), and indocyanine green (ICGA) angiography. Foveal granularity features were analyzed and described for each technique at baseline and follow-up. At baseline, 4/5 patients did not show white dots at funduscopic examination, but all subjects demonstrated hypo-fluorescent lesions on ICGA and areas of increased BAF. In all patients, foveal granularity was detectable on NIR-FAF as an irregular hypo-fluorescent area, persisting during follow-up visits. The corresponding SD-OCT scans revealed outer retinal layers' disruption resolving overtime. Foveal granularity can be the sole presenting sign of MEWDS. NIR-FAF and SD-OCT should be considered as non-invasive investigations in the detection of MEWDS-related foveal granularity.


Learner Phenotypes in Competency-Based Medical Education.
With the launch of competency-based medical education internationally, the practical realities of implementation have failed to live up to many of the proposed theoretical benefits. Specifically, as educators we have observed a number of assessment challenges that seem directly related to identified learner phenotypes. This commentary seeks to describe these specific learner phenotypes, along with actionable recommendations for programs and their competence committees in order to overcome the associated obstacles in assessment. We describe strategies related to both the individual and program level, which can be utilized for both short-term adjustments and long-term programmatic transformation.


Toxicoepidemiology in Zimbabwe: pesticide poisoning admissions to major hospitals.
Acute pesticide poisoning (APP) is a well-recognized cause of morbidity and mortality but is not well described in developing countries. We describe the toxicoepidemiology of APP in Zimbabwe. All cases of APP admitted to eight major referral hospitals in Zimbabwe from January 1998 to December 1999 (inclusive) were identified using ICD-9 codes and ward registers and relevant information recorded on a standard data collection sheet. There were a total of 914 single pesticide exposures. Almost half (49.1%) resulted from oral exposure to rodenticides, 42.2% from anticholinesterase-type pesticides (AChTP), mostly organophosphates (OP) that were responsible for over 90% of admissions from AChTP. Accidental and deliberate self-poisoning (27.1% and 58.6%, respectively) accounted for most cases with only eight homicides. The case fatality rate (CFR) in deaths/100 admissions was 6.8 [62 deaths; 95% Confidence Interval (CI) 5.2-8.6] and was significantly higher in males (9.4) than females (4.1) (CI for difference in proportions; 2.0-8.5). In addition, the CFR for deliberate self-poisoning (DSP), 6.5 deaths/100 admissions, was also significantly higher than that for accidental poisoning (0.8 deaths/100 admissions) (CI for difference in proportions 3.2-7.9). Organophosphates were implicated in 70.9% of all fatalities, with over 20% resulting from oral exposure to rat poison (RP). Organophosphates and rat poison (RP) are the leading causes of APP admissions to major referral hospitals in Zimbabwe, with most of the admissions being the result of deliberate self-poisoning. Greater control in the sale and use of these products could help prevent significant morbidity and mortality.


Visualizing the Dynamics of Cell Division by Live Imaging Drosophila Larval Brain Squashes.
The dramatic changes of subcellular structures during mitosis are best visualized by live imaging. In general, live imaging requires the expression of proteins of interest fused to fluorophores and a model system amenable to live microscopy. Drosophila melanogaster is an attractive model in which to perform live imaging because of the numerous transgenic stocks bearing fluorescently tagged transgenes as well as the ability to precisely manipulate gene expression. Traditionally, the early Drosophila embryo has been used for live fluorescent analysis of mitotic events such as spindle formation and chromosome segregation. More recent studies demonstrate that the Drosophila third instar neuroblasts have a number of properties that make them well suited for live analysis: (1) neuroblasts are distinct cells surrounded by plasma membranes; (2) neuroblasts undergo a complete cell cycle, consisting of G1, S, G2, and M phases; and (3) neuroblasts gene expression is not influenced by maternal load, and so the genetics are therefore relatively more simple. Finally, the Drosophila neuroblast is arguably the best system for live imaging asymmetric stem cell divisions. Here, we detail a method for live imaging Drosophila larval neuroblasts.


A water-soluble polysaccharide from Eucommia folium: the structural characterization and anti-tumor activity in vivo.
In this study, a water-soluble polysaccharide from Eucommia folium was extracted by hot water and purified using Sephadex G-200 gel columns. The results showed that the purified fraction (EFP) has a molecular weight of 9.98 × 105 Da and consisted of rhamnose, arabinose, galactose, glucose, mannose, xylose, galacturonic acid, and glucuronic acid (molar ratio: 0.226: 1.739: 2.183: 1: 0.155: 0.321: 0.358: 0.047). The combination of infrared spectroscopy and NMR analysis proved that EFP is an acidic polysaccharide whose main chain consists of α-L-Araf-(1 → , → 3,5)-α-Araf-(1 → , → 3)-β-Galp-(1 → , → 3,6)-β-Glcp-(1 → , → 2)-α-D-Manp-(1 → , → 4)-α-GalpA-(1 → , → 2,4)-α-Rhap-(1 → . In addition, the in vivo antitumoral activity of EFP was studied using a H22 tumor-bearing mice model. EFP effectively inhibited tumor growth in mice following intragastric administration. By Combining with the results of the apoptosis assay and JC-1 staining analysis, we confirmed that EFP induces apoptosis through the mitochondrial pathway. Furthermore, cell cycle analysis demonstrated that EFP blocks the cell cycle at S phase.


Removal of cesium ions from aqueous solution by adsorption onto local Taiwan laterite.
Utilization of local Taiwan laterite (LTL) to remove aqueous cesium was investigated in this work under the conditions of various contact time, cesium (Cs) loading and temperature. Experimental results show that adsorption is instantaneous. Freundlich and Langmuir simulation results demonstrate that local Taiwan laterite has high affinity and sorption capacity for Cs at low temperatures, which may be attributed to enhanced desorption as temperature increased. Thermodynamic parameters including DeltaH, DeltaG and DeltaS were calculated and it is indicated that Cs adsorption on LTL is an exothermic, spontaneous and physical adsorption reaction. Moreover, the adsorbed Cs is distributed evenly on the LTL surface, which is confirmed by SEM/EDS mapping images. Furthermore, the absence of apparent shifting or broadening of the kaolinite signal in XRD patterns after Cs adsorption is an indication of the non-expanding characteristic of kaolinite structure.


[Molecular mechanism of switching adipocyte / osteoblast differentiation through regulation of PPAR-gamma function].
Adipocytes and osteoblasts are derived from mesenchymal stem cells, and some adipocyte differentiation regulators suppress osteoblast differentiation. PPAR-gammaplays a pivotal role for adipocyte differentiation and glucose tolerance. PPAR-gammais a member of nuclear receptor super family and regulates mRNA expression level of target genes by binding to fatty acid derivatives and thiazolidinediones. Recently, it was found that PPAR-gammainhibits osteoblast differentiation and regulates bone metabolism. In this report, we show recent studies about the extracellular signals regulating the transactivation function of PPAR-gamma.


Management of the clinically positive neck in organ preservation for advanced head and neck cancer.
To investigate clinicopathologic predictive criteria for the optimal management of neck metastases in patients with advanced head and neck cancers treated with combined chemoradiotherapy. Prospective study, 48 patients. Mean length follow-up, 23 months. Neck stage predicted neck response to chemoradiotherapy; N3 necks showed more partial responses (P = 0.04), and N1 necks showed more complete responses (P = 0.12). Primary tumor site strongly predicted the pathologic response found on neck dissection in patients with a clinical partial response (cPR) following chemoradiotherapy. There was no difference in survival between patients with a clinical complete response (cCR) after chemoradiotherapy, and patients with a pathologic complete response (pCR) after neck dissection (P = 0.20); however, when grouped together, these patients survived longer than did patients with a pPR at neck dissection (P = 0.06). Clinical response to induction chemotherapy is a poor predictor of ultimate neck control. Induction chemotherapy followed by chemoradiotherapy, and planned neck dissection for patients with persistent cervical lymphadenopathy, provides good regional control.


Negotiation of gender responsibilities in resettled refugee populations through Relationship Enhancement training.
Being uprooted, displaced, and resettled can produce great tension in refugee marriages. This paper details a technique to help refugees recognize and manage changes and threats to traditional gender roles after resettlement to western countries. A case study from a multisite psycho-educational marriage project illustrates the application of the Relationship Enhancement model with a Bhutanese couple. Through empathy and structured dialogue, the couple is coached to identify their core concerns about the changes in their lives and come up with mutually beneficial solutions. Focusing on the redistribution of each gender's prescribed responsibilities allows the clinician to respond to the cultural structuring of equitable division of labor while helping families to address new responsibilities in managing household duties, parenting, employment, and finances.


Characterization of transgenic mice expressing cancer-associated variants of human NOTCH1.
The Notch1 receptor plays a critical role in cell fate decisions during development. Activation of Notch signaling has been implicated in several types of cancer, particularly T-cell acute lymphoblastic leukemia (T-ALL). Consequently, several transgenic mouse strains have been made to study the role of Notch1 in T-ALL. However, the existing Notch1 transgenic lines mimic a translocation event found in only ∼1% of T-ALL cases. Here we describe three novel NOTCH1 transgenic mouse strains that have Cre-inducible expression of the entire human NOTCH1 locus, each possessing a common mutation found in T-ALL. Unlike existing Notch1 transgenic strains, these NOTCH1 transgenic strains express full-length receptors from an endogenous human promoter that should be susceptible to a number of Notch antagonists that have recently been developed. These strains will allow researchers to modulate Notch signaling to study both normal development and cancer biology.


The competence of transformed keratinocytes to differentiate is accompanied by amplification of the LDL- and EGF-receptor genes but not of the insulin receptor gene.
The possible relationship between cell surface receptor numbers, receptor gene expression for low density lipoprotein (LDL), insulin and epidermal growth factor (EGF), and differentiation capacity has been studied in normal and SV40 transformed (SVK14) keratinocytes, various squamous carcinoma cell (SCC) lines and A431 cells. Our recent studies demonstrated that an inverse relationship exists between LDL- and EGF-receptor binding and the ability to differentiate of both normal and transformed keratinocytes. In the present study cloned LDL- and EGF-receptor complementary DNAs were used as probes to identify both LDL and EGF receptor gene fragments on genomic DNA blots. The extent of hybridisation was found to be increased to the highest extent in A431 cells and decreased in other cells in the following order SCC-4 greater than SCC-15. In SCC-12F2, SVK14 and normal keratinocytes no increase has been observed. The increased hybridisation of LDL- and EGF-receptors in A431, SCC-4 and SCC-15 cells was found to be due to gene amplification and not to aneuploidy. In contrast to the LDL- and EGF-receptor binding, no correlation has been found between insulin receptor binding and ability of cells to differentiate. Furthermore, no amplification of insulin receptor gene has been observed in any of the cells under study.


Prelimbic cortex drives discrimination of non-aversion via amygdala somatostatin interneurons.
The amygdala and prelimbic cortex (PL) communicate during fear discrimination retrieval, but how they coordinate discrimination of a non-threatening stimulus is unknown. Here, we show that somatostatin (SOM) interneurons in the basolateral amygdala (BLA) become active specifically during learned non-threatening cues and desynchronize cell firing by blocking phase reset of theta oscillations during the safe cue. Furthermore, we show that SOM activation and desynchronization of the BLA is PL-dependent and promotes discrimination of non-threat. Thus, fear discrimination engages PL-dependent coordination of BLA SOM responses to non-threatening stimuli.


Time-dependent miR-16 serum fluctuations together with reciprocal changes in the expression level of miR-16 in mesocortical circuit contribute to stress resilient phenotype in chronic mild stress - An animal model of depression.
MicroRNAs (miRNAs) are involved in stress-related pathologies. However, the molecular mechanisms underlying stress resilience are elusive. Using chronic mild stress (CMS), an animal model of depression, we identified animals exhibiting a resilient phenotype. We investigated serum levels of corticosterone, melatonin and 376 mature miRNAs to find peripheral biomarkers associated with the resilient phenotype. miR-16, selected during screening step, was assayed in different brain regions in order to find potential relationship between brain and peripheral alterations in response to stress. Two CMS experiments that lasted for 2 and 7 consecutive weeks were performed. During both CMS procedures, sucrose consumption levels were significantly decreased in anhedonic-like animals (p<0.0001) compared with unstressed animals, whereas the drinking profiles of resilient rats did not change despite the rats being stressed. Serum corticosterone measurements indicated that anhedonic-like animals had blunted hypothalamic-pituitary-adrenal (HPA) axis activity, whereas resilient animals exhibited dynamic responses to stress. miRNA profiling revealed that resilient animals had elevated serum levels of miR-16 after 7 weeks of CMS (adjusted p-value<0.007). Moreover, resilient animals exhibited reciprocal changes in miR-16 expression level in mesocortical pathway after 2 weeks of CMS (p<0.008). A bioinformatic analysis showed that miR-16 regulates genes involved in the functioning of the nervous system in both humans and rodents. Resilient animals can actively cope with stress on a biochemical level and miR-16 may contribute to a "stress-resistant" behavioral phenotype by pleiotropic modulation of the expression of genes involved in the function of the nervous system.


Wellness among nursing students: A qualitative study.
Nursing students typically experience high levels of stress and anxiety in nursing schools, and this is often compounded by having to combine complex classroom theories with practice. Healthy behaviors are subsequently neglected, diminishing academic efficiency and personal wellbeing. Student nurses need to adopt healthy lifestyles since wellness has been shown to promote positive health outcomes. Nonetheless, studies on the perception of wellness, and descriptions of its facilitators and barriers in wellness promotion among nursing students remain limited. This qualitative descriptive study aimed to explore facilitators and barriers to promote wellness among nursing students in Thailand. Data was gathered using focus groups with 80 undergraduate third and fourth-year nursing students, comprising 64 females and 16 males. Four themes emerged from content analysis regarding the facilitators of promoting wellness: healthy living; belief in animism; self-optimism; and receiving support. Barriers to wellness were three themes of stressors involved in students' lives: pressure from instructors; behaviors of staff nurses; and being perceived as untrustworthy. It is vital to promote wellness among nursing students to encourage their health care choices and to support them through their studies.


Effect of central air conditioning and meteorologic factors on indoor spore counts.
We have studied the effect of residential central air conditioning on indoor spore counts. The air of 6 pairs of homes (air-conditioned and non-air-conditioned) was sampled volumetrically 4 times daily for 3 consecutive days at 2-hr intervals in the kitchens, bedrooms, and basements with an Anderson sampler. Nearly simultaneous samples were taken outdoors at the same intervals. The total spore count was significantly lower (p less than 0.05) in the kitchens and bedrooms of air-conditined as compared to non-air-conditioned homes. Logarithmic conversion of the total spore count showed significant reduction in all indoor locations of air-conditioned homes. Multiple regression analysis revealed the lower relative humidity of air-conditioned homes to be associated with the lower spore counts. There was no difference in the percent concentration of the major genera within both types of homes. Since reducing the influx of outdoor spores decreases the total spore count without altering the relative concentration of the genera whereas filtration preferentially removes the larger spores, we conclude that the major mechanism in reducing spore counts in air-conditioned homes is the closed windows, although the lower relative humidity and perhaps filtration are also associated with lower spore counts.


Molecular organization of the xcp gene cluster in Pseudomonas putida: absence of an xcpX (gspK) homologue.
A DNA fragment containing xcp (gsp) gene homologues, required for extracellular protein secretion by the general secretory pathway (GSP) in various Gram-negative bacteria, was cloned from Pseudomonas putida (Pp) strain WCS358 and sequenced. The results presented here and those previously reported (de Groot, A., Krijger, J.-J., Filloux, A., Tommassen, J., 1996. Characterization of type II protein secretion (xcp) genes in the plant growth-stimulating Pseudomonas putida, strain WCS358 Mol. Gen. Genet. 250, 491-504) complete the sequence of the xcp gene cluster of Pp. Unlike that of Pseudomonas aeruginosa (Pa), the xcp gene cluster of Pp contains a gspN homologue. More surprisingly, in contrast to all known gsp gene clusters, the xcpX (gspK) homologue is not found. In addition, genes flanking the xcp cluster of Pp are not related to those flanking the xcp genes of Pa. Overall, the xcp gene products of Pp are as much related to those of Pa as to gsp gene products of enterobacterial species, suggesting that the xcp clusters of Pp and Pa have evolved separately.


Validation of automated forms processing. A comparison of Teleform with manual data entry.
We have used the computer program Teleform for automated forms processing (AFP) and have compared error rates, time consumption, and expenses with those of single or double manual data entry. For choice fields the error rate for AFP was very low and comparable to double manual data entry, while for numeric recognition the error rate was higher than for both single and double manual data entry. AFP reduced processing time, but we found that a very large number of forms need to be processed in order to recover the initial investment. A considerable amount of time and computer expertise was required for implementation of AFP.


Glucose-dependent action of glucagon-like peptide-1 (7-37) in vivo during short- or long-term administration.
In vitro, truncated glucagon-like peptides [GLP-1(7-36)-amide and GLP-1(7-37)] increase insulin secretion in a glucose-dependent manner, and desensitization to the action of GLP-1(7-37) has been demonstrated acutely with high concentrations. The purpose of these studies was to evaluate the glucose dependency and threshold of GLP-1(7-37) action in normal rats and in a rat model of type II diabetes and to assess the effects of long-term administration in vivo. All studies were conducted in conscious catheterized rats. An intravenous (IV) infusion of GLP-1(7-37) at 0.5, 5, or 50 pmol/min/kg during the second hour of a 2-hour 11-mmol/L hyperglycemic clamp in Sprague-Dawley rats produced a dose-related enhancement of the glucose-induced increase in plasma insulin concentration. A 1-hour infusion of a submaximal dose of GLP-1(7-37) (5 pmol/min/kg IV) in fasted and fed Sprague-Dawley rats produced small transient increases in plasma insulin (incremental increases above basal, 72 +/- 27 and 96 +/- 28 pmol/L, respectively) and decreases in plasma glucose (to levels > or = 5.2 mmol/L). Infusion of GLP-1(7-37) (5 pmol/min/kg IV) during a hyperglycemic clamp at two sequentially increasing concentrations of glucose, 11 and 17 mmol/L, produced incremental increases in insulin of 600 and 1,200 pmol/L, respectively, relative to levels in clamped control rats. Similarly, infusion of GLP-1(7-37) (5 pmol/min/kg IV) in hyperinsulinemic, hyperglycemic Zucker diabetic fatty (ZDF) rats produced a transitory increase in plasma insulin concentration and normalized the plasma glucose concentration.(ABSTRACT TRUNCATED AT 250 WORDS)


Semi-Prone Position Can Influence Variability in Respiratory Rate of Premature Infants Using Nasal CPAP.
To determine the effect of positions (supine, lateral, semiprone) on the physiological parameters (HR, RR, SpO2) of premature infants receiving NCPAP who were non-oxygen-dependent and non-BPD, and to identify significant clinical changes associated with these variables. A crossover study design with three different positions in the assigned sequence (supine-supine, supine-lateral and supine-semiprone) was used, and each position was maintained for 1h. The subjects' vital signs were recorded 30 min after initiation of each position and measured for 30 min. Forty-seven infants with a median GA of 28.6 weeks (range 26-35) were studied, and their median BW was 1210g (range 776-2920). Overall, position-related effects showed significant difference in the variability in RR (OR=0.68; CI 0.51-0.89), with the variability in RR being significantly lower in the semiprone position. The lateral position was associated with increased RR (B=2.9; p=0.02). Previous use of ventilator (PUV) was associated with increased HR, whereas BW and GA were negatively associated with higher HR. Cesarean birth, use of surfactant and PUV were associated with lower SpO2, whereas BW and GA were correlated with higher SpO2. GA was identified as a protective factor, while PUV was a risk factor for the variability in both HR and SpO2. Premature infants receiving NCPAP sleeping in the semiprone position may have more stable RR, while the lateral position did not improve RR. Thus, the semiprone and supine positions may be considered preferable when positioning the monitored premature infants with NCPAP.


Red blood cell distribution width is a potential index to assess the disease activity of systemic lupus erythematosus.
General population-based investigations have revealed that red blood cell distribution width (RDW) is associated with inflammatory indexes such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Chronic inflammation is one of the major components of many autoimmune diseases and RDW may reflect the severity of these autoimmune diseases as well. Therefore, the objective of this study was to investigate the correlation between RDW and disease activity of systemic lupus erythematosus (SLE). The medical records of 131 SLE patients were retrospectively analyzed. Correlations between RDW and disease activity or other inflammatory indexes were analyzed. The effect of glucocorticoid treatment for three months on RDW was estimated in 3 newly diagnosed SLE cases. Increased RDW was observed in SLE patients. RDW was positively correlated with serum IgM, CRP, ESR, and SLE Disease Activity Index 2000 (SLEDAI-2K). Glucocorticoid treatment decreased both SLEDAI-2K and RDW. RDW may be a useful index to estimate the disease activity of SLE.


Aberrant interaction between mutated ADAMTSL2 and LTBP4 is associated with adolescent idiopathic scoliosis.
Adolescent idiopathic scoliosis (AIS) is a complex spinal deformity with a prevalence of 1%-3%. Genetic factors have been associated with the etiology of AIS. However, previous studies mainly focused on common single nucleotide polymorphisms which confer modest disease risk. Recently, rare variants in FBN1 and other extracellular matrix genes have been implicated in AIS, suggesting a potential overlapping disease etiology between AIS and hereditary connective tissue disorders (HCTD). In this study, we systematically analyzed rare variants in a set of HCTD-related genes in 302 AIS patients who underwent exome sequencing. We firstly focused on pathogenic variants based on a monogenic inheritance and identified nine disease-associated variants in FBN1, COL11A1, COL11A2 and TGFBR2. We then explored the potential interactions between variants in different genes based on the case-control statistics. We identified three ADAMTSL2-LTBP4 variant pairs in three AIS patients and none in controls. Furthermore, we revealed that the variant pairs identified in these genes could affect the interaction between ADAMTSL2 and LTBP4 and upregulate TGF-β signaling pathway in human fibroblasts. Our findings implicate that the aberrant interaction between mutated ADAMTSL2 and LTBP4 was associated with AIS.


An exploratory study of the effects of strenuous exercise on markers of coagulation activation, circulating microparticles, and inflammation in sickle cell trait.
This exploratory study evaluated the effect of intense exercise on biomarkers of inflammation and coagulation activation in subjects with and without sickle cell trait (SCT). Fifteen healthy African American men (18-35 years, 5 SCT, 10 control) completed a strenuous exercise protocol. Microparticle-associated prothrombinase and tissue factor activities, as well as soluble VCAM, total white cell and monocyte count increased transiently in all subjects following exercise. In the SCT group, exercise resulted in increased d-dimer, erythrocyte phosphatidylserine exposure, as well as increased circulating erythrocyte- and endothelial-derived microparticle numbers. These alterations could contribute to exercise-related complications in people with SCT.


Biologic glue-molded "bio-mini-paddle" electrode used for atrial and ventricular pacing and defibrillation.
Atrial and ventricular dysrhythmias developing after cardiac operation further reduce cardiac output, posing a serious problem for postoperative management. We have developed a "bio-mini-paddle" electrode designed to be attached directly to the myocardium for atrial or ventricular defibrillation and pacing for intraoperative and postoperative cardiac management. We use fibrin glue for the paddle, which is biodegradable. The characteristics of this unique paddle were examined using mongrel dogs.


Influence of hydrodynamics and particle size on the absorption of felodipine in labradors.
To study the influence of GI hydrodynamics and drug particle size on felodipine absorption in the dog. Labradors fistulated at midjejunum were used to selectively study the influence of hydrodynamics and particle size on the in vivo dissolution and absorption of the poorly soluble, lipophilic drug felodipine. A combination of infusion and oral administration of either normal saline or a 5% glucose solution was used to maintain "fasted" and establish "fed" state motility patterns, respectively. The absorption characteristics of both a micronized (8 microm) and a coarse fraction (125 micom) of felodipine were subsequently studied under these two motility patterns. A reduction in particle size led up to an approximate 22-fold increase in maximum plasma concentration and up to an approximate 14-fold increase in area under the curve, with a commensurate decrease in the time at which the maximum plasma concentration occurred. Although the absorption of felodipine from the solution and micronized suspension was not influenced by a change in the hydrodynamics, felodipine was absorbed from the coarse suspension almost twice as well in the "fed" state as under "fasted" conditions. Absorption from coarse suspensions of felodipine was sensitive to luminal hydrodynamics, whereas micronized suspensions were not. However, the particle size seems to have a much more important influence on the bioavailability of felodipine than the hydrodynamics per se.


Effects of weight restriction and palatability on the apparent pharmacological regulation of alcohol consumption by rats in a limited access paradigm.
A number of different studies have suggested that the amount of alcohol consumed in a single bout by free-feeding rats is regulated by its pharmacological consequences. The present experiments were designed to test the limits of this apparent pharmacological regulation by examining the effect of weight restriction and enhanced palatability, two variables that have been shown to increase alcohol consumption when the alcohol is continuously available, on amount of alcohol consumed in a single bout. Increasing the palatability of the alcohol solution by the addition of saccharin enhanced consumption substantially such that the blood alcohol levels (BALS) achieved were more than twice those of animals which had drunk unadulterated alcohol. Weight restriction to 80% of free-feeding weight (FFW), however, did not increase alcohol consumption under these conditions. The similarity between these results and those obtained in studies of the regulation of feeding are discussed.


Genetic and shared environmental risk factors do not lead to eosinophil activation in healthy twins of IBD patients.
To examine the role of eosinophils in the pre-diagnostic phase of inflammatory bowel disease (IBD), we studied the influence of genetic and shared environmental risk factors in a twin cohort of IBD. We analysed eosinophil derived neurotoxin (EDN) and eosinophil cationic protein (ECP) in faecal samples from twin pairs with Crohn's disease (n = 37) or ulcerative colitis (n = 21) and from external healthy controls (n = 44). Eosinophils stained with eosinophil peroxidase (EPO) were quantified in rectal biopsies. Ratios with 95% confidence intervals were calculated. Twins with Crohn' disease displayed higher levels of EDN (Ratio = 2.98, 1.65-5.37) and ECP (Ratio 1.83, 1.24-2.70) than their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.52, 0.79-2.94 and ECP, Ratio = 0.93, 0.56-1.54). Higher levels of EDN (Ratio = 2.43, 1.13-5.24) and ECP (Ratio = 1.53, 0.92-2.53) were observed among twins with ulcerative colitis vs their healthy siblings. Levels did not differ between healthy twin-siblings and external controls (EDN, Ratio = 1.08, 0.51-2.25 and ECP, Ratio = 1.29, 0.74-2.26). Using intra-class correlation coefficient (ICC), we found no agreement in levels of EDN or ECP in discordant pairs, except for ECP in monozygotic Crohn's disease pairs (ICC = 0.63). In contrast, agreement was observed in monozygotic pairs concordant for Crohn's disease (EDN, ICC = 0.67 and ECP, ICC = 0.66). The number of eosinophils in rectum was increased in twins with ulcerative colitis vs their healthy sibling (Ratio = 2.22, 1.50-3.27). Activation of eosinophils in IBD seems to be a consequence of inflammation rather than an effect of genetic and shared environmental risk factors alone.


Osteochondrodystrophies with marked platyspondyly and distinctive peripheral anomalies.
Two patients with a unique generalised bone dysplasia demonstrating severe distinctive platyspondyly are reported. This group of crippling disorders defies metabolic and histological classification. The radiographic examination is, at present, the only practical method of documentation of these rare disorders.


Proton n.m.r. spectroscopic evidence for sulfur-aromatic interactions in peptides.
The downfield shift of the tyrosyl proton resonances and an increased chemical shift difference between the resonances for the 2',6' and 3',5' hydrogens in a series of deamino-oxytocin analogs modified in the disulfide bridge provide evidence for aromatic-sulfur interactions in d6-dimethylsulfoxide solutions.


MYBL1 induces transcriptional activation of ANGPT2 to promote tumor angiogenesis and confer sorafenib resistance in human hepatocellular carcinoma.
Angiogenesis is considered as an important process in tumor growth, metastasis of hepatocellular carcinoma (HCC) and associated with cancer progression, suggesting that an important research and development field of clinical molecular targeted drugs for HCC. However, the molecular mechanisms underlying tumor angiogenesis in HCC remains elusive. In the current study, we demonstrate that upregulation of AMYB proto-oncogene-like 1 (MYBL1) was associated with high endothelial vessel (EV) density and contributed to poor prognosis of HCC patient. Functionally, MYBL1 overexpressing enhanced the capacity of HCC cells to induce tube formation, migration of HUVECs, neovascularization in CAMs, finally, enhanced HCC cells metastasis, while silencing MYBL1 had the converse effect. Furthermore, HCC cells with high MYBL1 expression were more resistance to sorafenib treatment. We observed that CD31 staining was significantly increased in tumors formed by MYBL1-overexpressing cells but decreased in MYBL1-silenced tumors. Mechanistically, MYBL1 binds to the ANGPT2 promoter and transcriptionally upregulate ANGPT2 mRNA expression. Strikingly, treatment with monoclonal antibody against ANGPT2 significantly inhibited the growth of MYBL1-overexpressing tumors and efficiently impaired angiogenesis. Furthermore, the histone post-translational factors: protein arginine methyltransferase 5 (PRMT5), MEP50, and WDR5 were required for MYBL1-mediated ANGPT2 upregulation. Importantly, we confirmed the correlation between MYBL1 and ANGPT2 expression in a large cohort of clinical HCC samples and several published datasets in pancreatic cancer, esophageal carcinoma, stomach adenocarcinoma, and colon cancer. Our results demonstrate that MYBL1 upregulated the ANGPT2 expression, then induced angiogenesis and confer sorafenib resistance to HCC cells, and MYBL1 may represent a novel prognostic biomarker and therapeutic target for patients with HCC.


Endogenous phosphorylation of membrane proteins in normal and in hereditary spherocytosis erythrocytes.
The phosphorylation state of the proteins in hereditary spherocytosis erythrocyte membranes, incubated in the presence of [gamma-32P]ATP, appears to be different from that in normal ones. This is indicated by the finding that in the two types of erythrocyte membranes the ratios between the 32P-labeling of their phosphorylserine and phosphorylthreonine residues were different.


Block the light and sleep well: Evening blue light filtration as a part of cognitive behavioral therapy for insomnia.
The objective of the present study was to assess the effect of combining CBT-I with wearing blue-light blocking glasses 90 min prior to bedtime on subjective and objective sleep parameters and daily symptoms (anxiety, depression, hyperarousal). Thirty patients (mean age 48.1 ± 16.13 years, range 21-71, 15 men/15 women) completed a CBT-I group therapy program, with groups randomly assigned to either "active" (blue-light filtering glasses) condition or "placebo" (glasses without filtering properties) condition. Patients were continually monitored by wristwatch actigraphy, kept their sleep diaries and completed a standard questionnaire battery at admission and after the end of the program. Statistical analyses showed a greater reduction of BAI score in "active" (4.33 ± 4.58) versus "placebo" (-0.92 ± 3.68) groups of patients [F = 6.389, p = .019, Cohen's d = 1.26] and significant prolongation of subjective total sleep time in "active" (-36.88 ± 48.68 min.) versus "placebo" (7.04 ± 47.50 min.) [F = 8.56, p < .01, d = 0.91] group. When pre- and post-treatment results were compared in both groups separately, using paired-samples t-tests, significant differences were observed also in the active group for BDI-II score (t = 3.66, p = .003, Cohen's d = 0.95) and HAS score (t = 2.90, p = .012, Cohen's d = 0.75). No significant differences were found in the placebo group. In active group, there was also a significant reduction of subjective sleep latency (t = 2.65, p = .021, d = 0.73) and an increase of subjective total sleep time (t = -2.73, p = .018, d = -0.76) without change in objective sleep duration which was significantly shortened in the placebo group. We provide further evidence that blocking short-wavelength light in the evening hours may be beneficial for patients suffering from insomnia.


Pulmonary vascular disease in ventricular septal defect: structural and functional correlations in lung biopsies from 85 patients, with outcome of intracardiac repair.
Pulmonary vascular structure was analysed using morphometric techniques, and arterial wall abnormalities in lung biopsy specimens taken from 85 cases of ventricular septal defect, aged 3 weeks to 30 years were described. The defect was closed in 53 patients, 12 died at operation and 11 survivors were recatheterized. Structural examination revealed a characteristic pathological picture which appeared to precede classical grade IV pulmonary vascular disease. This predilatation phase was identified by finding pre-acinar obstructive intimal proliferation or fibrosis, associated with only a slight increase in intra-acinar arterial muscularity, in the absence of stigmata of grade IV disease in patients with a pulmonary resistance greater than 6 units m2. Predilatation features occurred in 62 per cent of patients who either died at repair or who had post-operative pulmonary hypertension. These findings help identify a high risk group in whom resistance is higher than expected in the absence of classical grade IV changes. In addition, a marked increase in muscularity without intimal obstruction can also be associated with a pre-operative resistance of more than 6 units m2. The presence of medial hypertrophy only does not ensure either survival or a normal post-operative pulmonary arterial pressure. Early intra-cardiac repair is recommended before obstructive intimal fibrosis develops during the second year.


Distribution of cadmium in body organs and hepatic metallothionein content following chelation therapy.
1. Calcium trisodium diethylene triamine penta-acetate (CaNa3DTPA), sodium 1,2 diaminocyclohexane tetra-acetate (Na2CDTA), triethylenetetramine hydrochloride (TETA.HCl) and sodium diethyldithiocarbamate (NaDDC) were investigated for their efficacy to mobilize cadmium (Cd) from various tissues and hepatic metallothionein (MT) in Cd-exposed rats. 2. All chelating agents reduced the hepatic Cd burden but did not elicit any influence on other tissues, except that TETA.HCl lowered pancreas Cd and NaDDC increased brain Cd. 3. Cadmium-induced hepatic MT was lowered upon treatment with CaNa3DTPA while it increased further following treatment with NaDDC. 4. The chelating agents, in split doses, are capable of reducing the hepatic burden of Cd and altering the hepatic MT level. 5. While all the chelating agents decreased Cu content of hepatic MT, only CaNa3DTPA decreased its Zn content and TETA.HCl mobilized MT-bound Cd. 6. The administration of chelating agents alone in normal animals showed that NaDDC induced greater hepatic MT synthesis and increased MT-bound Zn than other chelating agents.


The antiproliferative activity of 3-deoxyanthocyanins extracted from red sorghum (Sorghum bicolor) bran through P(53)-dependent and Bcl-2 gene expression in breast cancer cell line.
The aim of this study was to investigate the anti proliferative activity of 3-deoxyanthocyanin extracted from red sorghum bran on human breast cancer cell line MCF 7. The confirmatory tests were carried out in vitro through the expression studies of p(53) and (bcl) 2 genes in MCF 7 cells. The 3-deoxyanthocyanins were isolated from red sorghum bran and cytotoxic studies were performed in MCF 7 cell line by MTT assay. The mRNA expression levels of p(53) and (bcl) 2 genes were performed using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis in MCF 7 cells. On cytotoxic studies, the present data indicates sorghum anthocyanins, which showed 84.09% of inhibition in the proliferation of MCF 7 cells, and the CTC(50) value was 300 μg/ml. The sorghum 3-deoxyanthocyanins induced apoptosis in MCF 7 was mediated by stimulation of the p(53) gene and down regulation of the (bcl) 2 gene. The significance of our work was the anthocyanin isolated from red sorghum bran inhibits the proliferation of human breast cancer cell line.


Demonstration of useful differences between magnetoencephalogram and electroencephalogram.
For a dipole source, theory predicts 3 useful differences between the MEG and EEG spatial patterns over the head. These are seen when a comparison is made between theoretical MEG and EEG maps, due to the dipole in a spherical model of the head. If true, these differences would allow the MEG to better localize or differentiate neural sources in some ways than does the EEG. A first experimental test of the differences is made here. A comparison is made between MEG and EEG maps due to a neural source which appears to behave as a dipole (N20 of the somatic evoked response). The same 3 differences are seen, therefore the predicted differences are confirmed experimentally. The first 2 differences, due only to the tangential component of the dipole, are that the MEG pattern is rotated by 90 degrees from the EEG pattern and is one-third tighter. The first allows the MEG to localize a tangential dipole better in a preferred direction, across the dipole (while the EEG does so along the dipole); the second allows the MEG to localize somewhat better in its preferred direction than the EEG does in its preferred direction. The third difference is due only to the radial component of the dipole; while the MEG receives no contribution from this component, the EEG pattern is asymmetrical and is heavily weighted by it. This allows the MEG to reveal tangential sources which are obscured by the radial sources in the EEG. For sources which cannot be approximated by a dipole, the MEG-EEG differences will depend on the particular case; however, the spherical model can now be used with more confidence to predict differences in these cases.


Implementation of pharmacist-led tele medication management clinic in ambulatory care settings: A patient-centered care model in COVID-19 Era.
Over the past 20 years, owing to rapid advances in technological innovation, namely in telecommunication and telemedicine, healthcare institutions have integrated clinical practices with cutting-edge telecommunication technology to enhance access to patient care, improve continuity of clinical care, and ensure patient safety. Johns Hopkins Aramco Healthcare (JHAH) is a gold-certified tertiary care institution, and it is an excellent center for patient-centered care. In response to the Coronavirus 2019 (COVID-19) pandemic, it has adopted various telecommunication technologies to provide patient-care services. This article describes the integration of telecommunication technology, such as telephone and video consultation, with a pharmacist-led medication management clinic (MMC) to provide person-centered patient care services at JHAH. The JHAH pharmacy services were found to be essential in establishing face-to-face outcome-oriented pharmacist-led medication management services for patients requiring chronic ambulatory care. The established tele-MMC services enhanced patient engagement and treatment compliance, and the integration process and its challenges were assessed. Especially during this COVID-19 pandemic, the pharmacist-led tele-MMC services were beneficial to chronic disease patients and ensured the continuity of care, maintenance of up-to-date lab tests, management of polypharmacy, minimization of the use of unwanted medications and medication synchronization. Further, the pharmacist-led tele-MMC services provided comprehensive patient counseling, which included the use of visual aids. This new integrated model provides an example for other healthcare organizations to adopt and implement the program in ambulatory care settings, to better ensure the continuity of quality healthcare, especially for elderly patients and those with chronic diseases.