Effect of Formic Acid on Exopolysaccharide Production in Skim Milk Fermentation by Lactobacillus delbrueckii subsp. bulgaricus OLL1073R-1.
In yogurt, the formation of formate by Streptococcus thermophilus stimulates the activity of Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus). However, there have been no reports how formic acid acts on the exopolysaccharide (EPS) production of L. bulgaricus. Here, the effect of formate on the EPS production in skim milk by L. bulgaricus OLL1073R-1 was investigated. After incubation for 24 hr with 100 mg/l formate, cell proliferation and lactic acid production were accelerated. The viable and total cell numbers were increased about ten- and four-fold, respectively. The amount of EPS in culture with formate (~116 µg/ml) was also four-fold greater than that of the control (~27 µg/ml). Although elongation of cells was observed at 6 hr of cultivation in both cultures, cells cultivated with formate returned to a normal shape after incubation for 24 hr. The sensitivity to cell wall hydrolase and composition of surface layer proteins, as well as the cell membrane fatty acid composition of L. bulgaricus OLL1073R-1, were not influenced by formate. However, differences were observed in intracellular fatty acid compositions and sensitivity to antibiotics. Cell length and surface damage returned to normal in cultures with formate. These observations suggest that formic acid is necessary for normal cell growth of L. bulgaricus OLL1073R-1 and higher EPS production.


The radial alveolar count method of Emery and Mithal: a reappraisal 2--intrauterine and early postnatal lung growth.
The radial count method of Emery and Mithal was applied to the lungs of 37 infants of gestational age 19-42 weeks. The method could be used satisfactorily to evaluate airspace-containing lungs, whether alveolated or non-alveolated (saccule-containing). There was a progressive increase in complexity of terminal lung units throughout gestation, and a smooth transition was effected at 1 month of age between the radial counts of the intrauterine cohort and those of a separate group used to study postnatal lung growth. In the intrauterine and early postnatal group radial count results correlated very closely with the total gestational age (gestational age plus survival time after birth) of the child (r = +0.93). Prior inflation of the lungs affected the radial counts of alveolated lungs much more than those of saccule-containing lungs, so that results correlated most closely with those of Emery and Mithal in the period up to 34 weeks' gestation. Radial count estimation correlated better with total gestational age, crown-rump length, body weight, and fixed lung volume than did any other morphometric parameter assessed. The radial count method provides a reliable index of lung growth in intrauterine and early postnatal development.


The Health Policy and Legislative Awareness Initiative at the Pennsylvania State University College of Medicine: theory meets practice.
In a constantly evolving health care landscape shaped by many voices--including those of third party payers and government--physicians must learn to play a more proactive role to become better advocates for their patients and to uphold the basic tenets of their noble profession. As legislation and public health become increasingly intertwined with the practice of medicine, educators must provide future physicians with the tools to meet these new challenges. Accordingly, in 1996 Pennsylvania State University College of Medicine embarked on its Health Policy and Legislative Awareness Initiative, a medical school elective designed to provide theoretical knowledge as well as practical experience in legislative and policy issues for future physicians early in their careers. The Initiative has three key elements: a series of lectures taught by national and local experts covering a basic health policy curriculum, a mini-internship conducted at the office of a Pennsylvania State legislator, and a practical assignment leading to authorship of a resolution to a national medical organization or assisting in drafting a bill intended for introduction to the Pennsylvania State Legislature. Following several years of successful implementation and a moderate growth in enrollment, recent changes in the local and national scene have peaked the interest of most students to learn about the system in which they will practice medicine. Therefore, in addition to describing the Initiative in its current form, the authors discuss future plans for expanded elective opportunities and consider the issue of integrating health policy education into core medical school curricula.


Changes produced in mouse plasma proteins by acute bacterial infections.
The immunoelectrophoretic patterns of plasma proteins from mice are altered significantly by acute infections. Some proteins are dissociated into two or more components, some showed striking increase in plasma concentration, others are depleted, and certain ones appear which are undetectable in normal samples. beta(1)-C dissociated into two electrophoretic components under a variety of conditions in addition to infections. Endotoxins and killed organisms in vivo, and specific precipitate absorption, heat and aging in vitro produced this change. Endotoxins injected into mice also induced a rise in haptoglobin though not as sharply or predictably as acute infection. Preliminary results with samples from hospital patients with acute diseases are discussed. It was concluded that study of experimental diseases in laboratory animals by these techniques could provide a fruitful basis for the investigation of the plasma protein changes in similar human diseases.


Combining pharmacological therapy and vaccination in Chronic Myeloid Leukemia via model predictive control.
This paper describes a simulation study which aims at optimizing the therapy for the control of Chronic Myeloid Leukemia according to the following objectives: the reduction of the administered drug and vaccine amounts, the establishment of a auto-immune response and the long-term control of disease without reducing the effective of therapy with respect to the full treatment. A therapy optimization method is developed defining and solving a Model Predictive Control algorithm, preceded by an accurate Initial Guess search based on Monte-Carlo like approach. Simulation results show that the suggested procedure achieves the proposed goals.


The alpha adrenergic response of Down's syndrome platelets.
The alpha adrenergic responsiveness and pharmacological characteristics of alpha adrenergic receptors were examined using platelets from normal diploid and Down's syndrome (trisomy 21) individuals. Lower than normal doses of epinephrine were required to aggregate Down's syndrome platelets and promote ATP secretion. The concentrations of other platelet aggregating agents (ADP or thrombin) did not distinguish normal from Down's syndrome. Analysis of the alpha adrenergic receptor density and ligand affinity using the radioligand dihydroergocryptine indicated that the Down's syndrome platelets were not significantly different from normal. Likewise, the biochemical characteristics of the adenylate cyclase enzyme, e.g., its sensitivity to stimulation by prostaglandin E1 or inhibition by epinephrine, were not different when comparing Down's syndrome with normal platelet membranes. These data suggest that the enhanced epinephrine sensitivity of Down's syndrome platelets is independent of any change in the alpha adrenergic receptor or the adenylate cyclase enzyme complex.


Effects of L-ascorbic acid on growth, non-specific immunity, antioxidant capacity, and intestinal and hepatopancreatic histology of red swamp crayfish, Procambarus clarkii.
This study investigated the dietary effects of coated L-ascorbic acid (LA) on growth, feed utilization, survival, serum biochemical indices, immunity, antioxidant capacity, and intestinal and hepatopancreatic histology of the pre-adult red swamp crayfish. Four isoproteinous and isolipidic diets were formulated to contain several LA levels as 0, 1300, 1600, and 1900 mg/kg and designated as control (LA0), LA13, LA16, and LA19, respectively. However, the analyzed LA concentrations in diets were 0.00, 199.57, 360.45, and 487.50 mg/kg in LA0, LA13, LA16, and LA19, respectively. Triplicate treatments of crayfish (21.60 ± 0.14 g) were fed the test diets and reared in fiberglass tanks with a density of 20 individuals per each for eight weeks. Results revealed that all LA treatments had significantly enhanced growth performance compared to the control. Of interest, the LA16 treatment recorded the highest final tank biomass, biomass gain, total feed intake, condition factor, and muscle yield among the other treatments. The tank feed conversion ratio was significantly decreased in LA treatments compared to the control. Moreover, dietary LA16 and LA19 had significantly higher survival rates (93.3%) compared to (85.0%) in the LA0 group. All dietary doses of LA significantly increased serum parameters (total protein, albumin, globulin, lysozyme activity) and respiratory burst activity compared to the LA0 treatment. Dietary LA16 significantly boosted the hepatopancreatic antioxidant capacity, manifested by decreased malondialdehyde concentrations, increased catalase, superoxide dismutase, and glutathione peroxidase enzyme activities, and reduced glutathione content compared to the LA-free diet. A normal histoarchitecture of the hepatopancreatic tubules was found in all LA treatments except with some minor degenerative changes in the tubular lumen, and hepatopancreatic cells associated with enlarged nuclei were found in the LA19. However, normal intestinal histoarchitecture was found in all treatments with no recorded intestinal lesions. Of interest, the polynomial regression performed on the analyzed LA concentrations suggested that 380 mg/kg would be suitable to provide maximal biomass gain for pre-adult crayfish. In conclusion, results revealed that coated LA could enhance the growth, immunity, and antioxidant capacity of pre-adult red swamp crayfish, suggesting its potential as a functional and necessary micronutrient for crayfish diets.


CX3CL1/CX3CR1 Axis, as the Therapeutic Potential in Renal Diseases: Friend or Foe?
The fractalkine receptor chemokine (C-X3-C motif) receptor 1 (CX3CR1) and its highly selective ligand CX3CL1 mediate chemotaxis and adhesion of immune cells, which are involved in the pathogenesis and progression of numerous inflammatory disorders and malignancies. The CX3CL1/CX3CR1 axis has recently drawn attention as a potential therapeutic target because it is involved in the ontogeny, homeostatic migration, or colonization of renal phagocytes. We performed a Medline/PubMed search to detect recently published studies that explored the relationship between the CX3CL1/CX3CR1 axis and renal diseases and disorders, including diabetic nephropathy, renal allograft rejection, infectious renal diseases, IgA nephropathy, fibrotic kidney disease, lupus nephritis and glomerulonephritis, acute kidney injury and renal carcinoma. Most studies demonstrated its role in promoting renal pathopoiesis; however, several recent studies showed that the CX3CL1/CX3CR1 axis could also reduce renal pathopoiesis. Thus, the CX3CL1/CX3CR1 axis is now considered to be a double-edged sword that could provide novel perspectives into the pathogenesis and treatment of renal diseases and disorders.


High-strength, low-alloy steels.
High-strength, low-alloy (HSLA) steels have nearly the same composition as plain carbon steels. However, they are up to twice as strong and their greater load-bearing capacity allows engineering use in lighter sections. Their high strength is derived from a combination of grain refinement; precipitation strengthening due to minor additions of vanadium, niobium, or titanium; and modifications of manufacturing processes, such as controlled rolling and controlled cooling of otherwise essentially plain carbon steel. HSLA steels are less formable than lower strength steels, but dualphase steels, which evolved from HSLA steels, have ferrite-martensite microstructures and better formability than HSLA steels of similar strength. This improved formability has substantially increased the utilization potential of high-strength steels in the manufacture of complex components. This article reviews the development of HSLA and dual-phase steels and discusses the effects of variations in microstructure and chemistry on their mechanical properties.


Glecaprevir/Pibrentasvir: The First 8-Week, Pangenotypic HCV Treatment Regimen for Patients 12 Years of Age and Older.
Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, dosing, and cost information of glecaprevir/pibrentasvir in the treatment of hepatitis C virus (HCV). Data Sources: A literature search was conducted between September 2018 and July 2019 using PubMed and Google Scholar with the search terms glecaprevir, pibrentasvir, Mavyret, Maviret, and hepatitis C. Clinicaltrials.gov was searched using the same terms. References of published articles were assessed for additional information. Study Selection and Data Extraction: English-language preclinical and clinical studies on the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of glecaprevir/pibrentasvir were evaluated. Data Synthesis: Food and Drug Administration-approved glecaprevir/pibrentasvir is considered both safe and efficacious for the treatment of HCV genotypes 1 to 6 and in several patient populations, such as those with treatment-naïve or treatment-experienced HCV; with or without compensated cirrhosis, HIV-1 coinfection, or renal impairment; post-liver or post-kidney transplant; and ≥12 years of age. Sustained virological response rates ranged from 83% to 100% in clinical trials, and safety outcomes appear similar to other guideline-recommended HCV treatment options. Relevance to Patient Care and Clinical Practice: This review discusses the pharmacological, efficacy, and safety data found in glecaprevir/pibrentasvir clinical trials and relates this to guideline recommendations and the practical use of this medication for treatment of HCV. Conclusions: With HCV infection rates remaining elevated, it is important to have safe and efficacious treatment options. Glecaprevir/pibrentasvir is a safe and efficacious guideline-recommended, 8-week treatment for HCV in several patient populations, with these populations likely growing in the near future given ongoing and future studies.


Sperm function and structure and seminal plasma prostanoid concentrations in men with IDDM.
Semen from 18 men with insulin-dependent diabetes mellitus (IDDM) aged 20-40 yr was compared with that from 15 age-matched control subjects. Although semen volume, sperm count, and spermatozoal motility were similar in the two groups, semen from diabetic men had significantly greater numbers of abnormal spermatozoa and significantly lower ability to penetrate hamster eggs. Concentrations of prostaglandins E2, F2 alpha, and I2 and thromboxane A2 were significantly elevated in the seminal plasma from semen of diabetic subjects compared with control subjects. These observations indicate the need for a careful assessment of fertility in diabetic men, the mechanisms underlying the abnormalities in spermatozoa, and the relationship of these abnormalities to the increase in prostanoid concentrations in diabetic men.


Comparison of three differently shaped ROIs in free breathing breast radiotherapy setup using surface guidance with AlignRT®.
Setup accuracy within adjuvant radiotherapy of breast cancer treated in free breathing is well studied, but a comparison of the typical regions of interest (ROI) used in surface guided radiation therapy (SGRT) does not exist. The aim of this study was to estimate the setup accuracy obtained with differently shaped ROIs in SGRT. A total of 573 orthogonal image pairs were analyzed from free breathing breast patients in two groups: positioning using AlignRT® surface guidance system (Group A, n = 20), and setup using conventional laser and tattoo setup (Group L, n = 20). For SGRT, three different setup ROIs were used: a Breast-shaped, O-shaped and T-shaped (B-O and T-ROI). We evaluated the isocenter-, rotation-, pitch and arm position accuracy and residual errors for the chest wall and shoulder joint in kV orthogonal and tangential setup images with laser- or SGRT-based setup. Less isocenter variance was found in Group A than in Group L. Rotations and posture errors were larger in group L than in Group A (p ≤ 0.05). Rotation error was smaller with T-shaped ROI than with O- or B-shape (p = 0.01-0.04). Setup with AlignRT® improves reproducibility compared to laser setup. Between the different ROI shapes only small differences were found in the patient posture or the isocenter position in the images. The T-ROI is recommended to set up the chest wall bony structure and an additional B-ROI may be used to fine-tune the soft tissue accuracy.


Neoadjuvant and adjuvant chemotherapy for locally advanced bladder carcinoma: development of novel bladder preservation approach, Osaka Medical College regimen.
Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of "combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects ("Osaka Medical College regimen" referred to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21-814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review.


Patient-centered medical homes and oral anticoagulation therapy initiation.
Despite evidence-based guidelines, oral anticoagulation therapy (OAT) initiation is low among incident atrial fibrillation (AF) patients. Patient-centered medical homes (PCMHs) may increase access, quality, and value through coordinating care. As such, PCMHs hold potential for improving OAT initiation among AF patients. We estimated the effect of receiving care in accredited PCMHs on OAT initiation for incident AF patients compared with those not receiving care in accredited PCMHs. Our study, a retrospective cohort new user design, included privately insured patients in North Carolina during years 2006 to 2010. We developed propensity scores for PCMH exposure, performed inverse probability of treatment weighting, and estimated effects with generalized estimating equations. We found a positive association between PCMH exposure and OAT initiation in unadjusted (6.78%; p < .001) and adjusted (6.25%; p < .001) models. Greater implementation and optimization of PCMH model principles may enhance this association, reducing AF-related stroke morbidity and mortality.


[Scanning electron microscopic observations on gastric cancer].
On the basis of transmission electron microscopy of the gastric cancer, 10 cases with various types of the same tumor were further observed by Hitachii S-450 scanning electron microscope (SEM). The mucosa of the gastric cancer, para-cancer area and the perigastric lymph nodes were taken and fixed with penta-aldehyde and osmic acid, then processed into scanning specimens. By SEM, the para-cancer mucosa was quite similar to the "normal" gastric mucosa. Its free surface looked like strawberry. The gastric papule and fovea could be seen and the border of the cells was distinct. There was an uneven spacial structure similar to mountains and valleys at the border between the mucosa of the cancer and the non-cancer area. The mucosa of gastric adenocarcinoma showed wornout cotton-like erosion and destruction losing the normal tissue structures. The mucous epithelium was arranged disorderly adhered with marked dyskaryotic cancer cells. In the 2 cases of poorly differentiated adenocarcinoma and 1 undifferentiated carcinoma, metastatic cancer cells were found in the marginal sinuses of the perigastric lymph nodes. The scanogram of SEM showed a cluster of metastatic cancer cells neared and were adhering to the target organ. Some of the cells were observed stretching out their filament pseudopodia and invading the target organ. It implies a subsequent distant metastasis. Further study on the stereostructural changes of the surface membrane of cancer cells would help to explain the pathogenesis and development of gastric cancer.


Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines.
Somatic mutations binding to the patient's MHC and recognized by autologous T cells (neoepitopes) are ideal cancer vaccine targets. They combine a favorable safety profile due to a lack of expression in healthy tissues with a high likelihood of immunogenicity, as T cells recognizing neoepitopes are not shaped by central immune tolerance. Proteins mutated in cancer (neoantigens) shared by patients have been explored as vaccine targets for many years. Shared ("public") mutations, however, are rare, as the vast majority of cancer mutations in a given tumor are unique for the individual patient. Recently, the novel concept of truly individualized cancer vaccination emerged, which exploits the vast source of patient-specific "private" mutations. Concurrence of scientific advances and technological breakthroughs enables the rapid, cost-efficient, and comprehensive mapping of the "mutanome," which is the entirety of somatic mutations in an individual tumor, and the rational selection of neoepitopes. How to transform tumor mutanome data to actionable knowledge for tailoring individualized vaccines "on demand" has become a novel research field with paradigm-shifting potential. This review gives an overview with particular focus on the clinical development of such vaccines.


Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart.
Relaxin, a reproductive hormone of the insulin-like growth factor family, increases heart rate in experimental animals but its other actions on cardiac function and cellular mechanisms responsible for the positive chronotrophic effect remain unknown. We have studied the actions of human recombinant gene-2 relaxin on the release of atrial natriuretic peptide (ANP) and cardiac function (heart rate, contractile force, perfusion pressure) as well as the underlying signal transduction mechanisms by using the isolated perfused spontaneously beating rat heart preparation. The administration of relaxin into the perfusion fluid at concentrations of 1.5, 3 or 10 nM for 30 min caused a dose-dependent sustained increase in heart rate, while contractile force and perfusion pressure remained unchanged. In addition, infusion of relaxin at a concentration of 10 nM into the perfusate produced a gradual 1.5-fold increase in immunoreactive ANP (IR-ANP) secretion (from 456 +/- 76 to 701 +/- 124 pg/ml, F = 4.5, P < 0.001). The ANP secretory and chronotrophic effects of relaxin appear to involve the activation of protein kinase C, since administration of a protein kinase C inhibitor staurosporine at a concentration of 30 nM completely blocked the effect of relaxin (10 nM) on IR-ANP secretion (P < 0.001) and heart rate (P < 0.001). A cAMP-dependent protein kinase inhibitor, H-89 (100 nM), also substantially reduced the ANP secretory effect of relaxin and attenuated the increase in heart rate during the sustained phase of the relaxin infusion (P < 0.001). KN-62 (3 microM), a Ca2+/calmodulin-dependent protein kinase inhibitor, decreased the positive chronotrophic effect of relaxin (P < 0.001) but did not influence significantly the effect of relaxin on IR-ANP release in isolated perfused rat heart preparation. These results provide the first evidence that relaxin stimulates the secretion of ANP from isolated perfused rat hearts. Our results also suggest that relaxin modulates ANP secretion by activation of protein kinase C and cAMP-dependent protein kinase pathways.


The molecular characterization of antibody binding to a superantigen-like protein from a commensal microbe.
Microorganisms have coevolved diverse mechanisms to impair host defenses. A major one, superantigens, can result in devastating effects on the immune system. While all known superantigens induce vast immune cell proliferation and come from opportunistic pathogens, recently, proteins with similar broad specificity to antibody variable (V) domain families were identified in a commensal microbiota. These proteins, identified in the human commensal Ruminococcus gnavus, are called immunoglobulin-binding protein (Ibp) A and B and have been shown to activate B cells in vitro expressing either human VH3 or murine VH5/6/7. Here, we provide molecular and functional studies revealing the basis of this Ibp/immunoglobulin (Ig) interaction. The crystal structure and biochemical assays of a truncated IbpA construct in complex with mouse VH5 antigen-binding fragment (Fab) shows a binding of Ig heavy chain framework residues to the Ibp Domain D and the C-terminal heavy chain binding domain (HCBD). We used targeted mutagenesis of contact residues and affinity measurements and performed studies of the Fab-IbpA complex to determine the stoichiometry between Ibp and VH domains, suggesting Ibp may serve to cluster full-length IgA antibodies in vivo. Furthermore, in vitro stimulation experiments indicate that binding of the Ibp HCBD alone is sufficient to activate responsive murine B cell receptors. The presence of these proteins in a commensal microbe suggest that binding a broad repertoire of immunoglobulins, particularly in the gut/microbiome environment, may provide an important function in the maintenance of host/microbiome homeostasis contrasting with the pathogenic role of structurally homologous superantigens expressed by pathogens.


Prognostic and predictive factors for clinical and radiographic responses in patients with painful bone metastasis treated with magnetic resonance-guided focused ultrasound surgery.
Background: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is an alternative local therapy for patients with painful bone metastasis. However, little is known about the prognostic and predictive factors of MRgFUS in treating bone metastasis. Materials and methods: This retrospective study analyzed the performance status, treated site, pretreatment pain score, pretreatment tumor volume and lesion coverage volume factor (CVF) of 31 patients who underwent MRgFUS. A numerical rating scale for pain was used at the same time to assess the clinical response. Radiographic responses were evaluated using a modified version of The University of Texas MD Anderson Cancer Center criteria and reference to the MR imaging or computed tomography scans obtained 3 months after treatment. Univariate and multivariate logistic regression analyses were conducted to examine the effect of variables on clinical and radiographic responses. Results: The overall clinical response rate was 83.9% and radiographic response rate was 67.7%. Multivariate logistic regression analysis revealed that the better pretreatment Karnofsky performance status (KPS) (odds ratio: 1.220, 95% confidence interval (CI): 1.033-1.440; p = 0.019) was significantly associated with a more positive clinical response, and that the lesion CVF (odds ratio: 1.183, 95% CI: 1.029-1.183; p = 0.0055) was an independent prognostic factor for radiographic responses. The radiographic response of patients with lesion CVF ≥70% and CVF <70% were 91.7% and 52.6%, respectively (p = 0.0235). Conclusion: The pretreatment KPS was an independent prognostic factor for clinical responses, and lesion CVF was an independent prognostic factor for radiographic responses.


Factors Associated With Emergency Department Discharge, Outcomes and Follow-Up Rates of Stable Patients With Lower Gastrointestinal Bleeding.
Lower gastrointestinal bleeding (LGIB) is a common reason for hospitalization. However, recent data suggest low-risk patients may be safely evaluated as an outpatient. Here, we compare stable LGIB patients discharged from the emergency department (ED) with those admitted, determine factors associated with discharge and 30-day outcomes, and evaluate follow-up rates amongst the discharged cohort. A retrospective study of stable LGIB patients (heart rate < 100 beats/min, systolic blood pressure > 100 mm Hg and blood on rectal exam) who presented to the ED was conducted. Factors associated with discharge and rates of outpatient follow-up were determined in the discharged cohort. Therapeutic interventions and 30-day outcomes (including re-bleeding, re-admission and mortality rates) were compared between the admitted and discharged groups. Ninety-seven stable LGIB patients were reviewed, of whom 38% were discharged and characteristics associated with discharge included age (P < 0.001), lack of aspirin (P < 0.002) and anticoagulant (P < 0.004) use, higher index hemoglobin (P < 0.001) and albumin (P < 0.001), lower blood urea nitrogen (P < 0.001) and creatinine (P = 0.008), lower Oakland score (P < 0.001), lower Charlson Comorbidity Index (P < 0.001) and lack of transfusion requirements (P < 0.001). There was no statistical difference in 30-day re-bleeding, re-admission or mortality rates between admitted and discharged patients. Discharged patients had a 46% outpatient follow-up rate. While early discharge in low-risk LGIB patients appears to be safe and associated with a decrease in length of stay, further studies are needed to guide timely and appropriate outpatient evaluation.


Iatrogenic direct rectal injury: an unusual complication during suprapubic cystostomy (SPC) insertion and its laparoscopic management.
Suprapubic cystostomy (SPC) is commonly used, instead of indwelling urethral catheter- ization, as indicated in many pathological conditions. Although considered to be a safe procedure that can be easily performed in an outpatient basis several complications have been reported in international literature. Bowel injury can be a serious complication with the small intestine affected in the majority of cases. We present a case of an acci- dental rectal injury by a suprapubic catheter misplacement, in a 76 year old demented patient with prostatic hyperplasia and chronic urinary retention. The injury was confirmed by cystogra- phy and injection of contrast meterial through the suprapubic catheter, and successfully treated laparoscopically by an extraperitoneal approach. The patient was discharged after 10 days with- out any complications. The above method, in experienced hands, can be an effective primary treatment option for such rare but devastating complications. The case and management is unique as, to our knowledge, as no similar cases have been presented.


An Automated Broncho-Arterial (BA) Pair Segmentation Process and Assessment of BA Ratios in Children with Bronchiectasis Using Lung HRCT Scans: A Pilot Study.
Bronchiectasis in children can progress to a severe lung condition if not diagnosed and treated early. The radiological diagnostic criteria for the diagnosis of bronchiectasis is an increased broncho-arterial (BA) ratio. From high-resolution computed tomography (HRCT) scans, the BA pairs must be detected first to derive the BA ratio. This study aims to identify potential BA pairs from HRCT scans of children undertaken to evaluate suppurative lung disease through an automated approach. After segmenting the lung regions, the HRCT scans are cleaned using a histogram analysis-based approach followed by a potential arteries identification process comprising four conditions based on imaging features. Potential arteries and their connected components are extracted, and potential bronchi are identified. Finally, the coordinates of potential arteries and potential bronchi are matched as the last step of BA pairs extraction. A total of 8-50 BA pairs are detected for each patient. Additionally, the area and several diameters of the bronchi and arteries are measured, and BA ratios based on these are calculated. Through this approach, the BA pairs of a CT scan datasets are detected and utilizing a deep learning model, a high classification test accuracy of 98.53% is achieved, validating the robustness of the proposed BA detection approach. The results show that visible BA pairs can be identified and segmented automatically, and the BA ratio calculated may help diagnose bronchiectasis with less effort and time.


Voxel-based morphometry of grey matter structures in Parkinson's Disease with wearing-off.
Our study aimed to investigate the grey matter (GM) changes using voxel-based morphometry (VBM) in Parkinson's disease (PD) patients with wearing-off (WO). 3D-T1-weighted imaging was performed on 48 PD patients without wearing-off (PD-nWO), 39 PD patients with wearing-off (PD-WO) and 47 age and sex-matched healthy controls (HCs). 3D structural images were analyzed by VBM procedure with Statistical Parametric Mapping (SPM12) to detect grey matter volume. Widespread areas of grey matter changes were found in patients among three groups (in bilateral frontal, temporal lobes, lingual gyrus, inferior occipital gyrus, right precuneus, right superior parietal gyrus and right cerebellum). Grey matter reductions were found in frontal lobe (right middle frontal gyrus, superior frontal gyrus and precentral gyrus), right parietal lobe (precuneus, superior parietal gyrus, postcentral gyrus), right temporal lobe (superior temporal gyrus, middle temporal gyrus), bilateral lingual gyrus and inferior occipital gyrus in PD-WO group compared with the PD-nWO group. Our results suggesting that wearing-off may be associated with grey matter atrophy in the cortical areas. These findings may aid in a better understanding of the brain degeneration process in PD with wearing-off.


[Clinical, prognostic, and preventive significance of "premorbid" psychic states in adolescents and youths (observational study)].
This paper presents results of observational, clinico-epidemiological, and catamnestic studies including 856 adolescents and youths attending schools, professional and higher education institutions in Moscow. The data are analysed in terms of the prevalence, structure, and dynamics of different borderline psychic states depending on age. The frequency of "premorbid" psychic abnormalities in adolescents is shown to be 52.6% compared with 15.46% in youths. It is argued that subclinical psychic disorders in adolescents have more favourable prognosis and should be regarded as adaptive reactions to the processes associated with physiological pubertal crisis. Recommendations are proposed for differential primary and secondary prophylaxis of age-related premorbid psychic states.


Understanding the coping process from a self-determination theory perspective.
To explore conceptual links between the cognitive-motivational-relational theory (CMRT) of coping (Lazarus, 1991) and self-determination theory (SDT) of motivation (Deci & Ryan, 1985). We present a very brief overview of the two theories. We also discuss how components from the two theories can be examined together to facilitate research in the health/exercise domain. To this effect, we offer a preliminary integrated model of stress, coping, and motivation, based on the two aforementioned theories, in an attempt to illustrate and instigate research on how motivational factors are implicated in the coping process. We believe that the proposed model can serve as a platform for generating new research ideas which, besides their theoretical relevance, may have important applied implications.


Possible new method to improve detection of diabetic retinopathy: Polaroid non-mydriatic retinal photography.
Two retinal cameras (Canon CR2 45NM and CR3 45NM) have recently become available and are capable of producing an instant colour photography of a 45 degree field of retina, including the macula and optic disc, without dilatation of the pupils being necessary. The ability of each camera to detect diabetic retinopathy was compared with that of doctors in diabetic clinics using ophthalmoscopy during busy clinic hours. The CR3 was found to be considerably superior to the CR2 in terms of quality of photograph because it can use a smaller pupil. Overall, the detection rate of the camera was more than four times higher than that of ophthalmoscopy through undilated pupils and more than twice as high as that of ophthalmoscopy through dilated pupils. Lesions missed by ophthalmoscopy but detected by the camera included soft exudates and circinate rings of hard exudates, sometimes encroaching on the macula. Though various aspects of this system of screening for diabetic retinopathy, in particular its ability to detect new retinal vessels, have not yet been assessed, the system may prove beneficial in the detection and monitoring of diabetic retinopathy.


Methodological idiosyncracies, frameworks and challenges of non-pharmaceutical and non-technical treatment interventions.
In this brief article which summarises a presentation given at the "6. Diskussionsforum zur Nutzenbewertung im Gesundheitswesen" of the German Ministry of Education and Research "Gesundheitsforschungsrat (GFR)" and the Institute for Quality and Efficiency in Healthcare (IQWiG) I will analyse some methodological idiosyncrasies of studies evaluating non-pharmacological non-technical interventions (NPNTI). I will focus on how the methodological framework of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group may support design and appraisal of NPNTI. Specific design features that may be of particular value in NPNTI research, such as expertise-based randomised controlled trials, will be briefly described. Finally, based on an example, I will argue that - despite the methodological idiosyncrasies - there is neither a sufficient reason to accept different standards for the assessment of the confidence in the evidence from NPNTI nor for using study designs that are less rigorous compared to "simpler" interventions but that special measures have to be taken to reduce the risk of bias. The example that will be used in this article will primarily come from the field of respiratory rehabilitation, a typical multi-component or complex intervention and by definition a complex NPNTI, which has been evaluated in many randomised controlled trials. (As supplied by publisher).


[Chronic poisoning by organophosphoric VX].
Long-term observation of workers engaged into production of VX chemical diagnosed slow progressing manifestation of chronic occupational poisoning with the chemical. The characteristic nervous, digestive, locomotory, visual and cardiovascular symptoms were revealed. The authors presented laboratory and instrumental data on the cases. As the treatment appeared ineffective, further adjustment and improvement of the therapy is required. The article demonstrated the main underlying metabolic disorders that could be addressed by the pathogenetic therapy.


Parotid surgery and the otolaryngologist.
Otolaryngologists are performing more parotid surgery and are using otologic landmarks and methods to identify and preserve the facial nerve. Over the past 15 years in the Department of Otolaryngology-Head and Neck Surgery at Tulane Medical School, use of the tympanomastoid fissure as a guide to the facial nerve has reduced the incidence of immediate facial paralysis from 60% to 14% in benign parotid disease.


A repeated measures model for analysis of continuous outcomes in sequential parallel comparison design studies.
Previous authors have proposed the sequential parallel comparison design (SPCD) to address the issue of high placebo response rate in clinical trials. The original use of SPCD focused on binary outcomes, but recent use has since been extended to continuous outcomes that arise more naturally in many fields, including psychiatry. Analytic methods proposed to date for analysis of SPCD trial continuous data included methods based on seemingly unrelated regression and ordinary least squares. Here, we propose a repeated measures linear model that uses all outcome data collected in the trial and accounts for data that are missing at random. An appropriate contrast formulated after the model has been fit can be used to test the primary hypothesis of no difference in treatment effects between study arms. Our extensive simulations show that when compared with the other methods, our approach preserves the type I error even for small sample sizes and offers adequate power and the smallest mean squared error under a wide variety of assumptions. We recommend consideration of our approach for analysis of data coming from SPCD trials.


SPEAKers at the National Society of Hospital Medicine Meeting: A Follow-UP Study of Gender Equity for Conference Speakers from 2015 to 2019. The SPEAK UP Study.
Women continue to be underrepresented as speakers at national conferences, and research has shown similar trends in hospital medicine. The Society of Hospital Medicine (SHM) Annual Meeting has historically had an open call peer review process for workshop speakers and, in 2019, expanded the process for didactic speakers. We aimed to assess the overall conference trends for women speakers and whether the systematic processes in recruitment procedures (ie, open call) resulted in improved representation of women speakers. We also sought to understand how the proportion of women speakers might affect overall scores of the conference. From 2015 to 2019, the overall representation of women speakers increased, as did evaluation scores during the same time period. When selection processes included the open call peer review process, there were higher proportions of women speakers. An open call process with peer review for speakers may be a systematic process that national meetings could replicate to reduce gender inequities.


Advances in joint species distribution models to reveal community structure and its environmental response.
Species distribution models are commonly used in basic and applied ecological research to examine the factors driving the distribution and abundance of organisms. They are employed to quantify species' relationships with abiotic conditions, to predict species' response to land-use and climatic change, and to identify potential conservation areas. Biotic interactions have been rarely included in traditional species distribution models, wherein joint species distribution models (JSDMs) emerge as a feasible approach to simultaneously incorporate environmental factors and interspecific interactions, making it a powerful tool for analyzing the structure and assembly of biotic communities. Generally, the JSDMs are based on species distribution models (SDMs), with the abundance or occurrence of multiple species as response variables and environmental factors, species associations and species traits being incorporated in the modeling framework. These models commonly use generalized linear regression methods (GLM) to relate multivariate response to environmental variables, and capture species associations in the form of random effects. The limitation has been overcome by the introduction of latent variable models (LVMs). Typically, the model parameters are estimated using maximum likelihood estimation or Bayesian methods implemented by Laplace Approximation and Markov Chain Monte Carlo (MCMC) simulations, respectively. In this review, the generation and theoretical basis of JSDMs were summarized. The characteristics of different types of JSDMs and their applications in modern ecology were emphatically introduced. The problems and prospects of JSDMs were discussed. With the in-depth study of the relationship between environmental factors and multi-species interactions, JSDMs would be the focus of future studies of species distribution model.


Viability Loss of Salmonella Species, Staphylococcus aureus , and Listeria monocytogenes in Complex Foods Heated by Microwave Energy.
The chemical composition of five foods (UHT milk, beef broth, pudding, cream sauce, and liquid whole egg) was examined to determine factors important in achieving uniform temperatures within foods heated in a 700 W microwave oven. Proximate analyses were performed on all food systems to relate their chemical composition to temperatures and to destruction of microwave-heated Salmonella species, Listeria monocytogenes Scott A and V7 and Staphylococcus aureus ATCC 25923. Microwave heating times were chosen such that the final mixed mean temperature achieved by systems was 60°C for Salmonella spp. and L. monocytogenes , and 65°C for S. aureus . The amount of destruction of Salmonella spp. varied from 3.17 log CFU/ml in UHT milk to 0.44 log CFU/ml in beef broth. L. monocytogenes strains incurred the greatest amount of destruction in pudding (2.39 log CFU/g), while the least amount of destruction was observed in cream sauce (1.63 log CFU/ml). There were no significant differences in the amount of destruction of S. aureus heated in the five foods. The pH and aw of these foods did not affect survival of thermally stressed Salmonella , L. monocytogenes , or S. aureus cells. Of the food components examined, sodium content was the primary influence on the uniformity of temperatures achieved within foods, and, in turn, on the survival of bacteria.


Endovascular Repair of Blunt Thoracic Aortic Trauma: Is Postimplant Hypertension an Incidental Finding?
Blunt thoracic aortic injury (BTAI) is the second most common cause of death in trauma patients. Nowadays, thoracic endovascular aortic repair (TEVAR) has become the treatment of choice because of lower rates of mortality, paraplegia, and stroke. However, concerns have been raised whether graft implantation is related to the development of hypertension in the postoperative period. The aim of this study was to report short- and long-term outcomes of patients undergoing TEVAR for BTAIs at a tertiary hospital and to investigate postimplant hypertension. Between January 2005 and January 2016, 23 patients with blunt thoracic aortic trauma underwent TEVAR. Median age was 44 years (range, 18-73). Among them, 14 (60.9%) patients were diagnosed with aortic rupture, whereas 9 (39.1%) with pseudoaneurysm. Α single thoracic stent graft was deployed in 21 patients, and the rest 2 patients received 2 stent grafts. Complete exclusion of the injury was feasible in all subjects (100% primary success). The left subclavian artery (SCA) was intentionally covered in 6 patients (26%). Intraoperative complications included one nonfatal stroke managed conservatively and one external iliac artery rupture treated with iliofemoral bypass. One patient (4.3%) died on the first postoperative day in the intensive care unit (ICU) because of hemorrhagic shock. The overall 30-day mortality and morbidity were 4.3% and 8.7%, respectively. New-onset postimplantation arterial hypertension was observed in 8 (34.8%) previously nonhypertensive patients. Younger age (P = 0.027) and SCA coverage (P = 0.01) were identified as potential risk factors for the development of postimplant hypertension, whereas the presence of concomitant injuries (P = 0.3) and intraoperative complications (P = 0.1) were not. After a median follow-up of 100 months (range, 18-120), 6 of them still remain on antihypertensive therapy, whereas the other 2 did not require permanent treatment. TEVAR is a safe approach in the treatment of BTAI associated with low short- and long-term morbidity and mortality rates. Lower age and SCA coverage may contribute to the development of postimplant hypertension. Further larger cohort studies are warranted to elucidate the underlying mechanisms of postimplant hypertension.


The Coevolution of Cellularity and Metabolism Following the Origin of Life.
The emergence of cellular organisms occurred sometime between the origin of life and the evolution of the last universal common ancestor and represents one of the major transitions in evolutionary history. Here we describe a series of artificial life simulations that reveal a close relationship between the evolution of cellularity, the evolution of metabolism, and the richness of the environment. When environments are rich in processing energy, a resource that the digital organisms require to both process their genomes and replicate, populations evolve toward a state of non-cellularity. But when processing energy is not readily available in the environment and organisms must produce their own processing energy from food puzzles, populations always evolve both a proficient metabolism and a high level of cellular impermeability. Even between these two environmental extremes, the population-averaged values of cellular impermeability and metabolic proficiency exhibit a very strong correlation with one another. Further investigations show that non-cellularity is selectively advantageous when environmental processing energy is abundant because it allows organisms to access the available energy, while cellularity is selectively advantageous when environmental processing energy is scarce because it affords organisms the genetic fidelity required to incrementally evolve efficient metabolisms. The selection pressures favoring either non-cellularity or cellularity can be reversed when the environment transitions from one of abundant processing energy to one of scarce processing energy. These results have important implications for when and why cellular organisms evolved following the origin of life.


Fully Automated Volumetric Breast Density Estimation from Digital Breast Tomosynthesis.
Background While digital breast tomosynthesis (DBT) is rapidly replacing digital mammography (DM) in breast cancer screening, the potential of DBT density measures for breast cancer risk assessment remains largely unexplored. Purpose To compare associations of breast density estimates from DBT and DM with breast cancer. Materials and Methods This retrospective case-control study used contralateral DM/DBT studies from women with unilateral breast cancer and age- and ethnicity-matched controls (September 19, 2011-January 6, 2015). Volumetric percent density (VPD%) was estimated from DBT using previously validated software. For comparison, the publicly available Laboratory for Individualized Breast Radiodensity Assessment software package, or LIBRA, was used to estimate area-based percent density (APD%) from raw and processed DM images. The commercial Quantra and Volpara software packages were applied to raw DM images to estimate VPD% with use of physics-based models. Density measures were compared by using Spearman correlation coefficients (r), and conditional logistic regression was performed to examine density associations (odds ratios [OR]) with breast cancer, adjusting for age and body mass index. Results A total of 132 women diagnosed with breast cancer (mean age ± standard deviation [SD], 60 years ± 11) and 528 controls (mean age, 60 years ± 11) were included. Moderate correlations between DBT and DM density measures (r = 0.32-0.75; all P < .001) were observed. Volumetric density estimates calculated from DBT (OR, 2.3 [95% CI: 1.6, 3.4] per SD for VPD%DBT) were more strongly associated with breast cancer than DM-derived density for both APD% (OR, 1.3 [95% CI: 0.9, 1.9] [P < .001] and 1.7 [95% CI: 1.2, 2.3] [P = .004] per SD for LIBRA raw and processed data, respectively) and VPD% (OR, 1.6 [95% CI: 1.1, 2.4] [P = .01] and 1.7 [95% CI: 1.2, 2.6] [P = .04] per SD for Volpara and Quantra, respectively). Conclusion The associations between quantitative breast density estimates and breast cancer risk are stronger for digital breast tomosynthesis compared with digital mammography. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Yaffe in this issue.


Desorption kinetics of hydrophobic organic contaminants from marine plastic pellets.
This study investigated the desorption behavior of polychlorinated biphenyls (PCBs) from marine plastic pellets. Long-term desorption experiments were conducted using field-collected polyethylene (PE) pellets. The results indicate that the desorption kinetics highly depends on the PE-water partition coefficients of PCB congeners. After 128 d of the experiment, the smallest congener considered (CB 8) had desorbed nearly completely (98%), whereas major fractions (90-99%) of highly chlorinated congeners remained in the pellets. An intraparticle diffusion model mostly failed to reproduce the desorption kinetics, whereas an aqueous boundary layer (ABL) diffusion model well approximated the data. The desorption half-lives are estimated to 14 d to 210 years for CB 8 to CB 209 in an actively stirred solution (ABL thickness: 30 μm). Addition of methanol to water enhanced the desorption to a large extent. A need for further work to explore roles of organic matter in facilitating solute transfer is suggested.


[Various features of the formation and secretion of bile acids in spontaneous atherosclerosis].
Main pathways of cholesterol catabolism were found to be dissimilar in patients with spontaneous coronary atherosclerosis accompanied by hyperlipoproteinemia as compared with healthy persons of the same age. In the patients, independently of the hyperlipoproteinemia type, a longer pathway prevailed which terminated at the step of cholic acid formation, while in healthy persons the shorter pathway was found to be discontinuous after chenodeoxycholic acid production. The specific property of cholesterol catabolism in healthy persons appears to be due to a decrease in activity of V12 alpha-hydroxylase thus protecting against development of spontaneous atherosclerosis.


Welfare in veal calf units.
Compared to France, Italy, the Netherlands and Germany the production of white veal in the United Kingdom is relatively limited. Nevertheless, public interest in veal calf welfare appears to be lively. Although calves are sucklings of social-living ruminants, veal calves are not allowed to suck, to have a social life or to ruminate. This, added to anaemia in order to obtain white meat, and the high rate of morbidity caused by high density of the animals, sums up the welfare problems which arise. In principle, there are two types of housing: single housing in crates or group housing. Group housing is almost impossible for calves younger than six weeks, because of disease control and urine sucking. Even after this age it requires much skill and labour. Enforceable regulations within the European Economic Community concerning the amount of light in the fattening houses and the measurements of crates for individual housing are suggested. It is recommended that anaemia in young calves should be treated.


Cestode in North Dakota: echinococcus in field mice.
Field mice (Microtus pennsylvanicus and Peromyscus maniculatus) are naturally infected with Echinococcus multilocularis. Thus, the sylvatic cycle (fox to field mice to fox) has been established in North Dakota. This cestode is expected to extend its range to other agricultural regions of the continental United States where similar conditions favorable for the completion of its life cycle exist.


Torin1-mediated TOR kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells.
The target of rapamycin (TOR) kinase regulates cell growth and division. Rapamycin only inhibits a subset of TOR activities. Here we show that in contrast to the mild impact of rapamycin on cell division, blocking the catalytic site of TOR with the Torin1 inhibitor completely arrests growth without cell death in Schizosaccharomyces pombe. A mutation of the Tor2 glycine residue (G2040D) that lies adjacent to the key Torin-interacting tryptophan provides Torin1 resistance, confirming the specificity of Torin1 for TOR. Using this mutation, we show that Torin1 advanced mitotic onset before inducing growth arrest. In contrast to TOR inhibition with rapamycin, regulation by either Wee1 or Cdc25 was sufficient for this Torin1-induced advanced mitosis. Torin1 promoted a Polo and Cdr2 kinase-controlled drop in Wee1 levels. Experiments in human cell lines recapitulated these yeast observations: mammalian TOR (mTOR) was inhibited by Torin1, Wee1 levels declined and mitotic commitment was advanced in HeLa cells. Thus, the regulation of the mitotic inhibitor Wee1 by TOR signalling is a conserved mechanism that helps to couple cell cycle and growth controls.


CYP21A2 expression is localized in the developing distal epithelium of the human perinatal lung and is compatible with in situ production and intracrine actions of active glucocorticoids.
Glucocorticoids play essential roles in lung development. We investigated for expression of CYP21A2 (21-hydroxylase) as well as for the presence of the corresponding protein and identification of CYP21A2-expressing cells in several human developing lungs. Expression of some related genes was also assessed. CYP21A2 and CYP17A1 (P450c17) mRNAs were found in all the 34 lung samples from 17 to 40 weeks' gestation at variable levels. No correlation was found according to sex but a correlation with age was detected for CYP17A1 only. In contrast, CYP11B1 (11β-hydroxylase)- and CYP11B2 (aldosterone synthase)-mRNAs were not detected. Significant levels of the CYP21A2 protein were detected in all the analyzed samples, while only very low signals were detected for CYP17A1 protein. In situ hybridization revealed that CYP21A2 was almost exclusively expressed in the distal epithelium. It was reported that the lung distal epithelium of human fetuses also express 11β-hydroxysteroid dehydrogenase type 2, which catalyzes cortisol inactivation into cortisone. Based on this information, intracrine glucocorticoid actions should take place from CYP21A2 products through the glucocorticoid receptor in the absence of cortisol. In contrast, mineralocorticoid receptor activation did not seem to depend on deoxycorticosterone produced from local activity of CYP21A2 because of the reported circulating amounts of aldosterone.


Surface energy and surface proton order of the ice Ih basal and prism surfaces.
Density-functional theory (DFT) is used to examine the basal and prism surfaces of ice Ih. Similar surface energies are obtained for the two surfaces; however, in each case a strong dependence of the surface energy on surface proton order is identified. This dependence, which can be as much as 50% of the absolute surface energy, is significantly larger than the bulk dependence (<1%) on proton order, suggesting that the thermodynamic ground state of the ice surface will remain proton ordered well above the bulk order-disorder temperature of about 72 K. On the basal surface this suggestion is supported by Monte Carlo simulations with an empirical potential and solution of a 2D Ising model with nearest neighbor interactions taken from DFT. Order parameters that define the surface energy of each surface in terms of nearest neighbor interactions between dangling OH bonds (those which point out of the surface into vacuum) have been identified and are discussed. Overall, these results suggest that proton order-disorder effects have a profound impact on the stability of ice surfaces and will most likely have an effect on ice surface reactivity as well as ice crystal growth and morphology.


Analysis of serotype-specific neutralization epitopes on VP7 of human rotavirus by the use of neutralizing monoclonal antibodies and antigenic variants.
We analysed serotype-specific antigens of human rotavirus (HRV) by the use of neutralizing monoclonal antibodies (N-MAbs). The reactivity patterns of 12 serotype-specific N-MAbs against 15 HRV strains in a neutralization test revealed great intraserotypic antigenic variation especially those belonging to serotypes 2,3 and 4. On the basis of the protein specificity of the antibodies examined, it was suggested that whereas serotype 2-specific neutralization epitopes were present on both VP3 and VP7 outer capsid proteins, serotype 1-, 3- and 4-specific neutralization epitopes were located on VP7. Serotype-specific neutralization epitopes on VP7 of the serotype 1 HRV KU strain were analysed further using mutants of the KU strain resistant to different serotype 1-specific N-MAbs. The result suggested the presence of at least five operationally overlapping neutralization epitopes on VP7 of the KU strain, which collectively constituted a single large neutralization domain.


Patient Feedback Requirements for Medical Students: Do Perceived Risks Outweigh the Benefits?
Patient feedback has increasingly become part of medical students' training and formative assessment. We conducted a qualitative study using focus groups to explore students' experiences soliciting patient feedback, including the benefits, challenges, and potential strategies to obtain it. Fifteen medical students participated. Thematic analysis revealed students' (1) discomfort soliciting feedback and concern of being viewed as self-serving; (2) concerns about eroding patient trust; (3) indifference to nonspecific, positive feedback; and (4) belief that informally solicited feedback is most helpful for their learning. Strategies for soliciting more useful patient feedback included (1) team-based solicitation, (2) empowering patients as teachers, and (3) development of feedback instruments that allow patients to comment on specific student-identified learning goals. Solicitation of patient feedback is challenging for medical students and provokes discomfort. Strategies to integrate patient feedback into medical student training and assessment must attend to students' needs so the value of patient feedback can be realized.


Endometriosis is associated with alterations in the relative abundance of proteins and IL-10 in the peritoneal fluid.
A growing body of evidence suggests that endometriosis modulates the microenvironment of peritoneal cavity. Therefore, in this study, we compared the protein profile of peritoneal fluids from normal fertile women with those from patients with infertility, and patients with mild to severe endometriosis. Two-dimensional gel electrophoresis of peritoneal fluids from normal subjects exhibited a distinct and reproducible pattern of proteins in the size ranges of approximately 35 to 80 kD and pI close to 4.5 to 6.6. Infertility without evidence of endometriosis was not associated with changes in the relative abundance of proteins present in the peritoneal fluid. However, mild endometriosis was associated with a mild reduction in the amount of several peritoneal protein spots with the approximate molecular weights of 35-40 kD and pI close to 5.7-6.0. These changes became markedly apparent in the peritoneal fluid of patients who suffered from the severe form of this disease. Severe endometriosis was also associated with appearance of protein spots in the gels that were not detectable in the peritoneal fluids of normal subjects. Consistent with these data, enzyme-linked immunosorbent assay showed that moderate to severe endometriosis was associated with markedly elevated levels of IL-10 in the peritoneal fluid. Reverse transcription followed by polymerase chain reaction amplification using primers specific to IL-10 confirmed presence of IL-10 mRNA in cells derived from peritoneal fluids. These findings show that endometriosis is associated with disturbed secretion of proteins into the peritoneal cavity and with an elevated level of IL-10 in the peritoneal fluid. The studies also show cells resident in peritoneum as a major source of IL-10.


Direct notification of cervical cytology results to women improves follow-up in cervical cancer screening - A cluster-randomised trial.
Up to half of all women do not receive follow-up as recommended after cervical cytology testing and are thus at increased risk of dysplasia progression. Women from lower social positions are at increased risk of not receiving follow-up. Sample takers, often general practitioners, convey results to women, but communication problems constitute a challenge. We aimed to investigate the effect of direct notification of cervical cytology results on follow-up rates. In a 1:1 cluster-randomised controlled trial, we assessed if having the pathology department convey cervical cytology results directly to the investigated women improved timely follow-up, compared with conveying the results via the general practitioner as usual. All women with a cervical cytology performed in a general practice in the Central Denmark Region (2013-2014) and receiving follow-up recommendation were included (n = 11,833). The proportion of women without timely follow-up was lower in the group with direct notifications than in the control group of women receiving usual care, regardless of age, educational status, cohabitation status and ethnicity. Among the women with the most severe cervical cytology diagnoses who are recommended gynaecological follow-up within 3 months, the percentage without timely follow-up was 15.1% in the intervention group and 19.5% in the control group (prevalence difference: -0.04 (95%CI: -0.07; -0.02)). Improved timely follow-up was also observed for women with a recommendation to have follow-up performed at 3 and 12 months. Cervical cytology results conveyed directly by letter to women increased the proportion of women with timely follow-up without raising inequality in follow-up measured by social position. Trial registration: ClinicalTrials.gov (TRN: NCT02002468) 29 November 2013.


Lysophosphatidic acid-mediated signal-transduction pathways involved in the induction of the early-response genes prostaglandin G/H synthase-2 and Egr-1: a critical role for the mitogen-activated protein kinase p38 and for Rho proteins.
During inflammatory processes of the kidney, lesions of the glomerulus lead to aggregation of thrombocytes and infiltration of macrophages, which can release bioactive mediators. One of these important signalling molecules is lysophosphatidic acid (LPA). Incubation of rat mesangial cells with LPA induced mRNA and protein expression of the early-response genes pghs-2 (for prostaglandin G/H synthase-2/cyclo-oxygenase-2) and egr-1. As shown by antisense experiments, induction of egr-1 was related to the strong mitogenic effect of LPA. LPA-mediated gene expression was inhibited by pertussis toxin, indicating coupling to G-proteins of the Gi family. Specific inhibition of proteins of the small G-protein subfamily Rho with toxin B from Clostridium difficile led to changes in mesangial cell morphology without induction of apoptosis. LPA-mediated expression of pghs-2 and egr-1 was reduced to base-line levels by toxin B, indicating a role for Rho proteins in LPA-mediated gene induction. Of the two mitogen-activated protein kinase (MAPK) pathways investigated, the MAPK kinase-extracellular signal-regulated kinase pathway was involved in the induction of both pghs-2 and egr-1 mRNA expression, as shown by the inhibitory effect of PD98059. Activation of the MAPK p38, however, was only related to pghs-2 expression, whereas egr-1 expression was not affected by treatment of mesangial cells with the specific inhibitor SB203580. Taken together our data provide evidence that LPA-mediated activation of MAPK kinase and Rho proteins leads to the induction of the functionally distinct early-response genes pghs-2 and egr-1, whereas activation of MAPK p38 revealed considerable differences between the regulation of these two genes.


Quantifying Labial Strength and Function in Facial Paralysis: Effect of Targeted Lip Injection Augmentation.
Facial muscle weakness from paralysis or muscle dystrophy can significantly affect lip strength and function. Lip muscle weakness may result in articulation difficulties and spillage of food, both of which are socially and functionally disruptive for patients. There are few quantitative data on the effect of facial paralysis on lip strength. To quantify the effect of facial paralysis and muscular dystrophy on lip strength and evaluate the effectiveness of targeted lip injection augmentation. Analysis of patients at the Johns Hopkins Hospital between January 1, 2008, and July 31, 2014, presenting for treatment of lip incompetence due to facial paralysis and facial muscular dystrophy was prospectively undertaken. Patients who had undergone direct surgical lip procedures were excluded. Lip pressure measurements, anterior bolus spillage, and articulation of bilabial sounds before and after treatment were assessed by a single speech pathologist. Lip pressures were measured with the Iowa Oral Performance Instrument. Twenty-two patients with unilateral facial paralysis were evaluated for this study. Three patients with facioscapulohumeral muscular dystrophy were also evaluated. In unilateral facial paralysis, central lip strength was reduced in all patients compared with sex-corrected normative data (mean [SD] central lip strength, 5.5 [2.5] kPa in females and 9.6 [4.6] kPa in males). Compared with the nonparalyzed side, labial strength on the paralyzed sided was reduced by 69%. After injection augmentation of the paralyzed side, labial strength improved across the entire lip. Mean lip strength improved by 0.7-fold in the central lip from 5.60 to 9.30 kPa (P = .009), by 1.4-fold on the paralyzed side from 2.2 to 5.33 kPa (P = .006), and by 0.4-fold on the unaffected side from 7.11 to 9.56 kPa (P = .12). Lip strength in the 3 patients with facioscapulohumeral muscular dystrophy were uniformly reduced across the entire lip and improved by 6- to 7-fold after injection augmentation. All patients were noted by the speech pathologist to have improved articulation of plosive sounds and decreased anterior bolus spillage after the injection. Labial strength is reduced across the lip in patients with unilateral facial paralysis. The Iowa Oral Performance Instrument is an effective tool for measuring labial strength and can be use to evaluate the effectiveness of facial reanimation procedures. Injection augmentation of the lip is a simple and effective means of improving labial strength, bilabial sounds, and anterior spillage in patients with facial paralysis or facial muscular dystrophy. 3.


Analysis and mapping of gene families encoding beta-1,3-glucanases of soybean.
Oligonucleotide primers designed for conserved sequences from coding regions of beta-1,3-glucanase genes from different species were used to amplify related sequences from soybean [Glycine max (L.) Merr.]. Sequencing and cross-hybridization of amplification products indicated that at least 12 classes of beta-1,3-glucanase genes exist in the soybean. Members of classes mapped to 34 loci on five different linkage groups using an F(2) population of 56 individuals. beta-1,3-Glucanase genes are clustered onto regions of five linkage groups. Data suggest that more closely related genes are clustered together on one linkage group or on duplicated regions of linkage groups. Northern blot analyses performed on total RNA from root, stem, leaf, pod, flower bud, and hypocotyl using DNA probes for the different classes of beta-1,3-glucanase genes revealed that the mRNA levels of all classes were low in young leaves. SGlu2, SGlu4, SGlu7, and SGlu12 mRNA were highly accumulated in young roots and hypocotyls. SGlu7 mRNA also accumulated in pods and flower buds.


High-Throughput Immunogenetics for Clinical and Research Applications in Immunohematology: Potential and Challenges.
Analysis and interpretation of Ig and TCR gene rearrangements in the conventional, low-throughput way have their limitations in terms of resolution, coverage, and biases. With the advent of high-throughput, next-generation sequencing (NGS) technologies, a deeper analysis of Ig and/or TCR (IG/TR) gene rearrangements is now within reach, which impacts on all main applications of IG/TR immunogenetic analysis. To bridge the generation gap from low- to high-throughput analysis, the EuroClonality-NGS Consortium has been formed, with the main objectives to develop, standardize, and validate the entire workflow of IG/TR NGS assays for 1) clonality assessment, 2) minimal residual disease detection, and 3) repertoire analysis. This concerns the preanalytical (sample preparation, target choice), analytical (amplification, NGS), and postanalytical (immunoinformatics) phases. Here we critically discuss pitfalls and challenges of IG/TR NGS methodology and its applications in hemato-oncology and immunology.


Diagnosis of cure in Cushing's syndrome: lessons from long-term follow-up.
It is generally assumed that endocrine 'cure' of hypercortisolism after successful treatment for Cushing's syndrome (CS) is associated with reversal of increased morbidity and mortality, typical of the active disease. However, recent data do not support this idea; increased cardiovascular risk is still present 5 years after endocrine cure, and health-related quality of life (HRQoL), although improved when compared to the active phase of hypercortisolism, is still impaired when compared to normal population. Abnormal body composition typical of hypercortisolism (i.e., increased total and trunk fat, reduced bone mass and lean body mass) is not completely normalized, even years after controlling hypercortisolism. Thus, control of hypercortisolism in CS does not normalize HRQoL, long-term cardiovascular risk and morbidity, body composition nor some metabolic parameters. Whether the same occurs in patients exposed to pharmacological doses of exogenous glucocorticoids, and whether the body composition abnormalities associated with the exposure to exogenous glucocorticoids are reversible or not, are worth considering.


Meso-alpha,epsilon-diaminopimelate D-dehydrogenase: distribution and the reaction product.
A high activity of meso-alpha-epsilon-diaminopimelate dehydrogenase was found in extracts of Bacillus sphaericus, Brevibacterium sp., Corynebacterium glutamicum, and Proteus vulgaris among bacteria tested. B. sphaericus IFO 3525, in which the enzyme is most abundant, was chosen to study the enzyme reaction. The enzyme was not induced by the addition of meso-alpha-epsilon-diaminopimelate to the growth medium. The reaction product was isolated and identified as alpha-amino-epsilon-ketopimelate by a comparison of the properties of its 2,4-dinitrophenylhydrazone with those of an authentic sample in silica gel thin-layer chromatography, absorption, infrared and proton nuclear magnetic resonance spectrometry, and elemental analyses. The alpha-amino-epsilon-ketopimelate formed enzymatically was decarboxylated by H2O2 to yield L-alpha-aminoadipate. This suggests that the amino group with D-configuration in the substrate is oxidatively deaminated; the enzyme is a D-amino acid dehydrogenase. L-alpha-Amino-epsilon-ketopimelate undergoes spontaneous dehydration to the cyclic delta1-piperideine-2,6-dicarboxylate. The enzyme reaction is reversible, and meso-alpha-epsilon-diaminopimelate was formed in the reductive amination of L-alpha-epsilon-ketopimelate.


Persistent productive infection of human glial cells by human immunodeficiency virus (HIV) and by infectious molecular clones of HIV.
The nature of the interaction between human immunodeficiency virus (HIV) and human cells of astrocytic origin was studied in vitro with cultured glial cells and intact HIV or infectious molecular clones of the virus. Infection of glial cells with intact HIV was characterized by low-level expression of viral transcripts as detected by Northern blotting and in situ hybridization (less than 10 copies of HIV RNA per cell), transient virus replication, absence of viral antigens detectable by immunofluorescence, and complete lack of cytopathic effects. However, the HIV-infected glial cells persistently expressed HIV tatIII gene activity as detected by a chloramphenicol acetyltransferase assay, and HIV transcripts could be detected by in situ hybridization in 20 to 30% of cells up to 4 months after infection, suggesting that the lack of cytopathicity in HIV-exposed cells was not due to transient viral infection. To evaluate whether increased expression and replication of HIV in glial cells would have any effect on cell growth and viability, we established HIV-positive glial cell lines by cotransfection of cells with infectious molecular clones of HIV DNA and a selectable marker gene. Three clones were isolated which produced high levels of viral particles, were strongly positive for HIV antigens by immunofluorescence, and contained greater than 1,000 copies of HIV RNA per cell. These cell lines showed no cytopathic changes (lysis, fusion), and their growth kinetics were similar to HIV- controls, but significant morphological changes were detected (cytoplasmic swelling; increased numbers of rounded, presumably detaching cells). Our results show that astrocytic cells can support a persistent, replicative HIV infection with limited pathogenic effects.


Aurora B kinase activity is regulated by SET/TAF1 on Sgo2 at the inner centromere.
The accurate regulation of phosphorylation at the kinetochore is essential for establishing chromosome bi-orientation. Phosphorylation of kinetochore proteins by the Aurora B kinase destabilizes improper kinetochore-microtubule attachments, whereas the phosphatase PP2A has a counteracting role. Imbalanced phosphoregulation leads to error-prone chromosome segregation and aneuploidy, a hallmark of cancer cells. However, little is known about the molecular events that control the balance of phosphorylation at the kinetochore. Here, we show that localization of SET/TAF1, an oncogene product, to centromeres maintains Aurora B kinase activity by inhibiting PP2A, thereby correcting erroneous kinetochore-microtubule attachment. SET localizes at the inner centromere by interacting directly with shugoshin 2, with SET levels declining at increased distances between kinetochore pairs, leading to establishment of chromosome bi-orientation. Moreover, SET overexpression induces chromosomal instability by disrupting kinetochore-microtubule attachment. Thus, our findings reveal the novel role of SET in fine-tuning the phosphorylation level at the kinetochore by balancing the activities of Aurora B and PP2A.


Gene organization and transcription of TED, a lepidopteran retrotransposon integrated within the baculovirus genome.
A single copy of the retrotransposon TED, from the moth Trichoplusia ni (a lepidopteran noctuid), was identified within the DNA genome of the baculovirus Autographa californica nuclear polyhedrosis virus. Determination of the complete nucleotide sequence (7,510 base pairs) of the integrated copy indicated that TED belongs to the family of retrotransposons that includes Drosophila melanogaster elements 17.6 and gypsy and thus represents the first nondipteran member of this invertebrate group to be identified. The internal portion of TED, flanked by long terminal repeats (LTRs), is composed of three long open reading frames comparable in size and location to the gag, pol, and env genes of the vertebrate retroviruses. Sequence similarity with the dipteran elements was the highest within individual domains of TED open reading frame 2 (pol region) that are also conserved among the retroviruses and encode protease, reverse transcriptase, and integrase functions, respectively. Mapping the 5' and 3' termini of TED RNAs indicated that the LTRs have a retroviral U3-R-U5 structural organization that is capable of directing the synthesis of transcripts that represent potential substrates for reverse transcription and intermediates in transposition. Abundant RNAs were also initiated from a site within the 5' LTR that matches the consensus motif for the promoter of late, hyperexpressed baculovirus genes. The presence of this viruslike promoter within TED and its subsequent activation only after integration within the viral genome suggest a possible symbiotic relationship with the baculovirus that could extend transposon host range.


Investigating the Effects of Intervention Strategies on Pneumonia and HIV/AIDS Coinfection Model.
HIV/AIDS and pneumonia coinfection have imposed a major socioeconomic and health burden throughout the world, especially in the developing countries. In this study, we propose a compartmental epidemic model on the spreading dynamics of HIV/AIDS and pneumonia coinfection to investigate the impacts of protection and treatment intervention mechanisms on the coinfection spreading in the community. In the qualitative analysis of the model, we have performed the positivity and boundedness of the coinfection model solutions; the effective reproduction numbers using the next-generation operator approach; and both the disease-free and endemic equilibrium points' local and global stabilities using the Routh-Hurwiz and Castillo-Chavez stability criteria, respectively. We performed the sensitivity analysis of the model parameters using both the forward normalized sensitivity index criteria and numerical methods (simulation). Moreover, we carried out the numerical simulation for different scenarios to investigate the effect of model parameters on the associated reproduction number, the effect of model parameters on the model state variables, and the solution behavior and convergence to the equilibrium point(s) of the models. Finally, from the qualitative analysis and numerical simulation results, we observed that the disease-spreading rates, protection rates, and treatment rates are the most sensitive parameters, and we recommend for stakeholders to concentrate and exert their maximum effort to minimize the spreading rates by maximizing the protection and treatment rates.


Thermally activated delayed fluorescence in a mechanically soft charge-transfer complex: role of the locally excited state.
Molecular design for thermally activated delayed fluorescence (TADF) necessitates precise molecular geometric requirements along with definite electronic states to ensure high intersystem crossing (ISC) rate and photoluminescence quantum yield (PLQY). Achieving all these requirements synchronously while maintaining ease of synthesis and scalability is still challenging. To circumvent this, our strategy of combining a crystal engineering approach with basic molecular quantum mechanical principles appears promising. A holistic, non-covalent approach for achieving efficient TADF in crystalline materials with distinct mechanical properties is highlighted here. Charge transfer (CT) co-crystals of two carbazole-derived donors (ETC and DTBC) with an acceptor (TFDCNB) molecule are elaborated as a proof-of-concept. Using temperature-dependent steady-state and time-resolved photoluminescence techniques, we prove the need for a donor-centric triplet state (3LE) to ensure efficient TADF. Such intermediate states guarantee a naturally forbidden, energetically uphill reverse intersystem crossing (RISC) process, which is paramount for effective TADF. A unique single-crystal packing feature with isolated D-A-D trimeric units ensured minimal non-radiative exciton loss, leading to a high PLQY and displaying interesting mechanical plastic bending behaviour. Thus, a comprehensive approach involving a non-covalent strategy to circumvent the conflicting requirements of a small effective singlet-triplet energy offset and a high oscillator strength for efficient TADF emitters is achieved here.


Chronic cognitive impairment following laterothalamic infarcts: a study of 9 cases.
The occlusion of the lateral thalamic arteries leads to infarcts of ventrolateral thalamic nuclei, the ventroposterior nucleus, and the rostrolateral part of pulvinar, and produces hemisensory loss with or without hemiataxia. Cognitive impairment after such strokes has not been systematically studied. To determine the nature and the extent of long-lasting cognitive deficits following lateral thalamic strokes. Case series. Neurology department, Lausanne University Hospital, Lausanne, Switzerland. Nine patients with hemisensory loss due to an isolated laterothalamic infarct. Three to 6 months after stroke onset, standard neuropsychologic evaluation, including testing of language, ideomotor and constructive praxis, visual gnosis, spatial attention, learning abilities, and executive functions. Six of 9 patients showed some degree of cognitive impairment. Executive functions tasks, particularly verbal fluency, were impaired in 5 patients (4 with right and 1 with left lesion). Learning and delayed recall in visuospatial and verbal tasks, but not in recognition, were impaired in 3 patients (2 with right and 1 with left lesion). Difficulties in visual gnosia were observed in 1 patient with right lesion while word-finding difficulties were observed in 1 patient with left lesion. Our observations show that while learning, naming, and gnosic difficulties fit with the classical verbal/nonverbal dichotomy (left and right hemisphere, respectively), executive dysfunctions, including verbal fluency tasks, were more dominant after right thalamic infarcts. Although the observed deficits appeared to be less severe than those generally found with dorsomedial and polar thalamic strokes, the dominance of executive dysfunction suggests that ventrolateral thalamic lesions may disrupt frontothalamic subcortical loops.


The KRAB Domain of ZNF10 Guides the Identification of Specific Amino Acids That Transform the Ancestral KRAB-A-Related Domain Present in Human PRDM9 into a Canonical Modern KRAB-A Domain.
Krüppel-associated box (KRAB) zinc finger proteins are a large class of tetrapod transcription factors that usually exert transcriptional repression through recruitment of TRIM28/KAP1. The evolutionary root of modern KRAB domains (mKRAB) can be traced back to an ancestral motif (aKRAB) that occurs even in invertebrates. Here, we first stratified three subgroups of aKRAB sequences from the animal kingdom (PRDM9, SSX and coelacanth KZNF families) and defined ancestral subdomains for KRAB-A and KRAB-B. Using human ZNF10 mKRAB-AB as blueprints for function, we then identified the necessary amino acid changes that transform the inactive aKRAB-A of human PRDM9 into an mKRAB domain capable of mediating silencing and complexing TRIM28/KAP1 in human cells when employed as a hybrid with ZNF10-B. Full gain of function required replacement of residues KR by the conserved motif MLE (positionsA32-A34), which inserted an additional residue, and exchange of A9/S for F, A20/M for L, and A27/R for V. AlphaFold2 modelling documented an evolutionary conserved L-shaped body of two α-helices in all KRAB domains. It is transformed into a characteristic spatial arrangement typical for mKRAB-AB upon the amino acid replacements and in conjunction with a third helix supplied by mKRAB-B. Side-chains pointing outward from the core KRAB 3D structure may reveal a protein-protein interaction code enabling graded binding of TRIM28 to different KRAB domains. Our data provide basic insights into structure-function relationships and emulate transitions of KRAB during evolution.


ED misdiagnosis of cerebrovascular events in the era of modern neuroimaging: A meta-analysis.
With the emergency department (ED) being a high-risk site for diagnostic errors, we sought to estimate ED diagnostic accuracy for identifying acute cerebrovascular events. MEDLINE and Embase were searched for studies (1995-2016) reporting ED diagnostic accuracy for ischemic stroke, TIA, or subarachnoid hemorrhage (SAH). Two independent reviewers determined inclusion. We identified 1,693 unique citations, examined 214 full articles, and analyzed 23 studies. Studies were rated on risk of bias (QUADAS-2). Diagnostic data were extracted. We prospectively defined clinical presentation subgroups to compare odds of misdiagnosis. Included studies reported on 15,721 patients. Studies were at low risk of bias. Overall sensitivity (91.3% [95% confidence interval (CI) 90.7-92.0]) and specificity (92.7% [91.7-93.7]) for a cerebrovascular etiology was high, but there was significant variation based on clinical presentation. Misdiagnosis was more frequent among subgroups with milder (SAH with normal vs abnormal mental state; false-negative rate 23.8% vs 4.2%, odds ratio [OR] 7.03 [4.80-10.31]), nonspecific (dizziness vs motor findings; false-negative rate 39.4% vs 4.4%, OR 14.22 [9.76-20.74]), or transient (TIA vs ischemic stroke; false discovery rate 59.7% vs 11.7%, OR 11.21 [6.66-18.89]) symptoms. Roughly 9% of cerebrovascular events are missed at initial ED presentation. Risk of misdiagnosis is much greater when presenting neurologic complaints are mild, nonspecific, or transient (range 24%-60%). This difference suggests that many misdiagnoses relate to symptom-specific factors. Future research should emphasize studying causes and designing error-reduction strategies in symptom-specific subgroups at greatest risk of misdiagnosis.


Isozymes, plant population genetic structure and genetic conservation.
The exploration, conservation and use of the genetic resources of plants is a contemporary issue which requires a multidisciplinary approach. Here the role of population genetic data, particularly those derived from electrophoretic analysis of protein variation, is reviewed. Measures of the geographic structure of genetic variation are used to check on sampling theory. Current estimates justify the contention that alleles which have a highly localised distribution, yet are in high frequency in some neighbourhoods, represent a substantial fraction of the variation. This class, which is the most important class in the framing of sampling strategies, accounts for about 20-30% of variants found in 12 plant species. The importance of documenting possible coadapted complexes and gene-environment relationships is discussed. Furthermore, the genetic structure of natural populations of crop relatives might suggest the best structure to use in the breeding of crops for reduced vulnerability to pest and disease attack, or for adaptation to inferior environments. The studies reported to date show that whilst monomorphic natural populations do occur, particularly in inbreeding colonisers, or at the extreme margins of the distribution, polymorphism seems to be the more common mode. It is stressed here that the genetic resources of the wild relatives of crop plants should be systematically evaluated. These sources will supplement, and might even rival, the primitive land races in their effectiveness in breeding programmes. We may look forward to a wider application of gel electrophoresis in the evaluation of plant genetic resources because this technique is currently the best available for detecting genetic differences close to the DNA level on samples of reasonable size.


Facilitators and Barriers to Implementing Two Quality Improvement Interventions Across 10 Pediatric Intensive Care Units: Video Laryngoscopy-Assisted Coaching and Apneic Oxygenation.
To better understand facilitators and barriers to implementation of quality improvement (QI) efforts, this study examined 2 evidence-based interventions, video laryngoscopy (VL)-assisted coaching, and apneic oxygenation (AO). One focus group with frontline clinicians was held at each of the 10 participating pediatric intensive care units. Qualitative analysis identified common and unique themes. Intervention fidelity was monitored with a priori defined success as >50% VL-assisted coaching or >80% AO use for 3 consecutive months. Eighty percent of intensive care units with VL-assisted coaching and 20% with AO met this criteria during the study period. Common facilitator themes were adequate device accessibility, having a QI culture, and strong leadership. Common barrier themes included poor device accessibility and perception of delay in care. A consistently identified theme in the successful sites was strong QI leadership, while unsuccessful sites consistently identified insufficient education. These facilitators and barriers should be proactively addressed during dissemination of these interventions.


Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment.
Type 2 diabetes is a slowly progressive disease, in which the gradual deterioration of glucose tolerance is associated with the progressive decrease in beta-cell function. Hyperglycemia per se has deleterious effects on both beta-cell function and insulin action, which are partially reversible by the short-term control of blood glucose levels. We hypothesized that the induction of euglycemia, using intensive insulin therapy at the time of clinical diagnosis, could lead to a significant improvement in insulin secretion and action and thus alter the clinical course of the disease. Thirteen newly diagnosed diet-unresponsive type 2 diabetic patients were treated with continuous subcutaneous insulin infusion (CSII) for 2 weeks and followed longitudinally while being treated with diet alone. Four patients were considered therapeutic failures since CSII failed to induce euglycemia (n = 1) or glucose control deteriorated within 6 months after CSII (n = 3). The remaining nine patients were maintained on diet alone with adequate control from 9 to > 50 months (median +/- SE, 26 +/- 4.8 months). In five patients, glycemic control deteriorated after 9-36 months, but a repeat 2-week CSII treatment reestablished control in four patients. One of these patients underwent a third CSII treatment 13 months later. At the time this article was written, six patients of the initial group were still controlled without medication 16-59 months (median +/- SE, 45.5 +/- 6.6 months) after the initiation of treatment. Body weight remained unchanged in all patients. These findings suggest that in a significant proportion of type 2 diabetic patients who fail to respond to dietary measures, short-term intensive insulin treatment can effectively establish responsiveness, allowing long-term glycemic control without medication. Further studies are required to establish whether simpler treatment regimens could be equally effective. If the hypothesis offered here finds support, present approaches to the management of newly diagnosed type 2 diabetes may need to be revised.


Giant cell tumor of bone. A cytologic study of 24 cases.
Twenty-three patients with radiologic diagnoses of giant cell tumor of bone underwent fine needle aspiration cytology and needle biopsy for tissue diagnosis before curettage or resection. One patient had two tumors, making a total of 24 cases. The accuracy of the cytologic diagnosis was compared with that of tissue biopsy. Cytologically there were mononucleated and multinucleated cells. The former often occurred in clusters or, less often, were dispersed. They had spindle or plump cell bodies with moderate amounts of cytoplasm and well-defined cytoplasmic membranes. The oval nuclei demonstrated fine, evenly distributed chromatin and small nucleoli. The multinucleated cells were osteoclastlike and were associated with the clusters of mononucleated cells or lying freely. They had a well-demarcated cytoplasm and contained from a few to several dozen monomorphic nuclei. Cytologic diagnosis was made in 20 of 24 cases, and histologic diagnosis was made in 21 of 24. Insufficient diagnostic material for cytology was the reason for failure in 4 cases. This was attributed to faulty technique (2 cases), cystic change (1 case), and massive necrosis (1 case). As other benign and malignant bone tumors may contain benign giant cells, cytologic or histologic findings alone are not diagnostic of giant cell tumor of bone, but should be complemented with the clinicoradiologic findings. Aspiration cytology is as accurate as tissue needle biopsy, may be of high diagnostic value in deeply located lesions not amenable to cutting needle biopsy, and should be done with full knowledge of the clinicoradiographic information.


MicroRNA-218 instructs proper assembly of hippocampal networks.
The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. Post-transcriptional regulation by microRNAs (miRNAs) is a key aspect of this program. Indeed, deletion of neuron-enriched miRNAs induces strong developmental phenotypes, and miRNA levels are altered in patients with neurodevelopmental disorders. However, the mechanisms used by miRNAs to instruct brain development remain largely unexplored. Here, we identified miR-218 as a critical regulator of hippocampal assembly. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons (PNs) and GABAergic inhibitory interneurons (INs). Early life inhibition of miR-218 results in an adult brain with a predisposition to seizures. Changes in gene expression in the absence of miR-218 suggest that network assembly is impaired. Indeed, we find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Conditional knockout of Mir218-2 in INs, but not PNs, is sufficient to recapitulate long-term instability. Finally, de-repressing Kif21b and Syt13, two miR-218 targets, phenocopies the effects on early synchronous network activity induced by miR-218 inhibition. Taken together, the data suggest that miR-218 orchestrates formative events in PNs and INs to produce stable networks.