Exploiting the interactions of aromatic units for folding and assembly in aqueous environments.
A variety of non-covalent interactions (including hydrogen bonding, ionic interactions, metal coordination and desolvation/solvation) have been utilized to organize oligomers into well-defined structures. Herein is described a survey of aromatic foldamers that capitalize on electrostatic complementarity of substituted aromatic units to drive folding and assembly in aqueous environments. A brief description of recent advances in the understanding of aromatic interactions is provided, followed by examples of foldamers that exploit interactions between aromatic units to drive their assembly in predictable fashion. The history of our aromatic foldamers is traced from the first structure designed to fold into a pleated structure in an aqueous environment to a heteroduplex system more related to nucleic acids. Taken together, the results demonstrate that electrostatic complementarity of aromatic units provides a versatile framework for driving predictable folding and assembly in aqueous environments.


Coexistence of pancreatic carcinoma and pancreatic tuberculosis: case report.
Pancreatic tuberculosis (TB) is extremely rare and mimics pancreatic carcinoma both clinically and radiologically. This paper discusses the occurrence of 2 heterogeneous masses located in the head and tail of the pancreas in an adult male. In this patient, laparotomy was performed because of the high suspicion of pancreatic carcinoma. Intraoperative fine needle aspiration biopsy revealed the coexistence of pancreatic carcinoma with pancreatic TB, and a combined resection of the distal pancreas and spleen was successfully performed. Following surgery, the patient received standard chemotherapy for TB. At 7-month follow-up, computed tomography showed resolution of the mass in the pancreatic head. Clinicians must maintain a high index of suspicion for pancreatic TB in patients with pancreatic masses. The coexistence of malignancy and TB should be considered when patients present with multiple pancreatic masses.


CUBOID MANIPULATION AND EXERCISE IN THE MANAGEMENT OF POSTERIOR TIBIALIS TENDINOPATHY: A CASE REPORT.
Posterior tibialis tendinopathy is a prevalent musculoskeletal condition often resulting in gait abnormalities along with medial ankle and foot pain. The purpose of this case report is to describe the treatment of a patient with a three year history of posterior tibialis tendinopathy utilizing a combination of cuboid manipulation and exercise. The patient was a 23-year old female recreational runner and collegiate basketball player reporting a three year history of chronic left ankle and lower leg pain. Outcome measures included the numeric pain rating scale, lower extremity functional scale, strength, passive joint mobility, and functional activities including running distance. Standard care for the treatment of tendinopathy was followed for six weeks with minimal functional improvements. Clinical reasoning skills were applied to redirect the hypothesis implicating limitations in cuboid-calcaneus internal rotation joint mobility contributing to a posterior tibialis tendinopathy. Manipulation at this joint was utilized to restore mobility. This intervention resulted in an immediate reduction in symptoms and improved functioning. Both muscle strengthening and functional task training were implemented post manipulation. At discharge, the patient reported full recovery and no pain with running 14 miles. Her lower extremity functional score improved to 78/80, posterior tibialis strength increased to 4/5 and the patient was able to perform 12 single leg heel raises without pain. By restoring cuboid internal rotation mobility, associated midtarsal pronation, and lower extremity neuromuscular control, the posterior tibialis muscle was able to perform efficiently, thus resolving the chronic tendinopathy and returning the patient to optimum functional ability of running. 4.


Urinary excretion of acetazolamide in healthy volunteers after short- and long-term exposure to high altitude.
Acetazolamide is recommended for the prophylaxis of acute mountain sickness symptoms which sets in on climbing to high altitudes (H) above 2,500 m. It is primarily excreted unchanged in urine. In a previous study, we reported on the changes in urinary excretion of meperidine and its metabolite normeperidine on exposure to high altitude. In this study, we investigated the effect on urinary excretion of acetazolamide. The study was carried out in three groups of 12 healthy male volunteers each: at sea level (group L), these same volunteers the day after arrival at high altitude of 4,360 m (group HA), and subjects residing for approximately 10 months at high altitude (group HC). Urine was collected for the periods of 0-2, 2-4, 4-8, 8-12, 12-24 and 24-36 h after peroral administration of a single 250 mg dose. Urinary pH was measured and the concentrations of acetazolamide were determined. There were no significant changes observed in the amount of acetazolamide excreted in urine over 36 h. The urinary pH ranged from 4.5 to 7.8 for L, from 4.2 to 6.9 for HA and from 3.1 to 6.7 for HC. The Fel (fraction eliminated unchanged in urine) was calculated from the amount excreted in 36 h in urine and dose, assuming a bioavailability of 1 based on literature data. No significant changes in Fel were seen.


Phenotypic characterization of paranoiac and related mutants in Paramecium tetraurelia.
Paranoiac and related mutants of Paramecium tetraurelia display altered membrane excitability. We describe an extension of behavioral characterizations of the paranoiac, fast-2, and tetraethylammonium-insensitive mutants, comparing in detail their reactions to sodium stimulation under standard culture conditions, when grown at various temperatures and when starved. We also use freeze-fracture electron microscopic techniques to analyze in these stocks the morphology of organized arrays of membrane particles, the ciliary plaques. This group of mutants is diverse, showing differences in behavior under standard culture conditions and different reactions to temperature and starvation stresses. Ciliary plaque morphology is altered in some, but not all, of the mutants. The possibility is discussed that these plaques may be sites of potassium or sodium transport.


[Effect of the morphological structure of lung cancer on the choice of surgery].
The authors compare the character of surgical interventions in 1519 patients with the morphologically verified pulmonary carcinoma with its histological structure. It was found that underdifferentiated forms of cancer were characterized by the decreased operability and resectability, increased volume of operations and number of exploratory interventions.


Placental abruption and adverse perinatal outcomes.
Pregnancies complicated by abruption result in increased frequency of perinatal death and decreased fetal size and gestational duration, yet the extent of placental separation and its effect on these adverse outcomes is unknown. To assess the contribution of placental abruption and extent of placental separation to stillbirth, preterm delivery, and fetal growth restriction. Hospital-based, retrospective cohort study. Mount Sinai Hospital, New York City, NY. A total of 53,371 pregnancies occurring in 40,789 women who were delivered of singleton births between 1986 and 1996. Risks and relative risks for stillbirth (>20 weeks), preterm delivery (<37 weeks), and fetal growth restriction (birth weight below 10th percentile for gestational age) in relation to abruption. The incidence of abruption was 1 % (n = 530). Abruption was associated with an 8.9-fold (95% confidence interval [CI], 6.0-13.0) adjusted relative risk (aRR) of stillbirth. Preterm birth proportions among women with and without abruption were 39.6% and 9.1 %, respectively, yielding an aRR of 3.9 (95% CI, 3.5-4.4). In the abruption group, 14.3% of neonates were growth restricted, compared with 8.1 % among all other births (aRR, 2.0; 95% CI, 1.5-2.4). Extent of placental separation had a profound effect on stillbirth (aRR for 75% separation, 31.5; 95% CI, 17.0-58.4), although evident only among those with at least 50% separation. However, the risk of preterm delivery was substantially increased even for mild abruptions (aRR for 25% separation, 5.5; 95% CI, 4.2-7.3). In this cohort, placental abruption had a profound impact on stillbirth, preterm delivery, and fetal growth restriction. The risk of stillbirth was dramatically increased for severe placental separation, but preterm delivery was common even among women with lesser degrees of placental separation.


Financial reporting quality of ESG firms listed in China.
Given the growing importance of environmental protection in China, this study investigated the determinants of the financial reporting quality of environmental, social and governance (ESG) firms listed in China. The quality of financial reporting shows how informative the accounting numbers are for decision-making. Because business outlook can influence financial reporting quality, this study examined predictable, moderately predictable and unpredictable business outlooks. The study randomly selected 100 firms from the 2021 China ESG Top 500 Outstanding Enterprises published by the Sina Finance ESG Rating Centre and then analysed those firms in 2018, 2019 and 2020. It investigated determinants (financial health, governance and earnings management), controlling for the influence of known variables (firm age and firm-specific risk) on financial reporting quality measured as accruals quality and earnings smoothness. Ordinary robust least square regression was conducted. Financial health had a negative influence, but governance variables and earnings management did not affect financial reporting quality. Firm-specific risk had a positive effect, but firm age did not influence financial reporting quality. Changes in business outlook had no impact on the determinants' effect on financial reporting quality. The study found that ESG firms did not engage in earnings management and aggressively manage earnings, pointing to ethical behaviour. This is the first study to contribute to understanding the financial reporting quality of ESG firms listed in China. It examined different business outlooks to understand ESG firms' behaviour towards financial reporting quality. The findings invite replicable studies outside China to understand the contextual validity and reliability of the financial reporting quality of ESG firms, and to investigate the effect of determinants not examined in this study.


Sub-10 nm Graphene Nanoribbon Array field-effect transistors fabricated by block copolymer lithography.
Sub-10 nm Graphene Nanoribbon Arrays are fabricated over large areas by etching CVD-grown graphene. A mask is used made by the directed self-assembly of a cylindrical PS-b-PDMS block copolymer under solvent annealing guided by a removable template. The optimized solvent annealing process, surface-modified removable polymeric templates, and high Flory-Huggins interaction parameters of the block copolymer enable a highly aligned array of nanoribbons with low line edge roughness to be formed. This leads to a higher on/off ratio and stronger temperature dependence of the current for nanoribbon FETs, and a photocurrent which is 30 times larger compared to unpatterned graphene.


Historiography, affect, and the neurosciences.
Recent historiography has put to rest debates over whether to address the neurosciences. The question is how? In this article, I stage a dialogue between neurohistory and the history of the emotions. My primary goal is to survey these two clusters and clarify their conceptual commitments. Both center on the role of affect in embodied subjectivity; but their accounts widely diverge. Whereas neurohistorians tend to treat affects as automatic bodily processes, historians of the emotions generally emphasize that affects are meaningful and volitional activities. This divergence entails contrasting understandings of selfhood, embodiment, and historical change. More importantly, I argue, it reflects a broader realm of disputes within the neurosciences. The divisions among methodologies and commitments testify to the importance of historians' selection of evidence as well as the critical perspectives they can bring to scientific debates. The neurosciences do not offer readymade theories. Secondarily, I take stock of the shared limitations of neurohistory and the history of the emotions. Both conceptualize the biological bases of affection as a universal ground for historical inquiry. By reexamining this transhistorical approach to neuroscientific evidence, I suggest that historiography might widen the horizon of interdisciplinary scholarship beyond the present options. (PsycINFO Database Record


The use of functional neuroimaging to evaluate psychological and other non-pharmacological treatments for clinical pain.
A large number of studies have provided evidence for the efficacy of psychological and other non-pharmacological interventions in the treatment of chronic pain. While these methods are increasingly used to treat pain, remarkably few studies focused on the exploration of their neural correlates. The aim of this article was to review the findings from neuroimaging studies that evaluated the neural response to distraction-based techniques, cognitive behavioral therapy (CBT), clinical hypnosis, mental imagery, physical therapy/exercise, biofeedback, and mirror therapy. To date, the results from studies that used neuroimaging to evaluate these methods have not been conclusive and the experimental methods have been suboptimal for assessing clinical pain. Still, several different psychological and non-pharmacological treatment modalities were associated with increased pain-related activations of executive cognitive brain regions, such as the ventral- and dorsolateral prefrontal cortex. There was also evidence for decreased pain-related activations in afferent pain regions and limbic structures. If future studies will address the technical and methodological challenges of today's experiments, neuroimaging might have the potential of segregating the neural mechanisms of different treatment interventions and elucidate predictive and mediating factors for successful treatment outcomes. Evaluations of treatment-related brain changes (functional and structural) might also allow for sub-grouping of patients and help to develop individualized treatments.


Surgical management of recurrent colon haemorrhage of unknown origin.
Although both endoscopy and angiography have profoundly changed the management of lower GI bleeding, the choice, timing and sequence of these procedures as well as the indications for surgery remain a matter of debate. In cases of massive bleeding, early angiography should be performed as the first choice examination. When this fails, exploratory laparotomy, including peroperative colonoscopy after colonic wash-out, should not be discarded as a diagnostic possibility. If no source of bleeding is identified notwithstanding colonoscopic evaluation in excellent conditions, and it can be assumed that the bleeding has ceased, a conservative attitude may reasonably be advocated.


Variations in leucocyte count during menstrual cycle.
The neutrophil counts of seven women, three tkaing oral contraceptives and four nottaking them, showed cyclical variations during the menstrual cycle, most consistentlya fall in the neutrophil count at menstuation. The neutrophil count in women not taking oral contraceptives rose to a peak twice during each cycle. One womennot taking oral contraceptives was studied in detail over eight consecutive menstrualcycles. She showed two neutrophil peaks per cycle and a similiar variation in themonocyte count. The eosinophil count showed a reciprocal relation with the neutrophil count and the basophil count fell in mid-cycle. The changes in her neutrophil count seemed to follow changes in oestrogen level with a delay of one to two days. Oestrogen probably promotes release of neutrophils from the bone marrow rather than from the marginated pool.


Comparison of acetabular anterior coverage after Salter osteotomy and Pemberton acetabuloplasty: a long-term followup.
The Salter osteotomy and Pemberton acetabuloplasty are common procedures for a deficient acetabulum in patients with developmental dysplasia of the hip. However, the degree of increasing retroversion and anterior acetabular coverage of these two procedures remains unanswered. The purpose of this study is to show the change in anterior coverage and relevant parameters in measuring pain and function among patients who have undergone either a Salter osteotomy or Pemberton acetabuloplasty. Forty-two patients who underwent either a Salter or Pemberton procedure at one institution between January 1981 and December 2000 and were available for followup at least 10 years later (mean, 18 years; range, 12-28 years) were evaluated retrospectively. This represented 12% of the Salter and Pemberton procedures performed in patients between 12 and 36 months old at our institution during the study period. We measured vertical-center-anterior margin angle, anterior acetabular head index, and weightbearing zone acetabular index, and we made comparisons using the radiographic parameter ratio (the division of each radiographic measurement of the operative side by that of the nonoperated side). All patients completed SF-36 and Harris hip score questionnaires at followup. In the Salter group, there were no differences in vertical-center-anterior margin angle, anterior acetabular head index, or weightbearing zone acetabular index. In the Pemberton group, there was no difference in vertical-center-anterior margin angle or anterior acetabular head index, but the weightbearing zone acetabular index decreased, suggesting increased anterior acetabular coverage (surgically treated side, 6 [95% CI, 4.84, 7.16]; nonoperated side, 12 [95% CI, 10.07, 13.39]; p < 0.001). Compared with that in the Salter group, the weightbearing zone acetabular index ratio was smaller in the Pemberton group, which means more acquired anterior coverage after a Pemberton acetabuloplasty (Salter procedure, 0.94 [95% CI, 0.70, 1.17], Pemberton procedure, 0.53 [95% CI, 0.40, 0.65]; p < 0.001). Three patients in the Pemberton group had an anterior impingement sign at followup, whereas none in the Salter group did. The SF-36 and Harris hip scores were good and showed no differences between the two groups. Our study suggests the weightbearing zone acetabular index on false profile radiographs of the hip, a parameter focusing on morphologic features of the anterior acetabulum, decreased after Pemberton acetabuloplasty compared with the nonoperated side and after the Salter acetabuloplasty. This suggests that by modifying the shape of the acetabulum with a hinge in the triradiate cartilage, a Pemberton acetabuloplasty may result in increasing acetabular anterior coverage and the risk of hip impingement. However, the functional results with at least 10 years followup were good and similar for both procedures. Level III, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.


Recovery of consciousness after brain injury: a mesocircuit hypothesis.
Recovery of consciousness following severe brain injuries can occur over long time intervals. Importantly, evolving cognitive recovery can be strongly dissociated from motor recovery in some individuals, resulting in underestimation of cognitive capacities. Common mechanisms of cerebral dysfunction that arise at the neuronal population level may explain slow functional recoveries from severe brain injuries. This review proposes a "mesocircuit" model that predicts specific roles for different structural and dynamic changes that may occur gradually during recovery. Recent functional neuroimaging studies that operationally identify varying levels of awareness, memory and other higher brain functions in patients with no behavioral evidence of these cognitive capacities are discussed. Measuring evolving changes in underlying brain function and dynamics post-injury and post-treatment frames future investigative work.


Effect of point mutations in the lac promoter on transient and severe catabolite repression of the lac operon of Escherichia coli.
1. Experiments were devised to show whether the point mutations L8 and L29 in the lac promoter alleviate transient repression. 2. Several recombinants were picked from matings between a single F(-)p(+) strain and Hfr strains carrying mutations L8 and L29. All of the 19 p(-) recombinants tested proved to suffer no transient repression, whereas all of the eight p(+) recombinants tested suffered prolonged transient repression. 3. A diploid strain was constructed in which more than 90% of the thiogalactoside transacetylase is synthesized from the episome with a wild-type lac promoter, whereas 100% of the beta-galactosidase is synthesized from the chromosome with a promoter carrying mutation L8. In this diploid the synthesis of thiogalactoside transacetylase suffered transient repression but the synthesis of beta-galactosidase did not. 4. Exactly similar results were obtained with a diploid strain in which the chromosomal promoter carried mutation L29. 5. The same diploid strains were used in experiments to show whether mutations L8 and L29 alleviate the severe catabolite repression caused by growth in glucose plus gluconate. In both strains glucose+gluconate repressed the synthesis of beta-galactosidase much less than the synthesis of thiogalactoside transacetylase. 6. These and previously reported results can be explained by assuming (a) that both mutations L8 and L29 render the lac promoter partially, but not completely, insensitive to catabolite repression, and (b) that transient repression is an exceptionally severe form of catabolite repression.


[A direct accelerated method for detection of a whooping cough pathogen].
The developed direct method for the laboratory diagnosis of pertussis, which is based on isothermal amplification technologies, has a high (100%) specificity and sensitivity (102 m.cl.), can detect the pathogen of the disease just in the clinical sample from a patient within 7-8 hours after start of the study. The clinical trials conducted at Infectious Diseases Hospital One (Moscow) on examination of 103 patients (63 patients with the clinical diagnosis of pertussis and 40 with other respiratory tract diseases) provided evidence its high specificity and diagnostic efficiency as compared with a bacteriological test, the efficiency in different clinical types of the disease and during examinations of patients in different periods after the onset of the disease, as well as during examinations of patients with suspected pertussis and pertussis-like diseases.


Immunotherapies for hepatocellular carcinoma.
Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.


ICUD-SIU International Consultation on Bladder Cancer 2017: management of non-muscle invasive bladder cancer.
To provide a summary of the Third International Consultation on Bladder Cancer recommendations for the management of non-muscle invasive bladder cancer (NMIBC). A detailed review of the literature was performed focusing on original articles for the management of NMIBC. An international committee assessed and graded the articles based on the Oxford Centre for Evidence-based Medicine system. The entire spectrum of NMIBC was covered such as prognostic factors of recurrence and progression, risk stratification, staging, management of positive urine cytology with negative white light cystoscopy, indications of bladder and prostatic urethral biopsies, management of Ta low grade (LG) and high risk tumors (Ta high grade [HG], T1, carcinoma in situ [CIS]), impact of BCG strain and host on outcomes, management of complications of intravesical therapy, role of alternative therapies, indications for early cystectomy, surveillance strategies, and new treatments. The working group provides several recommendations on the management of NMIBC. Recommendations were summarized with regard to staging; management of primary and recurrent LG Ta and high risk disease, positive urine cytology with negative white light cystoscopy and prostatic urethral involvement; indications for timely cystectomy; and surveillance strategies. NMIBC remains a common and challenging malignancy to manage. Accurate staging, grading, and risk stratification are critical determinants of the management and outcomes of these patients. Current tools for risk stratification are limited but informative, and should be used in clinical practice when determining diagnosis, surveillance, and treatment of NMIBC.


Study on preparation and formation mechanism of n-alkanol/water emulsion using alpha-cyclodextrin.
Surfactants are usually used for the preparation of emulsions; however, some have an adverse effect on the human body such as skin irritation, hemolysis, and protein denaturation, etc. In this study, we examined the preparation and formation mechanism of n-alkanol/water emulsions using alpha-cyclodextrin (alpha-CD) as an emulsifier. Emulsions were prepared by mixing oil and water phases for 4 min at 2500 rpm using a vortex mixer. The mechanism of emulsification was investigated with some physico-chemical techniques. From phase diagrams of n-alkanol/alpha-CD/water systems, the emulsion phase extended as the chain length of n-alkanols and the amount of alpha-CD added increased. Furthermore, the emulsion was not formed in the region where the n-alkanol/alpha-CD complex didn't precipitate; however, the emulsion was formed in the region where the complex precipitated. In addition, it was clear that the emulsions have a yield stress value and correspond to the Maxwell model from rheological measurement. Our experiments clearly showed that the stable emulsions are formed because the precipitated complexes form a dense film at the oil-water interface and prevent aggregation among dispersed phases. Furthermore, it is suggested that the creation of a three-dimensional network structure formed by precipitated complexes in the continuous phase contributes to the stabilization of the emulsion. Thus, we concluded that the n-alkanol/water emulsions using alpha-cyclodextrin were a kind of the Pickering emulsion.


Indomethacin induces the suppression of plasma neutral proteinase activity in mice: possible relationship to efficacy as an anti-inflammatory drug and induction of alterations in the immune system.
Treatment of BALB/c, C57Bl/6 or C3H/HeJ mice with non-toxic concentrations of indomethacin (75-100 micrograms/day) led to a depression of plasma neutral proteinase activity as determined with an (125I)-caseinolytic assay. Lower concentrations of indomethacin (50 micrograms/day), aspirin (1 mg/day), LiCl (3 meq/kg/day), Sulindac (100 micrograms/day), indomethacin analogs (MK-410, MK-555) or lipopolysaccharide (100 micrograms) did not induce depression in proteinase activity. Indomethacin did not directly inhibit the proteinase activity of normal plasma in vitro. The in vivo effects of indomethacin were reversible and plasma proteinase activity returned to normal values within 8 days of cessation of treatment. These results indicate that indomethacin can uniquely alter plasma proteinase homeostasis in normal mice. While effective in depressing the plasma proteinase activity of normal mice, treatment of mice bearing either the BCL1 leukemia or the B16-F10 melanoma with indomethacin did not depress the elevated plasma proteinase levels detected in tumor-bearing animals. Thus the elevation in proteinases detected in tumor-bearing animals may not be the result of increased prostaglandin synthesis and plasma proteinase activity in such disease states may be regulated differently than in normal mice. However, the ability of this potent anti-inflammatory agent to alter proteinase metabolism may contribute to its therapeutic efficacy in the management of inflammatory disease.


In utero exposure to simvastatin reduces postnatal survival and permanently alters reproductive tract development in the Crl:CD(SD) male rat.
We showed previously that in utero exposure to the cholesterol-lowering drug simvastatin (SMV) during sex differentiation lowers fetal lipids and testicular testosterone production (T Prod) in Hsd:SD rats. Here, the effects of SMV on fetal lipids and T Prod in Crl:CD(SD) rats were correlated with postnatal alterations in F1 males. The current study was conducted in two parts: 1) a prenatal assessment to confirm and further characterize the dose response relationship among previously reported alterations of SMV on fetal T Prod and the fetal lipid profile and 2) a postnatal assessment to determine the effects of SMV exposure during the periods of major organogenesis and/or sexual differentiation on F1 offspring growth and development. We hypothesized that SMV would have adverse effects on postnatal development and sexual differentiation as a consequence of the disruptions of fetal lipid levels and testicular T Prod since fetal cholesterol is essential for normal intrauterine growth and development and steroid synthesis. In the prenatal assessment, SMV was administered orally at 0, 15.6, 31.25, 62.5, 80, 90, 100, and 110 mg SMV/kg/d from GD 14-18, the period that cover the critical window of sex differentiation in the male rat fetus. T Prod was maximally reduced by ~40% at 62.5 mg/kg/d, and higher doses induced overt maternal and toxicity. In the postnatal assessment, SMV was administered at 0, 15.6, 31.25, and 62.5 mg/kg/d from GD 8-18 to determine if it altered postnatal development. We found that exposure during this time frame to 62.5 mg SMV/kg/d reduced pup viability by 92%, decreased neonatal anogenital distance, and altered testis histology and morphology in 17% of the F1 males. In another group, SMV was administered only during the masculinizing window (GD14-18) at 62.5 mg/kg/d to determine if male rat sexual differentiation and postnatal reproductive development were altered. SMV-exposed F1 males displayed female-like areolae/nipples, delayed puberty, and reduced seminal vesicle and levator ani-bulbocavernosus weights. Together, these results demonstrate that in utero exposure to SMV reduces offspring viability and permanently disrupts reproductive tract development in the male offspring. While the effects of high dose, short term in utero exposure to SMV in the adult male are likely androgen-dependent and consistent with the 40% reduction in T Prod in the fetal testes, long-term, lower dose administration induced some effects that were likely not mediated by decreased T Prod.


Purification, characterization, and crystallization of single molecular species of beta-conglycinin from soybean seeds.
Four major molecular species of beta-conglycinin, alpha 3, alpha 2 beta, alpha beta 2, and beta 3, were isolated and purified from seeds of an alpha' subunit-deficient strain of soybeans (Glycine max). All components were found to be homogeneous by high pressure liquid chromatography, SDS-polyacrylamide gel electrophoresis, and amino acid and amino terminal sequence analyses. The amino acid compositions of the alpha 3 and beta 3 components agreed fairly well with the compositions deduced from the cDNA sequences, and all of the components were highly glycosylated. The alpha 3 and beta 3 components were compared regarding their secondary structures. The secondary structure of the alpha 3 component deduced from CD measurements showed a higher alpha-helix content than that of the beta 3 component. The beta 3 component was crystallized by decreasing the ionic strength from 0.5 to 0.14 in phosphate buffer, pH 7.3, and the crystals grew to a size (1.0 mm x 0.2 mm x 0.2 mm) suitable for X-ray crystallographic analysis. A preliminary X-ray analysis showed that the crystal belonged to an orthorhombic crystal system having the space group P2(1)2(1)2(1) and unit cell dimensions of a = 185.1 A, b = 107.9 A, and c = 97.6 A.


Biomechanics of the knee joint in flexion under various quadriceps forces.
Bioemchanics of the entire knee joint including tibiofemoral and patellofemoral joints were investigated at different flexion angles (0 degrees to 90 degrees ) and quadriceps forces (3, 137, and 411 N). In particular, the effect of changes in location and magnitude of restraining force that counterbalances the isometric extensor moment on predictions was investigated. The model consisted of three bony structures and their articular cartilage layers, menisci, principal ligaments, patellar tendon, and quadriceps muscle. Quadriceps forces significantly increased the anterior cruciate ligament, patellar tendon, and contact forces/areas as well as the joint resistant moment. Joint flexion, however, substantially diminished them all with the exception of the patellofemoral contact force/area that markedly increased in flexion. When resisting extensor moment by a force applied on the tibia, the force in cruciate ligaments and tibial translation significantly altered as a function of magnitude and location of the restraining force. Quadriceps activation generated large ACL forces at full extension suggesting that post ACL reconstruction exercises should avoid large quadriceps exertions at near full extension angles. In isometric extension exercises against a force on the tibia, larger restraining force and its more proximal location to the joint substantially decreased forces in the anterior cruciate ligament at small flexion angles whereas they significantly increased forces in the posterior cruciate ligament at larger flexion angles.


Inhalant use among incarcerated adolescents in the United States: prevalence, characteristics, and correlates of use.
To characterize patterns and correlates of inhalant use among incarcerated youth. Residents (N=723) of 27 Missouri Division of Youth Services facilities completed interviews assessing substance use, psychiatric symptoms, antisocial traits, trauma, suicidality, and criminality. Participants averaged 15.5 (S.D.=1.2) years of age, were ethnically diverse, and predominantly male. More than one-third (36.9%) reported lifetime inhalant use; 47.9% of users had tried four or more inhalant products. Comparatively high rates of use were observed for Hispanic and small town/rural youth. Commonly abused agents included gasoline (22%), permanent markers (15%), computer "air duster," (15%) and spray paint (12%). Inhalant users evidenced significantly higher levels of criminal behavior, antisocial attitudes, current psychiatric symptoms, earlier onset of offending and substance use, and more extensive histories of head injury, kidney disease, hormonal problems, mental illness, suicidality, trauma, and substance-related problems than nonusers. In multiple logistic regression models, race/ethnicity, geographic area of residence, fearlessness, suicidality, and polydrug use distinguished inhalant users and nonusers. Measures of cognitive impairment, impulsivity, fearlessness, blame externalization, polydrug use, and substance-related problems were positively associated with lifetime frequency of inhalant use. Inhalant use was widespread in this sample and associated with serious physical and mental health impairments.


Chemical identification of a tumor-derived angiogenic factor.
Neoplasms produce substances that induce blood vessel formation (angiogenesis). Fractions from ethanol extracts of the Walker 256 carcinoma were isolated by silica column chromatography and C18 reversed-phase high-performance liquid chromatography. Two of the isolated fractions induced neovascularization when tested in the rabbit corneal micropocket assay. One of the fractions was identified as nicotinamide by desorption-electron impact mass spectrometry, nuclear magnetic resonance spectroscopy, and gas chromatography-mass spectrometry. The second active fraction contained nicotinamide as part of a more complex, as yet unidentified, molecular arrangement. Microgram quantities of commercial nicotinamide induced neovascularization in the corneal micropocket assay and in the chick chorioallantoic membrane assay.


Adult Bochdalek Hernia with Organo-Axial Gastric Volvulus: Misdiagnosed as Hydropneumothorax.
Bochdalek hernia (BH) in an adult may manifest clinically with a myriad of abdominal or chest symptoms or a combination of them. Diagnosis of an adult BH is usually delayed in view of rarity of the lesion and its varied presentation. A 30-year-old adult gentleman presented to us with a left thoracostomy which was draining pus and ingested food particles. The tube thoracostomy had been performed in another hospital for an apparent left hydropneumothorax before he arrived in our hospital. Computed tomography of Chest and abdomen revealed a left diaphragmatic defect with herniation of stomach, spleen and omentum into the chest with organo-axial volvulus of the stomach. A thoracostomy tube was seen to be traversing through the stomach with its tip located close to the left pulmonary artery. The patient underwent left thoraco-abdominal exploration with dissection and reposition of the hernial contents in the abdominal cavity. The gastric perforations and the diaphragmatic defect were repaired. This case reiterates a well-known fact that an adult type BH must find a place in the differential diagnosis of a hydropneumothorax. Though the adult BH is a rare diagnosis, unawareness or reluctance to consider the possibility of adult BH may prolong the suffering of the patient as it happened in our patient who had iatrogenic perforation of the stomach due to tube thoracostomy.


Profiling the interaction of Al(III)-GFLX complex, a potential pollution risk, with bovine serum albumin.
Fluoroquinolone antibiotics (FQs), a new class of pollutants that seriously threaten human health through environmental and food residues, have aroused wide public concern. However, little attention has been paid to the potential toxicity of FQs' metal complex. Here, we firstly explore the proof-of-concept study of FQs' metal complex to bind bovine serum albumin (BSA) using systematical spectroscopic approaches. In detail, we have found that the complex of Al3+ with gatifloxacin (Al(III)-GFLX complex) can effectively bind to BSA via electrostatic interaction in PBS buffer (pH = 7.4, 1×), resulting in the formation of Al(III)-GFLX-BSA complex. The negative value of ΔG shows that the binding of Al(III)-GFLX complex to BSA is a spontaneous process. Circular dichroism spectra verify that Al(III)-GFLX complex effectively triggers the conformation changes of BSA's secondary structure. It has been proved that the interaction of small molecule with serum albumin has a significant effect on their in vivo biological effects such as absorption, distribution, metabolism, and excretion, and etc. Therefore, the results of this paper may offer a valuable theoretical basis for establishing safety standards of FQs' metal complex to ensure food and environmental health.


Safety and efficacy of riboflavin-assisted collagen cross-linking of cornea in progressive keratoconus patients: A prospective study in North East India.
Riboflavin- and ultraviolet (UV)-A-mediated collagen cross-linking of the cornea is a frequently used therapeutic measure for the treatment of progressive keratoconus (PK). First, riboflavin increases cross-linking and second, it serves as a protective shield to other deep ocular structures. However, pharmacogenomic variation in riboflavin efficacy is reported. As the Northeast Indian population represents a genetically diverse group of population compared to mainstream India, we have assessed the efficacy of the procedure in a northeastern population with PK. In this study, 78 eyes with PK were included (n = 39 in the treatment arm and n = 39 in the control arm). The primary objective was to evaluate the effect of corneal collagen cross-linking using riboflavin (C3R) (epithelium off) on maximum keratometry. The secondary objectives were evaluation of change in corneal topography parameters, i.e., minimum keratometry (Kmin), simulated keratometry (Sim K), subjective refraction (cylinder power, spherical power, and spherical equivalent [SE]), uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and contrast sensitivity (CS) and safety (intraocular pressure, endothelial cell density, and percentage hexagonality) at 1, 3, and 6 months following C3R procedure. Statistically significant improvement was noted in Kmin (6 months), Sim K (3 and 6 months), cylinder power (3 and 6 months), spherical power (3 and 6 months), SE (3 and 6 months), BCVA (6 months), and UCVA (1, 6 months) in the C3R group (n = 39) when compared to the control group (n = 39). The mean CS decreased at 1 month and gradually improved to achieve statistically significant value at 6 months in the C3R group (P < 0.05). Riboflavin-assisted C3R treatment showed promising efficacy in the treatment of PK patients in our population. As the collagen turnover rate of cornea is 2-3 years and the progression of PK is highly variable, we need long-term studies to evaluate the efficacy of C3R over time, requirement of repeat therapy, and safety of repeat cross-linking.


A specific interaction of small molecule entry inhibitors with the envelope glycoprotein complex of the Junín hemorrhagic fever arenavirus.
Arenaviruses are responsible for acute hemorrhagic fevers worldwide and are recognized to pose significant threats to public health and biodefense. Small molecule compounds have recently been discovered that inhibit arenavirus entry and protect against lethal infection in animal models. These chemically distinct inhibitors act on the tripartite envelope glycoprotein (GPC) through its unusual stable signal peptide subunit to stabilize the complex against pH-induced activation of membrane fusion in the endosome. Here, we report the production and characterization of the intact transmembrane GPC complex of Junín arenavirus and its interaction with these inhibitors. The solubilized GPC is antigenically indistinguishable from the native protein and forms a homogeneous trimer in solution. When reconstituted into a lipid bilayer, the purified complex interacts specifically with its cell-surface receptor transferrin receptor-1. We show that small molecule entry inhibitors specific to New World or Old World arenaviruses bind to the membrane-associated GPC complex in accordance with their respective species selectivities and with dissociation constants comparable with concentrations that inhibit GPC-mediated membrane fusion. Furthermore, competitive binding studies reveal that these chemically distinct inhibitors share a common binding pocket on GPC. In conjunction with previous genetic studies, these findings identify the pH-sensing interface of GPC as a highly vulnerable target for antiviral intervention. This work expands our mechanistic understanding of arenavirus entry and provides a foundation to guide the development of small molecule compounds for the treatment of arenavirus hemorrhagic fevers.


GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon.
Cortical gamma-aminobutyric acid (GABA)ergic neurons contribute to the orchestration of pyramidal neuron population firing as follows: (1) by releasing GABA on GABA(A) and GABA(B) receptors, (2) by releasing reelin in the proximity of integrin receptors located on cortical pyramidal neuron dendritic spines, and (3) through reelin contributing to the regulation of dendritic spine plasticity by modulating dendritic resident mRNA translation. In schizophrenia (SZ) and bipolar (BP) postmortem brains, the downregulation of mRNAs encoding glutamic acid decarboxylase 67 (GAD(67)) and reelin decreases the cognate proteins coexpressed in prefrontal cortex (PFC) GABAergic neurons. This finding has been replicated in several laboratories. Such downregulation suggests that the neuropil hypoplasticity found in the PFC of SZ and BP disorder patients may depend on a downregulation of GABAergic function, which is associated with a decrease in reelin secretion from GABAergic neuron axon terminals on dendrites, somata, or axon initial segments of pyramidal neurons. Indirectly, this GABAergic neuron downregulation may play a key role in the expression of positive and negative symptoms of SZ and BP disorders. The above described GABAergic dysfunction may be addressed by pharmacological interventions to treat SZ and BP disorders using specific benzodiazepines (BZs), which are devoid of intrinsic activity at GABA(A) receptors including alpha(1) subunits but that act as full positive allosteric modulators of GABA action at GABA(A) receptors containing alpha(2), alpha(3), or alpha(5) subunits. These drugs are expected to enhance GABAergic signal transduction without eliciting sedation, amnesia, and tolerance or dependence liabilities. BZs, such as diazepam, although they are efficient in equilibrating GABA(A) receptor signal transduction in a manner beneficial in the treatment of positive and negative symptoms of SZ, may not be ideal drugs, because by mediating a full positive allosteric modulation of GABA(A) receptors containing the alpha(1) subunit, they contribute to sedation and to the development of tolerance after even a brief period of treatment. In contrast, other BZ-binding site ligands, such as 6-(2bromophenyl)-8-fluoro-4H-imidazo [1,5-a][1,4] benzodiazepine-3-carboxamide (imidazenil), which fail to allosterically and positively modulate the action of GABA at GABA(A) receptors with alpha(1) subunits but that selectively allosterically modulate cortical GABA(A) receptors containing alpha(5) subunits, contribute to the anxiolytic, antipanic, and anticonvulsant actions of these ligands without producing sedation, amnesia, or tolerance. Strong support for the use of imidazenil in psychosis emerges from experiments with reeler mice or with methionine-treated mice, which express a pronounced reelin and GAD(67) downregulation that is also operative in SZ and BP disorders. In mice that model SZ symptoms, imidazenil increases signal transduction at GABA(A) receptors containing alpha(5) subunits and contributes to the reduction of behavioral deficits without producing sedation or tolerance liability. Hence, we suggest that imidazenil may be considered a prototype for a new generation of positive allosteric modulators of GABA(A) receptors, which, either alone or in combination with neuroleptics, should be evaluated in GABAergic dysfunction operative in the treatment of SZ and BP disorders with psychosis.


[Morphopathogenesis of the amniotic membrane after its transplantation in the course of experimental conjunctiva plasty].
The paper contains the results of an experimental study of the clinical healing of the standard wound defect in the bulbar conjunctiva of rabbit after conjunctiva-plasty involving the use of the human amnion transplant; there is also a description of a histological study of reparative processes in the adjacent tissues and a description of morphological changes occurring in the transplant during the healing process. The study was made on 14 rabbits (28 eyes). It was established that the wound-surface healing occurs, beneath the amnion transplant, without a pronounced inflammation, scarring or immunologic-rejection reaction; its sequence is typical of inflammation and compensatory processes with the formation, in the outcome, of the conjunctiva coating of the eyeball, whose color and composition are ordinary.


ARMS test for diagnosis of factor VLeiden mutation, a common cause of inherited thrombotic tendency.
We developed a simple and rapid amplification-refractory mutation system (ARMS) assay for the factor V mutation [R506Q] (factor VLeiden), which results in the autosomal dominant thrombotic tendency, resistance to activated protein C (rAPC). PCR primers within Exon 10 of the factor V gene were designed. A common upstream primer was paired with either a mutant or wild-type-specific downstream primer. The 3'-most nucleotide of the specific primers recognized either the mutant or normal allele, and the 3' penultimate nucleotide was mismatched to enhance specificity of the reaction. The assay was validated using authentic factor VLeiden DNA samples. Seven of 103 hematologically normal children (6.8%) were found to be heterozygotes. Among 27 patients studied by the rAPC assay, ARMS assay and rAPC results were concordant in 26. Among these were a 1-year-old child with a calcified clot in the inferior vena cava. Both the patient and his father were heterozygous for the mutation and both had abnormal rAPC assays. rAPC and factor VLeiden assays were discordant in a young girl with a history of stroke. Biochemical rAPC assay was abnormal, while ARMS assay revealed amplification only with wild-type primers, suggesting a non-[R506Q] mechanism for rAPC. This assay will be a valuable tool for studying subjects with thromboses and their family members.


Sclerosing mesenteritis presenting as protein-losing enteropathy: a fatal case.
Sclerosing mesenteritis is a rare, benign disorder characterized by non-specific and chronic inflammation of the mesenteric adipose tissue. The disease usually presents with gastrointestinal symptoms and abdominal masses. The long-term prognosis is favorable, but it often becomes severe. In the present report we describe a 77-year-old man who presented with diarrhea, massive ascites and an abdominal mass. The rapid deterioration of the general condition of the patient limited invasive examinations and left the primary disease unclear. Despite symptomatic therapy, malnutrition and hypovolemia were prolonged, and he died. The definitive diagnosis of sclerosing mesenteritis and the cause of the fatal outcome were disclosed at autopsy. This case indicates that sclerosing mesenteritis is a potentially-fatal disease and the need for aggressive treatment should be discussed.


Companilactobacillus pabuli sp. nov., a lactic acid bacterium isolated from animal feed.
A Gram-positive, facultative anaerobic, catalase-negative, non-motile, non-spore-forming and rod-shaped lactic acid bacterium strain, denoted as NFFJ11T and isolated from total mixed fermentation feed in the Republic of Korea, was characterized through polyphasic approaches, including sequence analyses of the 16S rRNA gene and housekeeping genes (rpoA and pheS), determination of average nucleotide identity and in silico DNA-DNA hybridization, fatty acid methyl ester analysis, and phenotypic characterization. Phylogenetic analyses based on 16S rRNA, rpoA and pheS gene sequences revealed that strain NFFJ11T belonged to the genus Companilactobacillus. The 16S rRNA gene sequence of strain NFFJ11T exhibited high similarity to Companilactobacillus formosensis S215T (99.66 %), Companilactobacillus farciminis Rv4 naT (99.53 %), Companilactobacillus crustorum LMG 23699T (99.19 %), Companilactobacillus futsaii YM 0097T (99.06 %), Companilactobacillus zhachilii HBUAS52074T (98.86 %) and Companilactobacillus heilongiiangensis S4-3T (98.66 %). However, average nucleotide identity and in silico DNA-DNA hybridization values for these type strains were in the range of 79.90-92.93 % and 23.80-49.30 %, respectively, which offer evidence that strain NFFJ11T belongs to a novel species of the genus Companilactobacillus. The cell-wall peptidoglycan type was A4α (l-Lys-d-Asp) and the G+C content of the genomic DNA was 35.7 mol%. The main fatty acids of strain NFFJ11T were C18 : 1 ω9c (43.3 %), C16 : 0 (20.1 %) and summed feature 7 (18.3 %; comprising any combination of C19 : 1 ω7c, C19 : 1 ω6c and C19 : 0 cyclo ω10c). Through polyphasic taxonomic analysis, it was observed that strain NFFJ11T represents a novel species belonging to the genus Companilactobacillus, for which the name Companilactobacillus pabuli sp. nov. is proposed. The type strain is NFFJ11T (= KACC 21771T= JCM 34088T).


Specific inhibition of nuclear RNA polymerase II by alpha-amanitin.
alpha-Amanitin, a toxic substance from the mushroom Amanita phalloides, is a potent inhibitor of DNA-dependent RNA polymerase II (the nucleoplasmic form) from sea urchin, rat liver, and calf thymus. This compound exerts no effect on the activity of polymerase I (nucleolar form) or polymerase III (also nucleoplasmic). The inhibition is due to a specific interaction with polymerase II or with a complex of DNA and polymerase II.


Methicillin-resistant Staphylococcus aureus in surgical patients: identification of high-risk populations for the development of targeted screening programmes.
Methicillin-resistant Staphylococcus aureus (MRSA)-related hospital-acquired infection (HAI) in surgical patients is associated with high morbidity, mortality and financial cost. The identification and characterisation of populations of patients who are at high risk of developing MRSA infection or colonisation could inform the design of more effective strategies to prevent HAIs and reduce transmission of MRSA. An analysis of historical discharge data for the whole of 2005 (7145 surgical in-patients) was performed, for all patients admitted to general surgery at the Royal Infirmary of Edinburgh. Analysis specifically focused on MRSA laboratory data and coding data for patient demographics, medical co-morbidities, and progress of in-patient stay. A total of 134 (1.88%) individual patients with colonisation or infection by MRSA were identified from indicated laboratory testing. Univariate analysis identified a significant association of concurrent MRSA-positive status with patients aged over 60 years (P < 0.01), a duration of inpatient stay > 7 days (P < 0.01), presence of a malignant neoplasm (P < 0.01), circulatory disease (P < 0.01), respiratory disease (P < 0.01), central nervous system disease (P < 0.01), renal failure (P < 0.01), and concurrent admission to ITU/HDU (P < 0.01). Multivariate analysis suggested MRSA colonisation or infection was strongest in those with co-morbid malignancy (P < 0.0001) or admission to ITU/HDU (P < 0.0001). This large observational study has identified cancer patients as a UK surgical patient subpopulation which is at significantly higher risk of colonisation by MRSA. These data could inform the development of focused hospital in-patient screening protocols and provide a means to stratify patient risk.


[Diabetogenic properties of Coxsackie A13 and Coxsackie B4 viruses in experimental infection in mice].
Studies of diabetogenic properties of Coxsackie A13 and B4 viruses in mice sensitive to diabetes (males, DBA line) and resistant (males and females F1(CBA X C57BL/6), females DBA/2 using in the latter case the subdiabetogenic doses of alloxan revealed in the infected animals biochemical changes manifested by reduction of glucose tolerance and disorders in the synthesis of immunoreactive insulin. Most marked changes were observed in males of DBA/2 line infected with Coxsackie B4 virus and in males F1 (CBA X C57BL/6) and females DBA/2 infected with Coxsackie A14 virus. With Coxsackie A13 virus such data have been obtained for the first time.


New insights into eyespot placement and assembly in Chlamydomonas.
Aspects of cellular architecture, such as cytoskeletal asymmetry cues, play critical roles in directing the placement of organelles and establishing the sites of their formation. In the model green alga Chlamydomonas, the photosensory eyespot occupies a defined position in relation to the flagella and microtubule cytoskeleton. Investigations into the cellular mechanisms of eyespot placement and assembly have aided our understanding of the interplay between cytoskeletal and plastid components of the cell. The eyespot, which must be assembled anew after each cell division, is a multi-layered organelle consisting of stacks of carotenoid-filled pigment granules in the chloroplast and rhodopsin photoreceptors in the plasma membrane. Placement of the eyespot is determined on both the latitudinal and longitudinal axes of the cell by the daughter four-membered (D4) microtubule rootlet. Recent findings have contributed to the hypothesis that the eyespot photoreceptor molecules are directed from the Golgi to the daughter hemisphere of the cell and trafficked along the D4 microtubule rootlet. EYE2, a chloroplast-envelope protein, forms an elliptical patch together with the photoreceptors and establishes the site for assembly of the pigment granule arrays in the chloroplast, connecting the positioning information of the cytoskeleton to assembly of the pigment granule arrays in the chloroplast.


Adenovirus-mediated overexpression of c-Jun and c-Fos induces intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 in human endothelial cells.
As distal targets and mediators of signal transduction pathways, activator protein-1 (AP-1), c-Jun, and c-Fos are among the primary regulators of genes involved in cell function, proliferation, and differentiation. By using adenovirus-mediated gene transfer, we show that overexpression of AP-1 proteins directly causes coinduction of gene expression of an adhesion molecule, intercellular adhesion molecule-1 (ICAM-1), and a chemokine, monocyte chemoattractant protein-1 (MCP-1), in human vascular endothelial cells (ECs). The AP-1-induced gene expression occurs through a mechanism independent of nuclear factor-kappaB. Because the induced expression of ICAM-1 and MCP-1 in ECs has been implicated in endothelial activation and a number of important vascular disorders, it is suggested that AP-1 activation may play an important role in the pathogeneses of inflammation, angiogenesis, and atherogenesis.


Immunohistological study of oestrogen receptors in breast carcinomas that are biochemically receptor negative.
The reliability of an immunohistological method, applied to paraffin wax sections, was assessed for determination of oestrogen receptor content of biochemically oestrogen receptor negative breast carcinomata. Sixty consecutive tumours with oestrogen receptor concentrations of less than 10 fmol/mg cytosol protein, as estimated by dextran-coated charcoal biochemical assay, were examined. Paraffin wax sections were treated with DNAse before applying a peroxidase-anti-peroxidase method using ER-ICA monoclonal antibodies. Fifty one cases (85%) were negative, six (10%) weakly positive, and three (5%) were moderately positive. No strongly positive cases were seen. It is suggested that cases with weakly positive staining, especially when localised to a small area, should be regarded as negative. On the other hand, as the three moderately stained cases included two small tubular carcinomas and an invasive ductal carcinoma with high progesterone receptor concentrations, it is more likely that the biochemical assay in these cases represented false negative results due to sampling error or inclusion of fibrous or other non-neoplastic tissue in the assayed samples. It is concluded that the immunohistological method used here is fairly reliable and would be especially valuable for determination of oestrogen receptor content in small, mammographically detected tumours from which no tissue would be available for biochemical assay or frozen section examination.


Molecular control of neuromuscular junction development.
Skeletal muscle innervation is a multi-step process leading to the neuromuscular junction (NMJ) apparatus formation. The transmission of the signal from nerve to muscle occurs at the NMJ level. The molecular mechanism that orchestrates the organization and functioning of synapses is highly complex, and it has not been completely elucidated so far. Neuromuscular junctions are assembled on the muscle fibers at very precise locations called end plates (EP). Acetylcholine receptor (AChR) clusterization at the end plates is required for an accurate synaptic transmission. This review will focus on some mechanisms responsible for accomplishing the correct distribution of AChRs at the synapses. Recent evidences support the concept that a dual transcriptional control of AChR genes in subsynaptic and extrasynaptic nuclei is crucial for AChR clusterization. Moreover, new players have been discovered in the agrin-MuSK pathway, the master organizer of postsynaptical differentiation. Mutations in this pathway cause neuromuscular congenital disorders. Alterations of the postynaptic apparatus are also present in physiological conditions characterized by skeletal muscle wasting. Indeed, recent evidences demonstrate how NMJ misfunctioning has a crucial role at the onset of age-associated sarcopenia.


Health assessment of American Oystercatchers (Haematopus palliatus palliatus) in Georgia and South Carolina.
The American Oystercatcher (Haematopus palliatus palliatus) is the only species of oystercatcher native to the Atlantic coast of North America and is restricted in distribution to intertidal shellfish beds in coastal areas. Currently, the American Oystercatcher population in South Carolina and Georgia is threatened by widespread habitat loss, resulting in low reproductive success and small population size. Oystercatchers could be an important indicator of ecosystem health because they depend on quality coastal breeding habitat and prey on bivalves, which can accumulate toxins and pathogens from the local environment. Data were collected from American Oystercatchers (n=171) captured at five sites in South Carolina and Georgia between 2001 and 2006. Iridial depigmentation was frequently noted during physical examination and was more prevalent in female birds. Female birds were larger than males on average, but ranges for weight and morphometric measurements had considerable overlap. Mean values were calculated for hematology, plasma biochemistry, and hormone levels, and prevalence of exposure to select pathogens was determined. Mercury was the only trace metal detected in blood samples. These data provide baseline health information needed for longitudinal monitoring and conservation efforts for American Oystercatchers. In addition, this study illustrates the potential use of this species as an indicator for the health of the southeastern US coastal nearshore ecosystem.


Bone grafting of cleft lip and palate patients for placement of endosseous implants.
Fixation of a prosthesis or single tooth replacement using osseointegrated implants has the potential to overcome functional and psychological inconveniences that many patients experience from such appliances. However, the dimensions of the recipient site are relatively often inadequate for implant placement. This study assessed grafting of this site with autogenous bone as a solution for the latter problem. Ten cleft lip and palate patients had bone grafts; six had iliac crest grafts to the maxillary sinus floor (31 implants), and four had chin bone grafts to the local defect in the anterior maxilla (six implants). Implants were inserted during the grafting procedure (one patient) or after 3 months (nine patients). No inflammation of the bone grafts or the maxillary sinus occurred. One implant was lost during the healing phase. Four single tooth restorations, one fixed bridge, and five implant-supported overdentures were made. During the follow-up, which was 47 months (range, 28 to 65 months) in the anterior maxilla group and 56 months (range, 28 to 68 months) in the posterior maxilla group, no loss of implants was observed, and all prosthetic appliances functioned well. It is concluded that bone grafting followed by placement of dental implants can serve as a reliable alternative for conventional prosthetic rehabilitation of cleft patients.


TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling.
The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.


A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.
The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.


Resonance Enhancement of Vibrational Polariton Chemistry Obtained from the Mixed Quantum-Classical Dynamics Simulations.
We applied a variety of mixed quantum-classical (MQC) approaches to simulate the VSC-influenced reaction rate constant. All of these MQC simulations treat the key vibrational levels associated with the reaction coordinate in the quantum subsystem (as quantum states), whereas all other degrees of freedom (DOFs) are treated inside the classical subsystem. We find that, as long as we have the quantum state descriptions for the vibrational DOFs, one can correctly describe the VSC resonance condition when the cavity frequency matches the bond vibrational frequency. This correct resonance behavior can be obtained regardless of the detailed MQC methods that one uses. The results suggest that the MQC approaches can generate semiquantitative agreement with the exact results for rate constant changes when changing the cavity frequency, the light-matter coupling strength, or the cavity lifetime. The finding of this work suggests that one can use computationally economic MQC approaches to explore the collective coupling scenario when many molecules are collectively coupled to many cavity modes in the future.


Studying scientific discovery by computer simulation.
BACON is a computer program that simulates some of the important processes of scientific discovery. When provided with data about temperatures before and after two substances are brought into contact, the program infers the concept of specific heat and arrives at Black's law of temperature equilibrium. Comparison of BACON's discovery methods with historical records of Black's work casts light on the relation between data-driven and theory-driven discovery.


Destiny rides again: the reappearance of silicone gel-filled breast implant toxicity.
Background Twenty-five years ago attorneys representing ailing women in class action litigation against silicone breast implant manufacturers made the procedural error of defining silicone-induced toxicity in the courtroom before it was properly studied in the exam room. This aberrant methodology perverted the proper research process, rendered verification of any real disease elusive, and cemented the groundwork for a repeat public health crisis potentially affecting two million women in the USA who possess new silicone gel devices inserted over the past 10 years. Patients and methods Six women, previously well, aged 27 to 53 (mean 42), were recipients of the new generations of cohesive silicone gel-filled breast implants approved for general use by the Food and Drug Administration (FDA) since December of 2006. They averaged seven years of total implantation time, and none experienced implant rupture. Results All six became ill on average 3.5 years from the time of implantation. By seven years the women manifested multiple types of skin rashes, polyarthritis, fatigue, protracted AM stiffness, myalgias, headaches, photosensitivity, hair loss, paresthesias, tinnitus, lymphadenopathy, chest pain, cognitive dysfunction, dry eyes, skin pigment changes, itching, muscle twitching, dizziness, nausea, easy bruising, and odor and smell sensitivity. Three of the four who were explanted noted improvement and/or resolution of at least 50% of their total disease manifestations. Conclusions These six women are representative of over 70,000 other breast implant recipients who, over the past three years, have had their new silicone devices permanently removed because of alleged gel-induced toxicity. The recurrence of this public health crisis has been fueled by manufacturers' research fraud, FDA ineptness, faulty informed consent, patient abandonment, proprietary manufacturing secrecy, misleading advertising, physician indifference, aberrant research methodology, and lax Congressional oversight.


Influence of maternal antibody on efficacy of embryo vaccination with cell-associated and cell-free Marek's disease vaccine.
Vaccination with turkey herpesvirus (HVT) of 18-day-old chicken embryos from a commercial source or from a cross (15 X 7) of two inbred lines induced better protection against early post-hatch challenge with virulent Marek's disease virus (MDV) than vaccination at hatch, despite the presence in embryos of maternally derived antibodies to HVT or to HVT and MDV. However, 50%-protective-dose (PD50) assays revealed that maternal antibodies in embryos reduced vaccine efficacy. The PD50 assays were conducted by vaccinating 15 X 7 embryos with serial dilutions of HVT at the 18th day of incubation. Embryonally vaccinated and unvaccinated chicks were challenged with MDV on the day of hatch. In the absence of maternal antibodies, the PD50 values in plaque-forming units for cell-associated and cell-free HVT were 57 and 328, respectively. In the presence of maternal antibodies, PD50 values for cell-associated and cell-free HVT were 105 and greater than 4,000, respectively.


[Spatial analysis for detecting clusters of cases during the COVID-19 emergency in Rome and in the Lazio Region (Central Italy)].
one of the most affected European countries by the COVID-19 epidemic is Italy; data show the strong geographical heterogeneity of the epidemic. to propose an analysis strategy to ascertain the non-random nature of the spatial spread of COVID-19 cases infection and identify any territorial aggregations, in order to enhance contact tracing activities in specific areas of the Lazio Region (Central Italy) and a large urban area as Rome. all cases of COVID-19 of the Lazio Region notified to the Regional Service for Epidemiology, Surveillance, and Control of Infectious Diseases (Seresmi) with daily updates from the beginning of the epidemic to April 27, 2020 were considered. The analyses were carried out considering two periods (the first from the beginning of the epidemic to April 6 and the second from the beginning of the epidemic to April 27) and two different levels of spatial aggregation: the entire Lazio region excluding the Municipality of Rome, where the 377 municipalities represent the area units, and the Municipality of Rome, where the area units under study are the 155 urban areas (ZUR). The Scan statistic of Kulldorff was used to ascertain the non-random nature of the spatial spread of infected cases and to identify any territorial aggregations of cases of COVID-19 infection, using a retrospective spatial analysis in two overlapping periods. analysis was conducted at regional level in the two survey periods and revealed the presence of 7 localized clusters. In the Municipality of Rome, a single cluster (Historic Centre) was identified in the first period which includes 7 urban areas, while in the second period two distinct clusters (Omo and Farnesina) were observed. Scan statistics are an important surveillance tool for monitoring disease outbreaks during the active phase of the epidemic and a useful contribution to epidemiological surveillance during the COVID-19 epidemic in a specific territory.


Nutrient content and protein and energy digestibilities of ethanol-extracted, low alpha-galactoside soybean meal as compared to intact soybean meal.
A study was conducted with adult Leghorn roosters to determine TMEn, dry matter digestibility, amino acid content and digestibility, and cellulose and hemicellulose content and digestibility of ethanol-extracted, low alpha-galactoside soybean meal (SBM). Results were compared to that of commercially available 47% CP SBM. Twenty-one roosters were utilized; seven roosters were precision-fed each of the two soybean meal treatments, and seven served as feed-deprived controls. Excreta were collected for 48 h after feeding. A second experiment compared the TMEn, as determined with roosters, to AMEn, as determined with male broiler chicks, of 44% and 47% CP SBM and three different ethanol extraction procedures to remove alpha-galactosides. The ethanol extraction procedure concentrated CP, gross energy, and TMEn. Dry matter digestibility of SBM increased from 52.1% (control SBM) to 63.3% (ethanol-extracted SBM) because of the ethanol extraction procedure. The average amino acid digestibility of ethanol-extracted SBM was 91.6%, compared to 88.0% for control SBM. The digestibility of methionine, alanine, valine, and lysine was improved by the ethanol extraction procedure. Total cellulose and hemicellulose digestion, measured as digestion of specific monosaccharide components, was increased by the ethanol extraction. The TMEn and AMEn values for the different control and extracted SBM were similar. These data indicate that the ethanol extraction of SBM to remove alpha-galactosides resulted in a product that is more protein and energy dense than commercial SBM. Advantages in digestion of amino acids and fiber may contribute to the increase in TMEn observed in both young and adult birds.


Hydroxysulfonylation of alkenes: an update.
The direct difunctionalization of inexpensive and widely available alkenes has been recognized as a strong and straightforward tool for the rapid fabrication of complex molecules and pharmaceutical targets by introducing two different functional groups on adjacent carbon atoms of common alkene moieties in a single operation. This synthetic strategy avoids the purification and isolation of the intermediates and thus makes synthetic schemes shorter, simpler and cleaner. In this family of reactions, the hydroxysulfonylation of alkenes has emerged as an increasingly promising strategy for the synthesis of β-hydroxysulfones, which are found in many biologically important molecules and widespread applications in organic synthesis. The objective of this review is to illustrate the advancements in the field of hydroxysulfonylation of alkenes with special emphasis on the mechanistic details of the reaction pathways.


Learning from the public: citizens describe the need to improve end-of-life care access, provision and recognition across Europe.
Despite ageing populations and increasing cancer deaths, many European countries lack national policies regarding palliative and end-of-life care. The aim of our research was to determine public views regarding end-of-life care in the face of serious illness. Implementation of a pan-European population-based survey with adults in England, Belgium (Flanders), Germany, Italy, The Netherlands, Portugal and Spain. Three stages of analysis were completed on open-ended question data: (i) inductive analysis to determine a category-code framework; (ii) country-level manifest deductive content analysis; and (iii) thematic analysis to identify cross-country prominent themes. Of the 9344 respondents, 1543 (17%) answered the open-ended question. Two prominent themes were revealed: (i) a need for improved quality of end-of-life and palliative care, and access to this care for patients and families and (ii) the recognition of the importance of death and dying, the cessation of treatments to extend life unnecessarily and the need for holistic care to include comfort and support. Within Europe, the public recognizes the importance of death and dying; they are concerned about the prioritization of quantity of life over quality of life; and they call for improved quality of end-of-life and palliative care for patients, especially for elderly patients, and families. To fulfil the urgent need for a policy response and to advance research and care, we suggest four solutions for European palliative and end-of-life care: institute government-led national strategies; protect regional research funding; consider within- and between-country variance; establish standards for training, education and service delivery.


Isolation and characterization of the complete chicken beta-globin gene region: frequent deletion of the adult beta-globin genes in lambda.
A library of bacteriophage lambda clones containing chicken chromosomal DNA was screened, using the adult beta-globin cDNA plasmid pHb 1001 as a probe. Sixteen overlapping clones were isolated containing 35 kilobase pairs (kbp) of chicken DNA. Characterization of these clones revealed four beta-like globin genes, some genomically repeated sequences, but no pseudo-genes. The four beta-like genes have an average intergenic distance of less than half of that found for the mammalian beta-like globin gene clusters so far characterized. The overall features of the map were confirmed by genomic Southern analysis. Frequent deletions were shown to occur between the various beta-like globin genes during phage propagation. The presumptive hatching gene in particular was always associated with abnormal lambda clones although we were able to find one such clone that did contain a normal copy of the hatching gene itself. Probably such deletions explain the failure to recover this gene in previous attempts.


If we can do it for misoprostol, why not for mifepristone? The case for taking mifepristone out of the office in medical abortion.
Given the highly political nature of abortion in the United States, the provision of medical abortion with mifepristone (Mifeprex®) and misoprostol has always occurred under a unique set of circumstances. The Food and Drug Administration-approved regimen requires clinicians to administer the mifepristone in the office and also requires women to return to the office for the misoprostol. In the US, where off-label drug use is an accepted practice when supportive evidence exists, most clinicians give women the misoprostol at the initial visit for her to take at home, eliminating an unnecessary visit to the office. This commentary suggests that, based on current studies, there is also enough evidence to offer women the option to self-administer mifepristone out of the office and that this is just another feature of off-label use. Six studies, enrolling over 1800 women, found that the option of taking mifepristone out of the office was popular and acceptable among women and providers. Given that it is safe, highly acceptable and not burdensome on providers, outside-office-use of mifepristone should be offered to all women as part of routine medical abortion services.


Controlled evaluation of rural regional perinatal care: developmental and neurologic outcomes at 1 year.
The effectiveness of a rural regionalized perinatal care (RPC) program was evaluated by a controlled, population-based design. The RPC program, begun in a carefully selected study region in July 1975, evolved into a system of care which included the following major components: identification of high-risk pregnancies and high-risk newborn infants; obstetric and newborn consultation and referral services between Level I, II, and III centers; professional education for physicians, nurses, and other health professionals; and nutrition and social work consultation. Substantial resources were made available from 1975 to 1980 to implement this "total package" of RPC. A matched, control region was identified which, except for the RPC program, was as comparable as possible to the study region. It was hypothesized that the RPC intervention would have the following effects when the study region was compared with the control region: reduction in fetal and neonatal mortality, no increase in postneonatal mortality, and reduction in obstetric and newborn morbidity. These findings were reported previously. This paper presents results of hypothesized reductions in adverse developmental, neurologic, maternal-infant attachment, and selected physical health outcomes. A sample of 447 infants was assessed by an extensive battery of instruments at 1 year, adjusted for gestational age. The most notable findings were mothers' reports of receptive language development and observations of maternal attachment behaviors that significantly favored the study region. No significant differences between study and control regions were observed for Bayley Mental and Motor Scores, abnormal neurologic signs, and the physical health measures.(ABSTRACT TRUNCATED AT 250 WORDS)


Salmonella typhimurium induces apoptosis in human monocyte-derived macrophages.
Salmonella species represent a leading cause of gastroenteritis worldwide. More recently, they have been proposed as putative vaccine delivery vehicles in humans. Oral infection with Salmonella leads to invasion of the intestinal epithelial barrier and subsequent interaction with mucosal macrophages. In this study, we investigated the fate of Salmonella typhimurium-infected human macrophages differentiated from blood monocytes by GM-CSF. Wild type S. typhimurium strain SL1344 induced macrophage surface blebbing and caused the release of host cytoplasmic lactate dehydrogenase beginning 30 min post-infection. Three hours later more than 80% of the macrophages in the culture were killed. In contrast, during the same period, macrophages infected with the non-invasive S. typhimurium strain BJ66 remained viable. Chromatin fragmentation is a hallmark of cells undergoing apoptosis. Using TUNEL analysis, we observed chromatin fragmentation in macrophages infected with SL1344 but not in BJ66 infected cells. Consistent with this observation, we found that pretreatment of human macrophages with an inhibitor of caspase-3, a member of the pro-apoptotic enzyme family shown to be involved in S. typhimurium-induced killing of mouse macrophages, reduced SL1344-mediated cytotoxicity by 40%. Our study provides the first evidence that invasive S. typhimurium induces apoptosis in human macrophages that were differentiated from blood monocytes by GM-CSF, and that cell death is a caspase-dependent phenomenon.


Pathobiological significance of vascular endothelial growth factor and Maspin expressions in human gastric carcinoma.
To investigate the correlation between expression of vascular endothelial growth factor (VEGF) and cell differentiation, invasion, metastasis and Maspin expression in gastric carcinoma. Formalin-fixed paraffin-embedded tissue specimens from 73 cases of gastric carcinoma were studied with SP immunohistochemistry, using anti-VEGF monoclonal antibody, and thirty-nine of them were studied using anti-Maspin monoclonal antibody. VEGF expression was compared with the clinical stage, lymph node metastasis, and Borrmann's and WHO's classification of gastric carcinoma. The positive rate of VEGF expression was significantly higher in adjacent non-carcinoma epithelia (ANCE) than in non-metaplastic, non-carcinoma gastric epithelia (NMNCE), which were at least 4 cm distant from the primary tumor (P = 0.000, chi2 = 73.03). The positive rate of VEGF expression was significantly higher in advanced gastric carcinoma (AGC) than in early gastric carcinoma (EGC) (P = 0.032, chi2 = 4.62). The positive rate of VEGF expression in gastric carcinomas with lymph node metastases was significantly higher than that in those without metastasis (P = 0.006, chi2 = 7.47). Maspin was weakly expressed in 16 out of 39 cases of NMNCE, and the positive immunoreaction was limited to gland cells of the stomach body. There was no significant correlation between the expression of VEGF and histological or gross classifications, and correlation between the expressions of VEGF and Maspin in gastric carcinoma (P = 0.648, chi2 = 0.21). Expression of VEGF is significantly correlated to the malignant biological behaviors of gastric carcinoma, but there is no significant correlation between the expression of VEGF and Maspin.


Strong and Broadly Tunable Plasmon Resonances in Thick Films of Aligned Carbon Nanotubes.
Low-dimensional plasmonic materials can function as high quality terahertz and infrared antennas at deep subwavelength scales. Despite these antennas' strong coupling to electromagnetic fields, there is a pressing need to further strengthen their absorption. We address this problem by fabricating thick films of aligned, uniformly sized semiconducting carbon nanotubes and showing that their plasmon resonances are strong, narrow, and broadly tunable. With thicknesses ranging from 25 to 250 nm, our films exhibit peak attenuation reaching 70%, ensemble quality factors reaching 9, and electrostatically tunable peak frequencies by a factor of 2.3. Excellent nanotube alignment leads to the attenuation being 99% linearly polarized along the nanotube axis. Increasing the film thickness blueshifts the plasmon resonators down to peak wavelengths as low as 1.4 μm, a new near-infrared regime in which they can both overlap the S11 nanotube exciton energy and access the technologically important infrared telecom band.


Efficient Selection of Enhancers and Promoters from MIA PaCa-2 Pancreatic Cancer Cells by ChIP-lentiMPRA.
A library of active genome regulatory elements (putative promoters and enhancers) from MIA PaCa-2 pancreatic adenocarcinoma cells was constructed using a specially designed lentiviral vector and a massive parallel reporter assay (ChIP-lentiMPRA). Chromatin immunoprecipitation of the cell genomic DNA by H3K27ac antibodies was used for primary enrichment of the library for regulatory elements. Totally, 11,264 unique genome regions, many of which are capable of enhancing the expression of the CopGFP reporter gene from the minimal CMV promoter, were identified. The regions tend to be located near promoters. Based on the proximity assay, we found an enrichment of highly expressed genes among those associated with three or more mapped distal regions (2 kb distant from the 5'-ends of genes). It was shown significant enrichment of genes related to carcinogenesis or Mia PaCa-2 cell identity genes in this group. In contrast, genes associated with 1-2 distal regions or only with proximal regions (within 2 kbp of the 5'-ends of genes) are more often related to housekeeping functions. Thus, ChIP-lentiMPRA is a useful strategy for creating libraries of regulatory elements for the study of tumor-specific gene transcription.


A narrative review of the effect of parent-child shared reading in preterm infants.
The benefits of book-reading interventions on language development in full-term infants have been well investigated. Because children born preterm face a greater risk of cognitive, language and emotional impairments, this narrative review examines the theoretical evidence, empirical findings, and practical challenges for introducing such intervention to this population. The effect of shared book interventions on typically developing infants is mediated by three components: a linguistic aspect (i.e., exposure to enriched linguistic input), an interactive aspect (i.e., eliciting more synchronous and contingent communication), and a parental aspect (i.e., reducing parental stress and increasing sense of control). Parental shared book reading in a neonatal intensive care unit (NICU) was found to be feasible and well accepted. It provides concrete support for positive parenting in a highly stressful context. Preliminary evidence supports a positive effect of shared reading sessions in physiological parameters of preterm infants in NICU. One study showed that parental shared book reading in an NICU is associated with lower decline in language development during the first 24 months compared to a historical control group. Findings from a community-based birth cohort confirm the positive effect of this intervention on cognitive development with a 2-year-follow up. More structured clinical trials are now needed to confirm these preliminary findings. Questions remain about possible moderators of these interventions, in particular cultural features.


Compressing the fluctuation of the magnetic field by dynamic compensation.
We present a dynamic compensation method to compress the spatial fluctuation of the static magnetic field (C-field) that provides a quantization axis in the atomic fountain clock. The coil current of the C-field is point-by-point modulated in accordance with the atoms probing the magnetic field along the flight trajectory. A homogeneous field with a 0.2 nT inhomogeneity is produced compared to a 5 nT under the static magnetic field with a constant current during the Ramsey interrogation. The corresponding uncertainty associated with the second-order Zeeman shift that we calculate is improved by one order of magnitude. The technique provides an alternative method to improve the uniformity of the magnetic field, particularly for large-scale equipment that is difficult to construct with an effective magnetic shielding. Our method is simple, robust, and essentially important in frequency evaluations concerning the dominant uncertainty contribution due to the quadratic Zeeman shift.


Gender differences in factors associated with delirium severity in older adults with dementia.
The purpose of this descriptive correlational study was to explore potential gender differences in the relationship of dementia severity, age, APOE status, cognitive reserve and co-morbidity (two potentially modifiable factors), to delirium severity in older adults. Baseline data from an ongoing clinical trial and a Poisson regression procedure were used in the analyses. Participants were 148 elderly individuals with dementia and delirium admitted to post-acute care. In women, delirium severity was related to dementia severity (p=0.002) and co-morbidity moderated that effect (p=0.03). In men, education was marginally associated with delirium severity (p=0.06). Implications for research are discussed.


Levomethadone Therapeutic Drug Monitoring to Aid Opioid Withdrawal Therapy: A Short Communication.
Therapeutic drug monitoring (TDM) is recommended for opioid maintenance therapy with levomethadone. However, TDM has not yet been applied to monitor opioid withdrawal therapy clinically, although tools to improve it are required. In this observational cohort study, repeated TDM with levomethadone was performed according to a prospective opioid withdrawal study protocol. Objective and subjective opioid withdrawal symptoms were measured using validated rating scales and correlated to levomethadone plasma concentrations. Plasma levels were measured using high-pressure liquid chromatography with column switching and spectroscopic detection of methadone and its major metabolite. This study included 31 opioid-dependent patients who participated in standardized opioid withdrawal therapy. The serum levels of levomethadone were found to be highly variable and below the recommended therapeutic reference range of 250 ng/mL for maintenance therapy. These serum levels were positively correlated with dosage (r = 0.632; P < 0.001) and inversely correlated with subjective (r = -0.29; P = 0.011) and objective (r = -0.28; P = 0.014) withdrawal symptoms. The evidence provided sheds light on how to improve levomethadone withdrawal therapy in patients with opioid dependence. It seems likely that higher initial doses at the beginning and lower dose reductions would have been advantageous. TDM can enhance the safety of opioid withdrawal therapies, minimize withdrawal symptoms, and reduce dropout rates.


Culture and PCR based detection of bacteria causing urinary tract infection in urine specimen.
Urinary tract infections are the second most common bacterial infections occurring at all ages and both sexes. The increasing rate of antibiotic resistance is a global concern. The use of routinely used antibiotics is resulting in treatment failure. The objective of this study was to diagnose the urinary tract infections by routine culture sensitivity test and by molecular methods. This study was conducted in Microbiology laboratory, Bolan Medical Complex Hospital, Quetta, from July 1st to 31st March 2019. Isolates were identified biochemically by API20E & API20NE. Antibiogram was performed using disc diffusion Kirby Bauer technique. The 16S rDNA gene approach was used for molecular identification of bacterial isolates. The presence of the bla NDM-1 gene was identified by polymerase chain reaction (PCR). We isolated 146 bacterial isolates namely Escherichia coli (n=99) 67.80%, Klebsiella pneumoniae (n=33) 22.60%, Pseudomonas aeruginosa (n=11) 7.53% and Proteus mirabilis (n=3) 2.05% from 2032 urine samples. The resistance pattern was dominated by Multi Drug Resistance (MDR). Remarkably, four isolates of Escherichia coli (n=3) and Klebsiella pneumoniae (n=1) were displaying resistance against a range of antibiotics used in the study, including carbapenems but sensitive to tigecycline and polymyxins only, suggesting extensive drug resistance having bla NDM-1 gene. This is the first report on direct molecular detection of bacterial pathogens from urinary tract infected patients in Balochistan. The presence of bla NDM-1 in different bacterial species and their extensive drug resistance pattern poses a significant clinical threat. Molecular detection of bacteria and resistant gene may reduce the diagnostic time of patients.


Classification of ankle fractures: the Lauge-Hansen or AO system?
Lauge-Hansen's system of classification of ankle fractures has been of pioneering importance and when correctly employed has improved the results of conservative treatment. Weber's classification scheme introduced by AO is simpler and more suited for surgical than nonoperative therapy. Both systems have deficiencies. Moreover, both are based on partly divergent concepts of the causative mechanisms of ankle fractures.


Distribution of lignin monomers and the evolution of lignification among lower plants.
Through application of chemical, biochemical and histochemical analyses, we provide new data on the absence/presence of syringyl lignins in the algal species Mastocarpus stellatus, Cystoseira baccata and Ulva rigida, the bryophytes Physcomitrella patens and Marchantia polymorpha, the lycophytes Selaginella martensii, Isoetes fluitans and Isoetes histrix, the sphenophyte Equisetum telmateia, the ferns Ceratopteris thalictroides, Ceratopteris cornuta, Pteridium aquilinum, Phyllitis scolopendrium and Dryopteris affinis, and the angiosperm Posidonia oceanica. Lignins, and especially syringyl lignins, are distributed from non-vascular basal land plants, such as liverworts, to lycopods and ferns. This distribution, along with the already reported presence of syringyl lignins in ginkgoopsids, suggests that syringyl lignin is a primitive character in land plant evolution. Here, we discuss whether the pathway for sinapyl alcohol recruitment was iterative during the evolution of land plants or, alternatively, was incorporated into the earliest land plants and subsequently repressed in several basal liverworts, lycopods, equisetopsids and ferns. This last hypothesis, which is supported by recent studies of transcriptional regulation of the biosynthesis of lignins, implies that lignification originated as a developmental enabler in the peripheral tissues of protracheophytes and would only later have been co-opted for the strengthening of tracheids in eutracheophytes.