Expulsion of Fibroids to the Endometrial Cavity after Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound Surgery (MRgFUS) Treatment of Intramural Uterine Fibroids.
This report seeks to introduce some cases of the patients who received magnetic resonance imaging (MRI)-guided high intensity focused ultrasound (HIFU) surgery (MRgFUS)-based intramural uterine fibroids treatment where the post-MRgFUS intramural uterine fibroids decreased in its volume and protruded towards the endometrial cavity to be expelled by hysteroscopy. Of the 157 patients who had received MRgFUS treatment in the Obstetrics and Gynecology of the Hospital from March, 2015 to February, 2016; this study examined 6 of the cases where, after high intensity focused ultrasound treatment, intramural uterine fibroids protruded towards the endometrial cavity to be removed by hysteroscopic myomectomy. The high intensity focused ultrasound utilized in the cases were Philips Achieva 1.5 Tesla MR (Philips Healthcare, Best, The Netherlands) and Sonalleve HIFU system. The volume of fibroids ranged from 26.0 cm3 to 199.5 cm3, averaging 95.6 cm3. The major axis length ranged from 4.0 cm to 8.2 cm, averaging 6.3 cm. Fibroid location in all of the patients was in intramural uterine before treatment but after the high intensity focused ultrasound treatment, the fibroids were observed to protrude towards the endometrial cavity in at least Day 5 or up to Day 73 to allow hysteroscopic myomectomy. In some cases, after an intramural uterine fibroid is treated with MRgFUS, fibroid volume is decreased and the fibroid protrudes towards the endometrial cavity. In this case, hysteroscopic myomectomy can be a useful solution.


C4b-binding protein binds to necrotic cells and DNA, limiting DNA release and inhibiting complement activation.
After cell death, via apoptosis or necrosis, the uptake of dead cells by neighboring cells or phagocytes prevents the release of intracellular content. An array of molecules, including initiation molecules of the complement system, are involved in marking dead cells for uptake. After binding of these molecules, complement activation takes place, which when uncontrolled might result in a proinflammatory state. In the current study we demonstrate that complement inhibitor, C4b-binding protein (C4BP), binds strongly to necrotic cells, irrespective of the cell type used or the method of induction. After binding of the C4BP-protein S (PS) complex to necrotic cells via PS-phosphatidylserine and C4BP-DNA interactions, C4BP-PS inhibits complement activation on these cells. C4BP binds DNA via a patch of positively charged amino acids, mainly on the second complement control domain of the C4BP alpha-chain (affinity constant: 190 nM). Furthermore, C4BP limits DNA release from necrotic cells and inhibits DNA-mediated complement activation in solution. The C4BP-necrotic cell interaction also occurs in vivo as necrotic areas of arteriosclerotic plaques and of various cancers stain strongly positive for C4BP. This study describes a novel mechanism in which C4BP limits the inflammatory potential of necrotic cells.


Modular microfluidics for gradient generation.
This paper describes a modular approach to constructing microfluidic systems for the generation of gradients of arbitrary profiles. Unlike most current microfluidic-based systems that have integrated architectures, we design several basic component modules such as distributors, combiners, resistors and collectors and connect them into networks that produce gradients of any profile at will. Using the system as a platform we can generate arbitrary gradient profiles that are tunable in real time. The key advantage of this system is that its operation is based on prefabricated components that are relatively simple. Particularly for non-specialists, the modular microfluidic system is easier to implement and more versatile compared to single, integrated gradient generators. The disadvantages associated with this system is that the total amount of liquids used is rather large compared with single chip-based systems. The system would be useful in simulating environments in vivo, e.g., studying how cells respond to temporal and spatial stimuli.


Fyn Kinase-Mediated PKCδ Y311 Phosphorylation Induces Dopaminergic Degeneration in Cell Culture and Animal Models: Implications for the Identification of a New Pharmacological Target for Parkinson's Disease.
Oxidative stress, neuroinflammation and apoptosis are some of the key etiological factors responsible for dopamin(DA)ergic degeneration during Parkinson's disease (PD), yet the downstream molecular mechanisms underlying neurodegeneration are largely unknown. Recently, a genome-wide association study revealed the FYN gene to be associated with PD, suggesting that Fyn kinase could be a pharmacological target for PD. In this study, we report that Fyn-mediated PKCδ tyrosine (Y311) phosphorylation is a key event preceding its proteolytic activation in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinsonism. MPP+/MPTP induced Fyn kinase activation in N27 DAergic neuronal cells and the mouse substantia nigra. PKCδ-Y311 phosphorylation by activated Fyn initiates the apoptotic caspase-signaling cascade during DAergic degeneration. Pharmacological attenuation of Fyn activity protected DAergic neurons from MPP+-induced degeneration in primary mesencephalic neuronal cultures. We further employed Fyn wild-type and Fyn knockout (KO) mice to confirm whether Fyn is a valid pharmacological target of DAergic neurodegeneration. Primary mesencephalic neurons from Fyn KO mice were greatly protected from MPP+-induced DAergic cell death, neurite loss and DA reuptake loss. Furthermore, Fyn KO mice were significantly protected from MPTP-induced PKCδ-Y311 phosphorylation, behavioral deficits and nigral DAergic degeneration. This study thus unveils a mechanism by which Fyn regulates PKCδ's pro-apoptotic function and DAergic degeneration. Pharmacological inhibitors directed at Fyn activation could prove to be a novel therapeutic target in the delay or halting of selective DAergic degeneration during PD.


Breast cancer in mice: effect of murine MUC-1 immunization on tumor incidence in C3H/HeOuj mice.
Mucin-1 (MUC-1), which is overexpressed in more than 90% of human breast cancers, is a potential target for immunotherapy. To develop a mouse model appropriate for the immunotherapy of human cancer, mouse mucin-1 (muc-1) fusion protein, containing ten tandem repeats, was made and used to immunize C3H/HeOuj mice, which supposedly have a high incidence of breast cancer. C3H/HeOuj mice were injected eight times with 5 microg oxidized mannan muc-1-glutathione-S-transferase (MMFP) with or without cyclophosphamide, which is used to increase cellular immunity. At 80 age weeks, only 12.1% (4 of 33) mice of the untreated C3H/HeOuj mice had mammary tumors. The reason for the low incidence of breast cancer in these mice is not known, but all the mammary tumors were MUC-1+ breast adenocarcinomas and were transplantable to C3H/HeOuj mice. The incidence was 11.4% (4 of 35) in mice injected with MMFP: 38.2% (13 of 34) in mice given cyclophosphamide; and 14.3% (2 of 14) in mice treated with glutathione-S-transferase. That is, cyclophosphamide increased the incidence of mammary tumors, and metastases were found in only these mice. Fewer tumors (6 of 34 or 17.6% compared with 13 of 34 or 38.2% with cyclophosphamide only) occurred in the group immunized with MMFP and cyclophosphamide. Mice immunized with MMFP had high levels of muc-1 antibodies and cellular immune responses (the frequency of the precursor of the cytotoxic Tlymphocyte cell was 1 of 40,000 to 1 of 100,000), which were not found in control groups. The occurrence of muc-1 immunity, particularly the presence of large amounts of anti-mucin-1 antibodies, had no effect on tumor incidence. Thus, the immunization with murine muc-1 reduced the tumor incidence in only cyclophosphamide-treated mice and led to strong muc-1 antibody production and to cellular responses. These findings have implications for human tumor immunotherapy in which strong antibody and weak cellular responses are to be expected and, indeed, have been found.


Habitat hydrology and geomorphology control the distribution of malaria vector larvae in rural Africa.
Larval source management is a promising component of integrated malaria control and elimination. This requires development of a framework to target productive locations through process-based understanding of habitat hydrology and geomorphology. We conducted the first catchment scale study of fine resolution spatial and temporal variation in Anopheles habitat and productivity in relation to rainfall, hydrology and geomorphology for a high malaria transmission area of Tanzania. Monthly aggregates of rainfall, river stage and water table were not significantly related to the abundance of vector larvae. However, these metrics showed strong explanatory power to predict mosquito larval abundances after stratification by water body type, with a clear seasonal trend for each, defined on the basis of its geomorphological setting and origin. Hydrological and geomorphological processes governing the availability and productivity of Anopheles breeding habitat need to be understood at the local scale for which larval source management is implemented in order to effectively target larval source interventions. Mapping and monitoring these processes is a well-established practice providing a tractable way forward for developing important malaria management tools.


Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture.
Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.


Effect of overexpression of PPARgamma on the healing process of corneal alkali burn in mice.
Wound healing involves both local cells and inflammatory cells. Alkali burn of ocular surface tissue is a serious clinical problem often leading to permanent visual impairment resulting from ulceration, scarring and neovascularization during healing. Behaviors of corneal cells and inflammatory cells are orchestrated by growth factor signaling networks that have not been fully uncovered. Here we showed that adenoviral gene introduction of peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits activation of ocular fibroblasts and macrophages in vitro and also induced anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. PPARgamma overexpression suppressed upregulation of inflammation/scarring-related growth factors and matrix metalloproteinases (MMPs) in macrophages. It also suppressed expression of such growth factors and collagen Ialpha2 and myofibroblast generation upon exposure to TGFbeta1. Exogenous PPARgamma did not alter phosphorylation of Smad2, but inhibited its nuclear translocation. PPARgamma overexpression enhanced proliferation of corneal epithelial cells, but not of fibroblasts in vitro. Epithelial cell expression of MMP-2/-9 and TGFbeta1 and its migration were suppressed by PPARgamma overexpression. In vivo experiments showed that PPARgamma gene introduction suppressed monocytes/macrophages invasion and suppressed the generation of myofibroblasts, as well as upregulation of cytokines/growth factors and MMPs in a healing cornea. In vivo re-epitheliazation with basement membrane reconstruction in the healing, burned, cornea was accelerated by PPARgamma-Ad expression, although PPARgamma overexpression was considered to be unfavorable for cell migration. Together, these data suggest that overexpression of PPARgamma may represent an effective new strategy for treatment of ocular surface burns.


Meeting Patients Where They Are: Construction And Maintenance Of Analytic Intimacy.
This paper aims to describe the processes of construction and maintenance of analytic intimacy, understood as a shared state of relative internal freedom that is most permeable to preconscious and unconscious communications, which facilitate the processes of subjectivation, dreaming, and digestion of unprocessed trauma. The author illustrates the theoretical and technical features related to the concept of intimacy, highlighting the transformations of a clinical case followed in supervision. This article is presented in the form of a conversation with the supervisee, so as to evoke in the reader the dialogic and co-constructive experience of thought construction.


Ketamine therapy for chronic pain in The Netherlands: a nationwide survey.
Ketamine is used to treat chronic refractory pain. However, there are no scientific guidelines for ketamine use in the Netherlands. The aim of this survey was to provide an overview of the use of ketamine for chronic pain in the Netherlands. All pain clinics in the Netherlands were contacted. A digital survey, available from June 2019 to January 2020, was sent to 68 pain clinics. The survey was completed by one pain physician as a representative of the entire pain department. The survey included questions about ketamine treatment indications, administration, dose, duration, treatment repetition and the inpatient or outpatient setting. The survey was completed by 51 pain clinics (75.0%). Thirty-one clinics used ketamine for chronic pain treatment. The most common indication was Complex Regional Pain Syndrome (83.9%). Pain clinics administered ketamine via intravenous infusions (96.8%), iontophoresis (61.3%), subcutaneous (3.2%) or oral administration (3.2%). Intravenous ketamine treatment was offered in an inpatient setting in 14 pain clinics, in both an inpatient and outpatient setting in 11 pain clinics and in six pain clinics in an outpatient setting. In the outpatient setting, the median starting dose was 5 mg/h (IQR=17.5-5). The median maximum dose was 27.5 mg/h (IQR=100-11.9). The median infusion duration was 6 h (IQR=8-4). In the inpatient setting, the median starting dose was 5 mg/h (IQR=5-1.5) and the median maximum dose was 25 mg/h (IQR=25-14). Patients were admitted to hospital for a median of 4 days (IQR=5-1). The results of this Dutch nationwide survey study show that there are heterogeneous treatment protocols with different indications, treatment setting and dosing regimen for the treatment of chronic pain with ketamine. This study encourages the formulation of a broader consensus and the development of evidence based guidelines for ketamine treatment.


Continuous negative extrathoracic pressure in neonatal respiratory failure.
In uncontrolled clinical trials, negative extrathoracic pressure has been shown to be an effective respiratory support. We aimed to assess its role in the context of current neonatal intensive care. A randomized controlled trial, with sequential analysis of matched pairs of infants. Matching was undertaken by stratified randomization from 15 groups divided according to gestational age, oxygen requirement, and whether patients were intubated at 4 hours of age. Two neonatal intensive care units. Two hundred forty-four patients (birth weight 1.53 +/- 0.69 kg (mean +/- SD); gestational age 30.4 +/- 3.5 weeks) with respiratory failure. Patients were randomized at 4 hours of age to receive either standard neonatal intensive care, or standard care plus continuous negative extrathoracic pressure (CNEP, -4 to -6 cmH2O) applied within a purpose-designed neonatal incubator. OUTCOME SCORES: Clinical scores were calculated for each infant at 56 days of age, or death if earlier. Scores included measures for mortality, respiratory outcome, the presence of cerebral ultrasound abnormalities, patent arterial duct, necrotizing enterocolitis, and retinopathy. The treatment given for the higher score for each pair was recorded and the cumulative net number of pairs favoring CNEP plotted in the sequential analysis to provide an ethical early termination strategy. Individual components of the outcome score and other secondary measurements were analyzed on completion of the trial. The sequential analysis reached a decision boundary after 122 out of a possible maximum of 124 pairs were completed. The overall outcome score showed an overall significant benefit for CNEP. Secondary analysis showed that the use of CNEP was associated with an increase in mortality, cranial ultrasound abnormalities, and pneumothoraces, which were not statistically significant. However, 5% fewer patients were intubated (95% confidence interval [CI], 0-10), and the total duration of oxygen therapy among surviving infants at 56 days was lower (20.5 days, compared with 38.9 in controls; difference 18.4 days, 95% CI 3.8 to 33.0). Among all infants, the mean total duration of oxygen therapy was 18.3 days among CNEP-treated infants compared with 33.6 days among the controls (difference -15.3 days, 95% CI -0.2 to -30.4). This reduction in mean levels is entirely attributable to substantially fewer patients requiring prolonged oxygen therapy, the median duration of treatment being very similar in the two groups. As a result, commensurately fewer surviving infants showed chronic lung disease of prematurity. The use of continuous negative pressure improves the respiratory outcome for neonates with respiratory failure.


Ribonucleases protect RNA from acid precipitation.
Four, widely used, ribonucleases were found to protect their substrates from acid precipitation by causing, evidently, a modification of their physicochemical properties. The protection was dependent on the kind of substrate while the ratio of protective to nucleolytic activity varied widely between the four enzymes. The protection was enhanced by some nucleotides like UMP, CMP and IMP and decreased in the presence of several bivalent ions like Zn++, Co++ and Cu++. It was completely abolished when the substrates were hybridized with their complementary ribohomopolymers. In the case of bovine pancreatic ribonuclease, the part of the molecule which was responsible for the protective activity was localized on the enzyme domain characterized as S-protein, which lacks nucleolytic activity. The observed property of ribonucleases could lead to false data when the measurement of TCA-soluble material is the method used to follow the purification of ribonucleases or to study their activity. It was also found that ribonuclease S-protein enhances the catalytic activity of B. Cereus RNAse. S-protein could potentiate other RNAses activity like onconase, which has recently been used as an anticancer agent.


Phospho-carboxyl-terminal domain binding and the role of a prolyl isomerase in pre-mRNA 3'-End formation.
A phospho-carboxyl-terminal domain (CTD) affinity column created with yeast CTD kinase I and the CTD of RNA polymerase II was used to identify Ess1/Pin1 as a phospho-CTD-binding protein. Ess1/Pin1 is a peptidyl prolyl isomerase involved in both mitotic regulation and pre-mRNA 3'-end formation. Like native Ess1, a GSTEss1 fusion protein associates specifically with the phosphorylated but not with the unphosphorylated CTD. Further, hyperphosphorylated RNA polymerase II appears to be the dominant Ess1 binding protein in total yeast extracts. We demonstrate that phospho-CTD binding is mediated by the small WW domain of Ess1 rather than the isomerase domain. These findings suggest a mechanism in which the WW domain binds the phosphorylated CTD of elongating RNA polymerase II and the isomerase domain reconfigures the CTD though isomerization of proline residues perhaps by a processive mechanism. This process may be linked to a variety of pre-mRNA maturation events that use the phosphorylated CTD, including the coupled processes of pre-mRNA 3'-end formation and transcription termination.


Laparoscopy versus robotic-assisted pyeloplasty in children: preliminary results of a pilot prospective randomized controlled trial.
The aim of this randomized controlled trial (RCT) is to compare the outcomes of conventional laparoscopic pyeloplasty (LP) versus robotic-assisted laparoscopic pyeloplasty (RALP) in the treatment of ureteropelvic junction obstruction (UPJO) in children. A total of 53 patients with UPJO were randomized as LP (Group 1, n: 27) and RALP (Group 2, n: 26). Redo cases and patients with anatomical abnormalities were excluded. Urinary ultrasound was performed at postoperative 3, 6 and 12 months; whereas, diuretic renal scintigraphy was performed at 1 year. Failure was defined as progressive hydronephrosis on ultrasound, decline in renal function, or symptom relapse. All parameters were statistically compared. The mean age of the patients was 55.53 ± 57.25 months. There were no statistical differences between the groups in terms of patient gender, body mass index, laterality, preoperative renal function, renal pelvis antero-posterior diameter and presence of crossing vessel. Mean total operative time in LP group was longer than RALP (139 min vs 105 min, respectively, p = 0.001). The hospital stay was similar between the two groups. After a mean follow-up of 12.43 ± 5.34 months, the complication and success rates were found comparable. Only two patients required re-do pyeloplasty in LP group. The mean total cost of RALP procedure was approximately four times higher than LP. This is the first RCT comparing LP and RALP in pediatric population. Both LP and RALP are safe and effective in children with comparable success and complication rates. Operative time was longer for LP; whereas, total cost was higher for RALP.


An Outpatient Performance Improvement Project: A Baseline Assessment of Adherence to Pain Reassessment Standards.
This performance improvement (PI) project was conducted to recommend improvements for pain reassessment workflow and policies at a large military primary care clinic. The Joint Commission survey identified inconsistent pain reassessment practices at the facility in 2012. A review of the literature reveals that pain reassessment procedures can be affected by unclear organizational policies, poorly designed documentation procedures, and redundant or inefficient workflow practices. This PI project was designed to assess pain reassessment compliance rates, associated documentation, and clinic workflow, and to identify opportunities for improvement. Pain reassessment compliance was evaluated using an Electronic Medical Record (EMR) query for patients treated between February 1 and May 30, 2013, who received Toradol at a large military outpatient clinic (n = 151). In addition, observations of clinic workflow were conducted using tracer methodology as recommended by The Joint Commission to track a convenience sample of 12 patients moving through clinic care processes. Pain reassessment documentation and workflow procedures were then evaluated using the Situation Awareness (SA) framework, which is an approach used to evaluate operational implications of factors affecting staff decisions and performance (e.g., stress and workload, interface design, automation, complexity of workflow, staff abilities and training, goals and expectations). The EMR review revealed compliance rates greater than 90% for all pain reassessment requirements with the exception of the maximum 30-minute interval between initial and follow-up pain assessment required by clinic policy, which had a compliance rate of 38%. Pain reassessments were documented to occur at a mean time of 48.25 minutes after initial assessment. During the tracer, none of the 12 patient encounters was fully compliant with clinic policies. An analysis of clinic workflow using the SA framework revealed that the SA of clinic staff was impacted by a lack of standardized procedures and heavy reliance on staff memory. Recommendations for improvement included possible extension of the 30-minute time requirement, development of a template for pain reassessment documentation in the EMR, standardizing hand off and admission/discharge processes, and designing an electronic or manual dashboard to indicate pain reassessment times. Future PI projects in other military clinics would benefit from use of the SA perspective to review clinic policies, EMR documentation, and workflow analysis. Further analysis will be needed to evaluate the impact of these improvements.


Structural and Biochemical Characterization of a Ferredoxin:Thioredoxin Reductase-like Enzyme from Methanosarcina acetivorans.
Bioinformatics analyses predict the distribution in nature of several classes of diverse disulfide reductases that evolved from an ancestral plant-type ferredoxin:thioredoxin reductase (FTR) catalytic subunit to meet a variety of ecological needs. Methanosarcina acetivorans is a methane-producing species from the domain Archaea predicted to encode an FTR-like enzyme with two domains, one resembling the FTR catalytic subunit and the other containing a rubredoxin-like domain replacing the variable subunit of present-day FTR enzymes. M. acetivorans is of special interest as it was recently proposed to have evolved at the time of the end-Permian extinction and to be largely responsible for the most severe biotic crisis in the fossil record by converting acetate to methane. The crystal structure and biochemical characteristics were determined for the FTR-like enzyme from M. acetivorans, here named FDR (ferredoxin disulfide reductase). The results support a role for the rubredoxin-like center of FDR in transfer of electrons from ferredoxin to the active-site [Fe₄S₄] cluster adjacent to a pair of redox-active cysteines participating in reduction of disulfide substrates. A mechanism is proposed for disulfide reduction similar to one of two mechanisms previously proposed for the plant-type FTR. Overall, the results advance the biochemical and evolutionary understanding of the FTR-like family of enzymes and the conversion of acetate to methane that is an essential link in the global carbon cycle and presently accounts for most of this greenhouse gas that is biologically generated.


Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension: extended study results.
Macitentan is an orally active, potent, dual endothelin receptor antagonist and is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality in a long-term study. We have recently reported that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension in a 24-week prospective study and well tolerated without adverse events. We now aimed to evaluate clinical efficacy, safety of switch in a larger patient population, in a 24-month prospective study. This is a single-institution, 24-month prospective study. Patients ≥12 years with idiopathic/heritable, pulmonary arterial hypertension, or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan treatment were included. Concomitant treatment with oral phosphodiesterase type 5 inhibitors/inhaled prostanoids was allowed. Outcome measures included change from baseline to 24 months, in the 6-minute walk distance, functional class, oxygen saturation at rest/after walk distance test, and natriuretic peptide levels. Safety end points included adverse events, laboratory abnormalities. Twenty-seven patients (19 adults/8 children, mean age: 21.1 ± 6.3 years (12-36), weight: 53.1 ± 15.7 kgs (26-87)) were included. Mean duration of macitentan treatment: 22.3 ± 3.9 months (9-24). Six-minute walk distance significantly improved from baseline (mean: 458 ± 79 m (300-620)) at 6 months (mean: 501 ± 73 m (325-616) + 43 m) (p < 0.05), at 12 months (mean: 514 ± 82 m (330-626) + 56 m) (p < 0.05), and at 24 months (mean: 532 ± 85 m (330-682) + 74 m) (p < 0.05). We observed a significant improvement during the first 6 months but no incremental improvement after 6 months (p > 0.05). Macitentan did not significantly change functional class, oxygen saturation, and natriuretic levels (p > 0.05). None of the patients had anaemia, hepatotoxicity, and peripheral edema. Our study is the first study which showed that switch from bosentan to macitentan improved exercise capacity in children and young adults with pulmonary arterial hypertension significantly in the first 6 months and compared to baseline in 24 months and well tolerated without adverse events.


Modulation of O(2) sensitive K (+) channels by AMP-activated protein kinase.
Hypoxic inhibition of K(+) channels in type I cells is believed to be of central importance in carotid body chemotransduction. We have recently suggested that hypoxic channel inhibition is mediated by AMP-activated protein kinase (AMPK). Here, we have further explored the modulation by AMPK of recombinant K(+) channels (expressed in HEK293 cells) whose native counterparts are considered O(2)-sensitive in the rat carotid body. Inhibition of maxiK channels by AMPK activation with AICAR was found to be independent of [Ca(2+)](i) and occurred regardless of whether the alpha subunit was co-expressed with an auxiliary beta subunit. All effects of AICAR were fully reversed by the AMPK inhibitor compound C. MaxiK channels were also inhibited by the novel AMPK activator A-769662 and by intracellular dialysis with the constitutively active, truncated AMPK mutant, T172D. The molecular identity of the O(2)-sensitive leak K(+) conductance in rat type I cells remains unclear, but shares similarities with TASK-1 and TASK-3. Recombinant TASK-1 was insensitive to AICAR. However, TASK-3 was inhibited by either AICAR or A-769662 in a manner which was reversed by compound C. These data highlight a role for AMPK in the modulation of two proposed O(2) sensitive K(+) channels found in the carotid body.


Sensitivity and specificity of clinical trials. Randomized v historical controls.
The relative accuracy of randomized control trials (RCTs) and historical control trials (HCTs) in determining effective therapies has not been compared since there is no external verification of efficacy. We reviewed six therapies studied by both methods. Most HCTs concluded therapy was better than control, but few RCTs agreed. We calculated sensitivity and specificity for each type of trial by combining published results with all possible combinations of effectiveness. The sensitivity of HCTs was 0.80 to 1.00 (mean, 0.90) and specificity was 0.0 to 0.27 (mean, 0.11). The sensitivity of RCTs was 0.0 to 0.27 (mean, 0.12) and specificity was 0.67 to 1.00 (mean, 0.88). Defects of RCTs are more easily corrected than those of HCTs. Readers should consider trial design and the probability of errors when deciding how much credence to give to a clinical trial.


Effects of breeding season length and calving season on range beef cow productivity.
A 5-yr study was conducted beginning in 1983 with 460 cows to evaluate the effects of three breeding seasons (30, 45, and 70 d in length) and two times of spring calving, March (early) and April (late), on cattle production under Nebraska Sandhills range conditions. Criteria evaluated included pregnancy and weaning percentages, calving date and distribution, cow weights and body condition at four intervals, calf birth and weaning weights, and cow productivity. The 30-d breeding season included a 10-d estrus synchronization and AI period; in the other breeding seasons only natural breeding was used. The same sires were used over the entire study period. Percentage of cows pregnant and percentage of calves weaned were lower (P less than .01) for cows bred for 30 d than for cows bred for 45 or 70 d. Average calving dates were similar among the breeding groups within the early and late calving herds. Pregnancy rates from AI were higher (P less than .01) for the cows calving in April (64%) than for the cows calving in March (41%). Cows calving in April lost less weight between precalving and prebreeding and were heavier (P less than .05) at prebreeding time than the cows calving in March. Calf weaning weights were not different (P greater than .10) among any of the breeding season groups or between the two calving herds when calves were weaned at a similar age. Cow productivity (calf weaning weight per breeding female) was highest (P less than .05) for the cows bred for 70 d (186 kg), intermediate for the cows bred for 45 d (172 kg), and lowest for cows bred for 30 d (162 kg).(ABSTRACT TRUNCATED AT 250 WORDS)


Heavy metals in offal and canned food sold in the Malaysian market.
Food contaminated with heavy metals poses a serious threat to consumers. This study aims to assess levels of lead (Pb) and cadmium (Cd) in offals of chicken, cattle, and pig as well as tin (Sn) in canned food. A total of 378 offal samples was collected from wet markets, while 218 canned food samples were purchased locally. Samples were digested using a microwave before analysis with inductively coupled plasma mass spectrometry (ICP-MS). Pb was determined, highest in cattle lung (0.11 ± 0.20 mg/kg) followed by cattle spleen (0.09 ± 0.14 mg/kg), and cattle tripe (0.09 ± 0.12 mg/kg). For Cd, the highest concentrations were in cattle liver (0.13 ± 0.12 mg/kg), pig liver (0.08 ± 0.05 mg/kg), and chicken liver (0.03 ± 0.02 mg/kg). Significant variations of Sn levels existed in different canned food categories with 3.21% samples (n = 7) exceeded the maximum level of 250 mg/kg set by Codex Alimentarius. All offal samples were below the Malaysian regulatory limits, indicating their safety for human consumption. However, Sn levels varied significantly among canned food categories, with the highest levels found in canned pineapple chunks in syrup, mixed pineapple cubes in syrup, pineapple slices and longan. Samples exceeding the maximum level set by Codex Alimentarius may pose a risk to consumers.


Women with gestational diabetes mellitus want clear and practical messages from credible sources about physical activity during pregnancy: a qualitative study.
What are the attitudes of women diagnosed with gestational diabetes mellitus (GDM) towards physical activity during pregnancy? What are the perceived barriers to and enablers of physical activity during pregnancy in women with GDM? A qualitative study with phenomenology and interpretative description as theoretical frameworks. Pregnant women experiencing an uncomplicated singleton pregnancy, diagnosed with GDM, and aged 18 to 40 years were recruited using purposive sampling. Semi-structured interviews were recorded, transcribed verbatim and returned to participants for member checking. Three researchers independently and thematically analysed the qualitative data using an inductive method. Data were coded and compared, and themes were developed, discussed and defined. Recruitment continued until data saturation. Emergent themes were sent to participants and peer reviewed for confirmation. The participants were 27 women, with mean age 32 years (SD 3), mean gestation 30 weeks (SD 5), mean pre-pregnancy body mass index 26 kg/m2 (SD 5), and born in 10 different countries. The process of communicating information about physical activity (messaging) was the main theme to emerge. Sub-themes included: wanting information about physical activity from credible sources; wanting clear, specific information about safe physical activity during a GDM pregnancy; receiving information at GDM diagnosis because this event triggered women's desire to be more physically active; understanding why physical activity is important to improving outcomes for themselves and their babies; and wanting information about flexible, convenient and practical physical activity options. To feel confident and safe about being physically active during pregnancy, women with GDM wanted clear, simple and GDM-specific messages from credible sources. Health professionals can support women with a GDM pregnancy with targeted physical activity messages.


Oxytocin regulates reunion affiliation with a pairmate following social separation in marmosets.
While separation from significant social partners produces a host of neurobiological and behavioral perturbations, including behavioral distress and increased glucocorticoid production, positive social interactions upon reunion are critical for the reestablishment of normative relationship dynamics and the attenuation of the biobehavioral stress response. The hormone oxytocin has critical and pervasive roles in reproductive and behavioral processes across the lifespan, and plays a particularly prominent role in social bonding. In this study, we examined the extent that oxytocin modulates interactions with a pairmate following separation challenges that varied in both social context (isolation; separation) and duration (long; short), in marmosets. We demonstrated that the impact of pharmacological manipulations of the oxytocin system on the expression of affiliation upon reunion depended on both the context and duration of the separation challenge. Specifically, marmosets treated with an oxytocin antagonist spent less time in proximity with their pairmate upon reunion following a long-separation challenge. During the short-separation challenge, marmosets engaged in more social gaze when separated with an opposite-sex stranger, but not when separated with their mate. Furthermore, marmosets that received the most social gaze from opposite-sex strangers spent the most time in proximity with their long-term mate upon reunion. We also showed that marmosets treated with an OT agonist received increased levels of gaze from opposite-sex strangers, but not from their mate. Overall, these results suggest that marmosets are sensitive to the nature of the social interactions during separation, and subsequently alter their expression of affiliation upon reunion with their long-term mate. These findings further implicate oxytocin as a bond-enhancing molecule that regulates the reestablishment of normative levels of affiliation with a mate following separation, and add to the emerging literature that suggests the OT system underlies critical behavioral processes that contribute to the preservation of long-lasting social bonds.


The O-GlcNAc modification promotes terminal differentiation of human corneal epithelial cells.
Dynamic modification of nuclear and cytoplasmic proteins with O-linked β-N-acetylglucosamine (O-GlcNAc) plays an important role in orchestrating the transcriptional activity of eukaryotic cells. Here, we report that the O-GlcNAc modification contributes to maintaining ocular surface epithelial homeostasis by promoting mucin biosynthesis and barrier function. We found that induction of human corneal epithelial cell differentiation stimulated the global transfer of O-GlcNAc to both nuclear and cytosolic proteins. Inflammatory conditions, on the other hand, were associated with a reduction in the expression of O-GlcNAc transferase at the ocular surface epithelia. Loss- and gain-of-function studies using small interfering RNA targeting O-GlcNAc transferase, or Thiamet G, a selective inhibitor of O-GlcNAc hydrolase, respectively, revealed that the presence of O-GlcNAc was necessary to promote glycocalyx barrier function. Moreover, we found that Thiamet G triggered a correlative increase in both surface expression of MUC16 and apical epithelial cell area while reducing paracellular permeability. Collectively, these results identify intracellular protein O-glycosylation as a novel pathway responsible for promoting the terminal differentiation of human corneal epithelial cells.


Extra-cellular signal-regulated ERK-1/ERK-2 pathway activation in human salivary gland mucoepidermoid carcinoma: association to aggressive tumor behavior and tumor cell proliferation.
Information on oncogenetic events accompanying salivary gland mucoepidermoid carcinoma is so far limited. Activation of extracellular signal-regulated kinases ERK-1 and ERK-2 is strongly correlated to cancer. Using an antibody specific for phosphorylated (active) ERK-1/ERK-2, we examined human salivary gland mucoepidermoid carcinoma samples by immunohistochemistry. The comparison in paired tumor and normal tissue samples showed that phosphorylated ERK-1/ERK-2 immunoreactivity was higher in tumor cells as compared to surrounding normal salivary parenchyma. ERK-1/ERK-2 phosphorylation was observed in approximately 39% of mucoepidermoid carcinomas. Those tumors where the ERK-1/ERK-2 pathway was activated had a more aggressive tumor behavior as compared to the group where this pathway was inactive. The association of ERK-1/ERK-2 phosphorylation to a worse prognosis was independent of histological grade. ERK-1/ERK-2 phosphorylation was associated with increased Ki67 and cyclin A indexes, which indicated that ERK-1/ERK-2 pathway activation increased tumor cell proliferation. There was no relationship between ERK-1/ERK-2 phosphorylation and HER-2/neu or p16/INK4a protein expression. In conclusion, ERK-1/ERK-2 pathway is active in salivary gland mucoepidermoid carcinoma and this activation is associated to a more aggressive tumor behavior and a higher proliferative activity. These data suggest that deregulation of ERK-1/ERK-2 pathway contributes to mucoepidermoid carcinoma phenotype and, possibly, represents a target for new anticancer drugs.


Factors associated with non-utilization of postnatal care among newborns in the first 2 days after birth in Pakistan: a nationwide cross-sectional study.
Recent data indicated that approximately four in every ten newborns in Pakistan do not receive postnatal care (PNC) services in the first 48 hours after delivery. This study aimed to identify factors associated with the non-utilization of PNC for newborns in Pakistan using the 2017-18 Pakistan Demographic and Health Survey (PDHS). This was a cross-sectional analytical study utilizing data from 3887 live-born newborns recorded in the 2017-18 PDHS. Non-utilization of PNC was assessed against a set of independent factors using multilevel logistic regression analysis, and the population attributable risk estimates of factors associated with non-utilization of PNC were also calculated. There were 1443 newborns (37%) in Pakistan whose mothers did not utilize PNC check-ups in the first 2 days after delivery. The non-utilization of PNC was largely attributable to newborns delivered at non-health facilities 53% (47% to 59%) and those born to uneducated women 27% (13% to 38%). Adjusted analyses indicated that newborns with higher birth order and with a birth interval of more than 2 years, women who perceived their baby to be small at birth, women with no formal education and those living in regional areas of Khyber Pakhtunkhwa and Federally Administered Tribal Areas were significantly associated with non-utilization of PNC services. Tailored health messages by community health workers, including door-to-door visits on utilizing health facilities through pregnancy to the postnatal periods, are needed and should target places of low socioeconomic status, including educationally disadvantaged women from regional areas of Pakistan.


Effects of Serum Antibody Test Reagent Discontinuation on Diagnosis of Amebiasis in Japan: Interrupted Time-Series Analysis.
Amebiasis is a notifiable infectious disease in Japan, and the number of reported cases had been on the rise, but since the discontinuation of insurance-covered serum antibody testing reagent in 2017, concerns have arisen regarding the decrease in reported cases. This study aimed to investigate changes occurring after discontinuation of the serum antibody test reagent production. We retrospectively analyzed amebiasis cases from January 2014 to December 2019 using the National Center for Epidemiology of Infectious Diseases system. Interrupted time-series regression analysis was used to evaluate trends in weekly amebiasis cases before and after the discontinuation period. The study period was divided into prediscontinuation (2014-2017) and discontinuation (2018-2019) periods. A total of 6,179 amebiasis cases were reported. The average numbers of weekly cases were 21.5 during 2014-2017 and 16.3 during 2018-2019. The frequency of diagnoses decreased in the discontinuation period (prevalence rate ratio = 0.78; 95% CI, 0.67-0.89; P < 0.01). Subgroup analysis showed lower diagnostic rates, particularly for extraintestinal amebiasis (prevalence rate ratio = 0.37; 95% CI, 0.22-0.55; P < 0.01). We observed a significant decrease in the number of reported amebiasis cases per week after discontinuation of the serum antibody test reagent in Japan. Our findings hold significance for both public health policy and practice in Japan, underscoring the requirement for enhanced amebiasis diagnostic tools and strategies. To ensure accurate diagnosis, availability of antibody reagents for serum testing, covered by insurance, should be encouraged.


Identifying changes in the role of the infection preventionist through the 2014 practice analysis study conducted by the Certification Board of Infection Control and Epidemiology, Inc.
The Certification Board of Infection Control and Epidemiology, Inc (CBIC) is a voluntary autonomous multidisciplinary board that provides direction and administers the certification process for professionals who are responsible for the infection prevention and control program in a health care facility. The CBIC performs a practice analysis approximately every 4-5 years. The practice analysis is an integral part of the certification examination development process and serves as the backbone of the test content outline. In 2013, the CBIC determined that a practice analysis was required and contracted with Prometric to facilitate the process. The practice analysis was carried out in 2014 by a diverse group of subject matter experts from the United States and Canada. The practice analysis results showed a significant change in the number of tasks and associated knowledge required for the competent practice of infection prevention. As authorized by the CBIC, the test committee is currently reclassifying the bank of examination questions as required and is writing and reviewing questions based on the updated test specifications and content outline. The new content outline will be reflected in examinations that are taken beginning in July 2015. This iterative process of assessing and updating the certification examination ensures not only a valid competency tool but a true reflection of current practices.


Evaluating rms spot radii by ray tracing.
The computation of rms spot radii from ray trace calculations is investigated in relation to the number of rays to be traced to achieve a prescribed accuracy. It is shown that the usual simple averaging formulas will only have as limits for infinitely many rays the correct center of mass and gyration radius if a square ray grid point distribution is used throughout the limiting process. For other ray distributions the ray trace data are given weight according to the local grid point density. Using the simple averaging formulas deviations in computed image radii of 15-20% may be encountered due solely to variations in grid point distributions. A computing method is suggested using a fourth-order quadrature formula giving 1% accuracy with ~20 rays and 0.01% accuracy with ~40-50 rays.


Channels with Helical Modulation Display Stereospecific Sensitivity for Chiral Superstructures.
By means of coarse-grained molecular dynamics simulations, we explore chiral sensitivity of confining spaces modelled as helical channels to chiral superstructures represented by polymer knots. The simulations show that helical channels exhibit stereosensitivity to chiral knots localized on linear chains by effect of external pulling force and also to knots embedded on circular chains. The magnitude of the stereoselective effect is stronger for torus knots, the effect is weaker in the case of twist knots, and amphichiral knots do exhibit no chiral effects. The magnitude of the effect can be tuned by the so-far investigated radius of the helix, the pitch of the helix and the strength of the pulling force. The model is aimed to simulate and address a range of practical situations that may occur in experimental settings such as designing of nanotechnological devices for the detection of topological state of molecules, preparation of new gels with tailor made stereoselective properties, or diffusion of knotted DNA in biological conditions.


Automated Detection of Sepsis Using Electronic Medical Record Data: A Systematic Review.
Severe sepsis and septic shock are global issues with high mortality rates. Early recognition and intervention are essential to optimize patient outcomes. Automated detection using electronic medical record (EMR) data can assist this process. This review describes automated sepsis detection using EMR data. PubMed retrieved publications between January 1, 2005 and January 31, 2015. Thirteen studies met study criteria: described an automated detection approach with the potential to detect sepsis or sepsis-related deterioration in real or near-real time; focused on emergency department and hospitalized neonatal, pediatric, or adult patients; and provided performance measures or results indicating the impact of automated sepsis detection. Detection algorithms incorporated systemic inflammatory response and organ dysfunction criteria. Systems in nine studies generated study or care team alerts. Care team alerts did not consistently lead to earlier interventions. Earlier interventions did not consistently translate to improved patient outcomes. Performance measures were inconsistent. Automated sepsis detection is potentially a means to enable early sepsis-related therapy but current performance variability highlights the need for further research.


Schisandra chinensis and its phytotherapeutical applications.
Schisandra (Schisandra chinensis) has been used for centuries as a plant of traditional Chinese medicine. Its biological activity and pharmacological use are associated with dibenzocyclooctadiene lignans, while specific polysaccharides may also be involved. The lignans of schisandra are genus-specific. Their activity has been investigated in hundreds of studies that have confirmed adaptogenic effects, central nervous system stimulation, hepatoprotective effects and potential anticancer potential. This summary review of the literature synthesizes the current state-of-the-art in research on bioactivities of schisandra constituents, description of folk use of extracts, overview of clinical studies and additional information on in vitro tests bringing insight into mechanisms of action.


Effect of milk deprivation during the lactation period on performance and digestive enzyme activities of the piglets following weaning.
Post-weaning performance of piglets from systems where lactation is disrupted (e.g. from multisuckling systems) is superior to conventionally reared piglets. The objective of this study was to establish whether restricted growth prior to weaning caused by disruption of suckling was an important factor in post-weaning performance and also whether there were related changes in gastro-intestinal development. Ten litters of eight piglets were used in a split-plot design. Half of each litter (limited suckling, LS) had suckling disrupted by separation from their dam for 7 h/day from day 14 to 28 after farrowing. The remainder of each litter was allowed to suck normally (normal suckling, NS). The same amount of creep feed was offered to LS piglets as consumed by NS littermates on the previous day. There were no differences in weight between LS and NS piglets at 14 days of age, but restricting access to the sow reduced weaning weight at 28 days of age (7.96 v. 9.00 kg; LS v. NS; P < 0.01; s.e.d. 0.23). Feed intakes were greater for LS than NS piglets over the first 28 days post weaning, particularly in the 1st week after weaning when feed efficiency was also improved (0.91 v. 0.62 kg gain per kg feed; P < 0.01; s.e.d. 0.08). As a result, LS piglets grew more rapidly in the first 28 days post weaning, particularly in the first 7 days after weaning. Subsequent performance to 8 weeks was similar for both groups. Digestive organ weights were not different at 2 and 9 days after weaning; nor were small intestine specific enzyme activities significantly different ( P>0.05). Pancreatic trypsin activity was, however, greater ( P < 0.01) for LS pigs on both days 2 and 9 post weaning. In conclusion the restriction of growth as a result of limited suckling itself is an important factor in determining post-weaning performance and may be related to development of pancreatic trypsin activity.


[Motives for choice of specialty during and after medical school].
The basis for preference and choice of specialty is a complicated mixture of individual interests and job opportunities. We wanted to investigate the possible explanations for such preferences and choices. Two groups of Norwegian doctors, 421 who entered medical school in 1993 and 631 who completed medical school in 1993 and 1994, received four questionnaires between 1993 and 2003 which included questions on preference or choice of specialty and possible motives for this. Individual preferences change extensively over time, but there is also a remarkably stabile distribution between the specialist categories. A specialty's prestige was emphasized less after medical school and the importance of having an optimal combination of an interesting job and a good private life increased This was also the case after controlling for the female respondents. Those who chose surgery or internal medicine were more motivated by medical challenges and career possibilities, while those who chose psychiatry or general medicine were more motivated by conditions such as variety and time for own family. The motives behind choice of specialty are complicated and difficult to interpret, but seem to be a combination of ambitions and prestige on one hand, and lifestyle and family on the other. Recruitment into low status specialties may be achieved by increasing the possibilities for doctors to lead more normal family and social lives.


Mycosporine glycine protects biological systems against photodynamic damage by quenching singlet oxygen with a high efficiency.
This report concerns physiological function of mycosporine-like amino acids (MAA) as an active defense against the photooxidative effects of sunlight in marine organisms. Mycosporine glycine (MG) is a representative member of MAA family and was found to effectively suppress various detrimental effects of the Type-II photosensitization in biological systems, such as inactivation of mitochondrial electron transport, lipid peroxidation of microsomes, hemolysis of erythrocytes and growth inhibition of Escherichia coli. The presence of MG in solutions of eosin Y or methylene blue resulted in a marked decrease in the level of singlet oxygen (1O2) produced by the sensitizers under illumination. The rate constant of 1O2 quenching by MG was determined to be 5.6 x 10(7) M(-1) s(-1) by the time-resolved 1O2 luminescence decay method, which is higher than, or at least comparable to, the values for 1O2 reaction of well-known quenchers such as 1,4-diazabicyclo[2,2,2]octane and furfuryl alcohol. The results suggest that MG probably together with some other active MAA may play an important role in protecting marine organisms against sunlight damage by eliminating 1O2 generated from certain endogenous photosensitizers.


Genetics of ulcerative colitis: putting into perspective the incremental gains from Indian studies.
Ulcerative colitis (UC), one of the two clinical subtypes of inflammatory bowel disease is perceived as a potential 'sleeping giant' in the Indian subcontinent. Clinical manifestation is overall believed to be the same across ethnic groups but overwhelming genetics from large European and fewer non-European studies have revealed shared as well as unique disease susceptibly signaturesbetween them, pointing to population specific differences at genomic and environmental levels. A systematic recount of the four major eras in UC genetics spanning earliest linkage analysis, cherry picked candidate gene association studies, unbiased genomewide association studies, their logical extension in trans-ethnic setting (Immunochip study), lastly whole exome sequencing efforts forrare variant burden; and lessons learnt thereof in context of genetically distinct Indian population was attempted in this review. Genetic heterogeneity manifesting at allelic/locus level across these approaches has been the consistent finding through the range of pan India studies. On the other hand, these salient findings also highlight the limitations of even the best of these genetic leadsfor prognostic/clinical application. The imminent need, therefore, for the UC research community to adopt newer approaches/tools with improved study design to (i) gain better insight into genetic/mechanistic basis of disease; (ii) identify biomarkers of immediate translational value; and (iii) develop new/alternate therapeutic options is emphasized at the end.


Life expectancy and mortality in 363 cities of Latin America.
The concept of a so-called urban advantage in health ignores the possibility of heterogeneity in health outcomes across cities. Using a harmonized dataset from the SALURBAL project, we describe variability and predictors of life expectancy and proportionate mortality in 363 cities across nine Latin American countries. Life expectancy differed substantially across cities within the same country. Cause-specific mortality also varied across cities, with some causes of death (unintentional and violent injuries and deaths) showing large variation within countries, whereas other causes of death (communicable, maternal, neonatal and nutritional, cancer, cardiovascular disease and other noncommunicable diseases) varied substantially between countries. In multivariable mixed models, higher levels of education, water access and sanitation and less overcrowding were associated with longer life expectancy, a relatively lower proportion of communicable, maternal, neonatal and nutritional deaths and a higher proportion of deaths from cancer, cardiovascular disease and other noncommunicable diseases. These results highlight considerable heterogeneity in life expectancy and causes of death across cities of Latin America, revealing modifiable factors that could be amenable to urban policies aimed toward improving urban health in Latin America and more generally in other urban environments.


Can the Mayo Adhesive Probability Score Predict Perioperative Outcomes in Laparoscopic Total and Partial Adrenalectomy?
This study aimed to determine whether the Mayo adhesive probability (MAP) score could predict perioperative outcomes in transperitoneal laparoscopic total adrenalectomy (LTA) and laparoscopic partial adrenalectomy (LPA). The clinical data of 139 patients who underwent transperitoneal LTA (n=116) or LPA (n=23) between March 2013 and September 2022 were retrospectively analyzed. According to the images obtained from preoperative contrast-enhanced computed tomography or magnetic resonance imaging, the patients were divided into two groups: the low MAP score group (0-1 points) and the high MAP score group (2-5 points). General clinical features and perioperative outcomes were compared between the groups. In patients with a high MAP score, the mean body mass index (BMI) (p: 0.005), tumor size (p: 0.005), operative time (p: 0.002), estimated blood loss (EBL) (p: 0.001), and complication rate (p: 0.013) were significantly higher compared to those with a low MAP score. The comparison of the patients between the LTA and LPA subgroups revealed that operative time and EBL were significantly higher in both subgroups among the patients with a high MAP score. Moreover, the complication rate in the LTA subgroup was significantly higher in the high MAP score group compared to the other group. The Multivariate analyses revealed that a high MAP score was a risk factor for prolonged operative time (Odds Ratio [OR]: 3.081, 95% Confidence Interval [CI]: 1.284-7.398, p: 0.012), increased EBL (OR: 2.495, 95% CI: 1.114-5.588, p: 0.026) and complications (OR: 6.085, 95% CI: 1.532-24.171, p: 0.01) Conclusion: Patients with a high MAP score had a prolonged operative time, increased EBL, and a higher complication rate compared to those with a low MAP score. In addition, we found that a high MAP score was an independent risk factor for perioperative parameters and complications in patients who underwent LTA and LPA.


[Chromosomal differences in moose (Mammalia, Artiodactyla, Alces alces L.)].
Earlier studies on differences in moose (Alces alces) chromosome sets concerned only European (Scandinavia, Finland, the Volga region, and western Siberia) and American (the United States and Canada) forms. The first group had a 68-chromosome set, and the second group, a 70-chromosome set. These differences were considered interspecies chromosomal polymorphism. However, the chromosome number in A. alces living in eastern and northeastern Siberia remains unknown, although these data are important for elucidation of the geographical variation of karyotypes of moose from genus Alces. Four moose from different regions of Sakha were studied. It was found that their karyotypes contained 70 chromosomes; i.e., they were similar to the American form. These data indicate a strong differentiation within the species. Two chromosomal forms can be distinguished: the European one (2n = 68) living in Europe and western Siberia and the American one (2n = 70) living in North America, the Far East, and eastern Siberia. The existence of two forms is confirmed by data on their morphology, sound signals, electrophoretic mobility of proteins, and differences in nutrition. These results indicate that long-term isolation of European and American moose led to the high divergence between these two forms; therefore, they can be considered different species.


Optimizing a ultrahigh pressure liquid chromatography-time of flight-mass spectrometry approach using a novel sub-2μm core-shell particle for in depth lipidomic profiling of Caenorhabditis elegans.
Lipid profiling or lipidomics is currently applied in many different research fields. It refers to the global analysis of a samples lipid content using different analytical chemistry methods, with mass spectrometry as the mostly employed technology. We developed a comprehensive in-depth analysis method for the lipidome of the soil-dwelling nematode Caenorhabitis elegans, a widely used model organism. Four different columns were compared with a generic gradient and a novel sub-2-μm core-shell column, Waters Cortecs C18, showed superior performance in case of chromatographic peak characteristics, e.g. plate numbers and number of detected lipid features. Retention time deviation was generally less than 1% within one column and below 5% for columns from different batches. Intensity variation was lower than 30% for most detected features. Improved chromatographic separation showed enhanced resolution for isomeric lipids and allowed collection of highly detailed MS/MS spectra for lipid identification. In total 1304 lipid features were detected in positive ionization mode and 265 in negative mode. Lipids from different classes were annotated and MS/MS spectra obtained by data dependent fragmentation were used for identification purposes.


Supramolecular hydrogels for wound repair and hemostasis.
The unique network characteristics and stimuli responsiveness of supramolecular hydrogels have rendered them highly advantageous in the field of wound dressings, showcasing unprecedented potential. However, there are few reports on a comprehensive review of supramolecular hydrogel dressings for wound repair and hemostasis. This review first introduces the major cross-linking methods for supramolecular hydrogels, which includes hydrogen bonding, electrostatic interactions, hydrophobic interactions, host-guest interactions, metal ligand coordination and some other interactions. Then, we review the advanced materials reported in recent years and then summarize the basic principles of each cross-linking method. Next, we classify the network structures of supramolecular hydrogels before outlining their forming process and propose their potential future directions. Furthermore, we also discuss the raw materials, structural design principles, and material characteristics used to achieve the advanced functions of supramolecular hydrogels, such as antibacterial function, tissue adhesion, substance delivery, anti-inflammatory and antioxidant functions, cell behavior regulation, angiogenesis promotion, hemostasis and other innovative functions in recent years. Finally, the existing problems as well as future development directions of the cross-linking strategy, network design, and functions in wound repair and hemostasis of supramolecular hydrogels are discussed. This review is proposed to stimulate further exploration of supramolecular hydrogels on wound repair and hemostasis by researchers in the future.


Study protocol: a systematic review of pediatric shared decision making.
Shared decision making in pediatrics is unique because it often involves active participation of both the child or adolescent patient and his or her caregiver(s) in the decision making process with the clinician or care team, and the extent to which the patient is involved is commensurate with their developmental level. However, little is known about the nature of pediatric-specific shared decision making interventions and their impact. We will perform a systematic review with the objective of summarizing the nature of shared decision making practices, tools, techniques and technologies in the pediatric setting as well as their effects. A literature search will include Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Library, Web of Science, Scopus and Ovid PsycInfo databases in addition to consultation of a group of shared decision making experts to identify unpublished or in-progress works. We will include original research studies involving patients <18 years, their caregivers, or both, and summarize methods and approaches designed to engage participants in the health care decision making process with clinicians. Perinatal and research participation decisions will be excluded. Descriptions of participants involved, interventions used and the measured outcomes will be reported. Quality assessment will be performed according to the design of each study, where possible. We anticipate that the paucity of published quantitative data and the heterogeneous nature of the reported results will preclude quantitative analysis. In this event, a meta-narrative approach will be undertaken. PROSPERO registration number: CRD42013004761.


Novice Meditators of an Easily Learnable Audible Mantram Sound Self-Induce an Increase in Vagal Tone During Short-term Practice: A Preliminary Study.
The autonomic nervous system (ANS) plays a vital role in regulation of the physiological processes during normal and pathological conditions. Heart rate variability (HRV) is regarded as a major indicator of the self-regulatory strength and balance of parasympathetic nervous system (PNS) and sympathetic nerve system (SNS) impulses, as interpreted by the intrinsic nervous system of the heart. The present study focuses on the evaluation of the effects of audible and mindful practice of chanting meditation on HRV and on the cognitive disposition. The subjects were randomly assigned to 2 different sounds based on monotone repetition. One was the Hare Krishna Mantram (HKM-Sanskrit experimental sound) and the other was a concocted sound (Sanskrit placebo). Changes in vagal tone were measured with respect to both time domain and frequency domains. Five-min baseline and postmeditation measurements were obtained on different days over the next 6 wk. The subjects who chanted the placebo/sham sound switched to the experimental sound at the 4-wk mark for the next 2 wk. All subjects completed an experience survey. Paired t test results for all HRV parameters achieved statistical significance in the test group. Statistical significance in all the aforementioned measures of HRV was also observed on switching the control group placebo sound chanting to the experimental sound. HRV wave forms showed relaxation, a pattern and experience survey suggests an increase in attributes associated with higher self-regulation. This study suggests statistically significant efficacy data and that a larger randomized study is feasible to test the potential of the audible repetition of the HKM in clinical settings. It may therefore enable beneficial lifestyle for health creation and thus play a role in the prevention of chronic diseases. Further, large scale studies are required for a better perspective on the effect of mantram repetition on the HRV.


Prevalence of HIV infection and HIV-related sex risk behaviors in men who have sex with men in Shandong Province, China.
Recently, men who have sex with men (MSM) have become a population at high risk ofHIV infection in China, and more investigations of and intervention programs targeting this hidden population are urgently needed. The objective of this study was to assess the prevalence of HIV-positive individuals, HIV-related knowledge, and sex risk behaviors in MSM in large and middle-sized cities. Subjects were 1,617 interviewees who were selected by snowball sampling in 8 cities of Shandong Province and who were interviewed using a structured questionnaire. Their serological specimens were tested in a laboratory to confirm infection with HIV. Results indicated a prevalence of HIV infection of 1.3%, which is low when compared to that in metropolitan areas worldwide, although the prevalence of unsafe sexual behaviors was relevantly high and there was a lack of accessibility to HIV/STD testing and peer education. This study revealed the urgent need to make intervention programs universal, effective, and much more accessible to MSM in typical large and middle-sized cities in China.


Incidence and Predictors of Adverse Drug Events Among People Receiving Drug Resistant Tuberculosis Treatment in Uganda: 8-Year Retrospective Cohort Study.
Adverse drug events (ADEs) are regarded as the most essential therapeutic issue during management of drug-resistant tuberculosis (DR-TB) due to the long duration of therapy and concurrent use of many second-line medications. This study aimed to determine the incidence and factors associated with ADEs among patients receiving DR-TB treatment at Mulago hospital in Uganda. A retrospective cohort study was conducted among 417 DR-TB patient records at Mulago National Referral Hospital from January 2013 to December 2020. Using the data abstraction form, data were collected on socio-demographic and clinical factors, adverse drug events and treatment follow-up time. Data were double entered in Epi data version 3.2 and later exported to Stata version 14.0 for analysis. The incidence rate of adverse drug events was computed using number of cases of ADE divided by overall patient follow-up time. Poisson regression model was used to determine the factors associated with ADEs. The predictors were considered significant at if p< 0.05. The overall incidence was 5.56 ADEs per 100 person months (95% confidence interval (CI) 5.01, 6.15). Treatment regimens containing an aminoglycoside (incident rate ratio (IRR) 1.106, 95% CI 1.005-1.216 p=0.0391), linezolid (IRR 1.145, 95% CI 1.008-1.229 p = 0.037) or pyrazinamide (IRR 1.226, 95% CI 1.072-1.401 p = 0.003) and the treatment duration (in months) (IRR 1.005, 95% CI 1.001-1.010 p = 0.042) were associated with ADEs. Regimens containing aminoglycosides, linezolid, or pyrazinamide and increase in treatment duration (months) were associated with an increased risk of ADEs. Clinicians should quickly adopt all oral shorter treatment regimens to obviate the need for aminoglycosides and reduce exposure duration.


Neuroimmune cardiovascular interfaces control atherosclerosis.
Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.


The Ser(326)Cys polymorphism of 8-oxoguanine glycosylase 1 (OGG1) is associated with type 2 diabetes in Mexican Americans.
Human 8-oxoguanine glycosylase 1 (OGG1) excises oxidatively damaged promutagenic base 8-oxoguanine, a lesion previously observed in a rat model of type 2 diabetes (T2DM). The objective of the present study is to determine whether genetic variation in OGG1 is associated with type 2 diabetes (T2DM) in a Mexican American cohort. Ten SNPs including two tagging SNPs (rs1052133, rs2072668) across the OGG1 gene region were selected from the Hapmap database and genotyped in the entire cohort (n = 670; 29% diabetes; 39 families) by TaqMan assay. Association analyses between the SNPs and T2DM were performed using the measured genotype approach as implemented in the program SOLAR. Of the ten SNPs genotyped, only five were polymorphic. The minor allele frequencies of these 5 SNPs ranged from 1-38%. Of the SNPs examined for association, the Ser(326)Cys (rs1052133) exhibited significant association with T2DM (p = 0.016) after accounting for age and sex effects. Another intronic variant (rs2072668), which was in strong linkage disequilibrium (r(2) = 0.96) with Ser(326)Cys also exhibited significant association with T2DM (p = 0.031). These results suggest for the first time that the variants in OGG1 could influence diabetes risk in these Mexican American families and support a role for alterations of OGG1 in the pathogenesis of T2DM.


Appraising Otolaryngology-Head and Neck Surgery Clinical Practice Guidelines for Effective Dissemination and Implementation Design.
Dissemination and implementation (D&I) science analyzes interventional strategies that aid in spreading scientific knowledge, adopting evidence into practice, and identifying barriers to maximize successful integration of science into practice. This study set out to critically appraise the published D&I strategies of the American Academy of Otolaryngology-Head and Neck Surgery Foundation (AAO-HNSF) Clinical Practice Guidelines (CPGs) and to introduce the theories of D&I science. The 15 AAO-HNSF CPGs underwent appraisal by 2 independent reviewers using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) instrument. CPGs were rated over 23 key items in 6 domains. Each item was rated on a 7-point scale from 1 (strongly disagree) to 7 (strongly agree). CPGs were rated and quality assessments were performed. Intrarater reliability was assessed. The overall mean score of the CPGs was 85.2% (95% confidence interval, 83.4%-86.9%). Individual CPG mean scores ranged from 80.4% to 90.9%. Mean interrater reliability was strong. All domains of the AGREE II instrument, except the Applicability domain, scored a mean of 90.7% or better. D&I strategies within the CPGs, as calculated by the Applicability domain score, ranged from 22.9% to 77.1%. There is a paucity of published D&I strategies within the AAO-HNSF CPGs. Nesting a D&I framework, such as the Quality Improvement Framework, within CPGs would allow for identification of barriers to CPG adoption and evaluation of CPG-directed interventions. A D&I framework within the AAO-HNSF CPGs would allow for objective measurement of the overall impact of CPGs on otolaryngology practices.


Long-term synaptic potentiation in the superior cervical ganglion.
Brief tetanic stimulation of the preganglionic nerves to the superior cervical ganglion enhances the postganglionic response to single preganglionic stimuli for 1 to 3 hours. This long-term potentiation of transmission through the ganglion is apparently not attributable to a persistent muscarinic action of the preganglionic neurotransmitter, acetylcholine, since neither the magnitude nor the time course of the phenomenon is reduced by atropine. The decay of long-term potentiation can be described by a first-order kinetic process with a mean time constant of 80 minutes. We conclude that long-term potentiation, once considered a unique property of the hippocampus, is in fact a more general feature of synaptic function. This form of synaptic memory may significantly influence information processing and control in other regions of the nervous system, including autonomic ganglia.


Hyper/hypoglycemia and acute kidney injury in critically ill patients.
Abnormalities of blood glucose (BG) concentration (hyper- and hypoglycemia), now referred to with the cumulative term of dysglycemia, are frequently observed in critically ill patients, and significantly affect their clinical outcome. Acute kidney injury (AKI) may further complicate glycemic control in the same clinical setting. This narrative review was aimed at describing the pathogenesis of hyper- and hypoglycemia in the intensive care unit (ICU), with special regard to patients with AKI. Moreover, the complex relationship between AKI, glycemic control, hypoglycemic risk, and outcomes was analyzed. An extensive literature search was performed, in order to identify the relevant studies describing the epidemiology, pathogenesis, treatment and outcome of hypo- and hyperglycemia in critically ill patients with AKI. Patients with AKI are at increased risk of both hyper-and hypoglycemia. The available evidence does not support a protective effect on the kidney by glycemic control protocols employing Intensive Insulin Treatment (IIT), i.e. those aimed at maintaining normal BG concentrations (80-110 mg/dl). Recent guidelines taking into account the high risk for hypoglycemia associated with IIT protocols in critically ill patients, now suggest higher BG concentration targets (<180 mg/dl or 140-180 mg/dl) than those previously recommended (80-110 mg/dl). Notwithstanding the limited evidence available, it seems reasonable to extend these indications also to ICU patients with AKI.


Hypertension and decreased renal blood flow following methylene blue injection.
Renal blood flow (RBF) and arterial blood pressure (BP) were monitored in 12 patients undergoing nephrolithotomy in the lateral flexed position. All patients were preoxygenated and were anesthetized with sodium thiopental, N2O, O2, and fentanyl. Maintenance relaxation was obtained with pancuronium bromide. Arterial pressure was monitored by percutaneous arterial catheter. Following exposure of the kidney and renal pedicle, an electromagnetic flow probe was attached to the renal artery and baseline flows recorded. Following baseline measurements, 20 ml of 1 percent methylene blue was given intravenously. All patients studied showed an immediate rise in BP, and 11/12 showed a simultaneous decrease in RBF. The average fall in RBF was 35 percent at one minute. Both parameters returned to normal values on the average in 177 seconds. The decreased RBF appeared to be part of a generalized vasoconstrition caused either by sympathetic reflexes or by the direct action of methylene blue.


Nucleotide sequence of KB cell 5S RNA.
The nucleotide sequence of 5S RNA derived from KB carcinoma cell ribosomes has been determined. The molecule has a length of either 120 or 121 nucleotides with uridine at its 3'-terminus and guanylic acid at its 5'-terminus. If, in addition to Watson-Crick base-pairing, one accepts occasional base-pairing of guanylic acid to uridylic acid, long sequences of complementary nucleotides can be identified within the molecule. Two regions of the molecule contain sequences complementary to four or five bases in the pentanucleotide sequence guanylic acid, ribothymidylic acid, pseudouridylic acid, cytidylic acid, guanylic acid, which is common to most transfer RNA molecules. This is the first time the sequence of an animal-cell RNA has been determined.


Health care providers' advice to quit smoking, National Health Interview Survey, 2000, 2005, and 2010.
Although the prevalence of cigarette smoking has declined in the United States, little documentation exists to ascertain which health care providers (HCPs) promote smoking cessation. We used data from the 2000, 2005, and 2010 Cancer Control Supplement of the National Health Interview Survey to examine changes in the number of adults who received smoking cessation advice from their HCP. The percentage of smokers who received cessation advice was 53.3% in 2000, 58.9% in 2005, and 50.7% in 2010. To affect noticeably declining rates, HCPs should increase their efforts to advise smokers to quit.


Pharmacological treatment of childhood obsessive-compulsive disorder: from theory to practice.
Discusses pharmacological treatment of childhood obsessive-compulsive disorder (OCD), chronic and underrecognized psychiatric condition that affects up to 2% to 3% of children and adolescents. Research in OCD in children, including neuropharmacology, brain imaging, genetics, and clinical phenomenology, informs current views of OCD pathophysiology. Contemporary research supports the notion of a dysregulation in serotonin subsystems in the central nervous system, with target areas of dysfunction including basal ganglia and orbitofrontal cortex. Pharmacotherapy, along with cognitive-behavioral approaches, constitutes the indicated treatment for childhood OCD. Pharmacological treatment is best guided by a phenomenological understanding of the type of obsessions and compulsions, the intensity and frequency of their presentation with attention to behavioral reinforcements, and psychosocial factors that affect the course of the disease. Serotonin-enhancing agents, such as fluoxetine, fluvoxamine, paroxetine, and sertraline and citalopram (SSRIs) are first-line pharmacological agents, whereas refractory symptoms can be treated by augmentation with neuroleptics or other agents. Clomipramine is as effective as the SSRIs but its use may be accompanied by increased side effects. Genetic factors probably influence susceptibility to OCD as well as response to treatment, and the elucidation of these and other risk factors will be important elements in the future understanding and treatment of this disorder.


Role of Azolla in controlling mosquito breeding in Ghaziabad district villages (U.P.).
A survey was carried out during post-monsoon period (1988-89) in villages of Dhaulana Primary Health Centre, Distt. Ghaziabad (U.P.) to evaluate the utility of Azolla pinnata for the control of mosquito breeding in different habitats. Results of the survey revealed that pools, ponds, wells, rice fields and drains were infested with Azolla. Infestation rate and intensity of infestation varied from habitat to habitat. Maximum infestation (36.5%) was observed in pools and minimum (3.7%) in rice fields. Anopheline breeding was almost completely suppressed (0-1.6/dip) in pools, wells and ponds completely covered with Azolla. The breeding of Culex spp. was not completely inhibited in any habitat, though reduction in immature density was observed in comparison to control. The role of Azolla in controlling mosquito breeding and its association with the blue green algae which fixes nitrogen is discussed.


Effect of glutathione depletion on metallothionein synthesis induced by paraquat in mice.
The effect of Glutathione (GSH) depletion on the induction of metallothionein (MT) synthesis by paraquat (PQ) was examined in ICR mice. An increase in hepatic MT level in mice was observed after a single PQ administration. Pretreatment of mice with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, enhanced the induction of hepatic and renal MT synthesis by PQ depending on the decreased tissue GSH level. A similar result was obtained by pretreatment with diethylmaleate, a GSH depleting agent. The ratio of hepatic MT-I to MT-II induced by PQ was not changed by BSO pretreatment. An increase in the hepatic MT level in GSH depleted mice was observed from 3 hr to 24 hr after PQ administration. An increase in the hepatic MT-I mRNA level after treatment with PQ was observed prior to hepatic MT induction in BSO pretreated mice. Pretreatment with actinomycin D, an inhibitor of mRNA synthesis, inhibits the PQ-induced increase in hepatic MT and MT-I mRNA levels in BSO pretreated mice. Pretreatment with BSO did not affect the induction of MT synthesis by zinc, cadmium or dexamethasone. Pretreatment with dexamethasone, an anti-inflammatory agent, enhanced the hepatic MT induction by PQ treatment in GSH depleted mice, while dexamethasone reduced the MT induction by turpentine oil, which is known to induce inflammation and hepatic MT synthesis. These findings suggest that GSH depletion enhances the induction of MT synthesis by PQ because of an increase in the transcription rate, and this enhancement of MT synthesis is not due to an inflammatory response caused by PQ.


Radiological and pathological findings of interval cancers in a multi-centre, randomized, controlled trial of mammographic screening in women from age 40-41 years.
The aim of this study was to analyse the radiographic findings of the screening mammograms of women with interval cancer who participated in a multi-centre, randomized, controlled trial of mammographic screening in women from age 40-48 years. The screening and diagnostic mammograms of 208 women with interval cancers were reviewed. Abnormalities were classified as malignant, subtle and non-specific. Eighty-seven (42%) of women had true, 66 (32%) occult and 55 (26%) false-negative interval cancers. The features most frequently missed or misinterpreted were granular microcalcification (38%), asymmetric density (27%) and distortion (22%). Thirty-seven percent of abnormal previous screens were classified as malignant, 39% subtle change and 21% as non-specific. Granular calcifications were significantly more common on the diagnostic mammograms of false-negative interval cancers than those of true interval cancers (28 versus 14%, p=0.04). Occult interval cancers were more likely to be <10 mm and <15 mm in invasive pathological size than other interval cancers (p=0.03 and 0.005, respectively). True interval cancers were more likely to be histologically grade 3 than other interval cancers (p=0.04). Women who developed true and false-negative interval cancers had similar background patterns, but women with occult cancers had a higher proportion of dense patterns (p<0.05). Interval cancers in a young screening population have a high proportion of occult lesions that are small and occur in dense background patterns. The proportion of interval cancers that are false negative is similar that seen in older populations and granular microcalcification is the commonest missed mammographic feature.


The value of pharmaceutical representative visits and medication samples in community-based family practices.
Interactions between the pharmaceutical industry and physicians have been discussed in numerous publications; however, most articles are limited to surveys and self-report data and often focus on academic or training contexts. We describe the role of pharmaceutical representatives and the use of samples in community-based family practices, using data obtained by directly observing clinical encounters. We collected detailed descriptive field notes of the direct observations of 53 primary care clinicians and 1588 patient encounters in 18 purposefully selected Nebraska family practices. We used a comparative case study design, that used depth interviews of clinicians and office staff, and included details of the interactions with pharmaceutical representatives and the use of samples in clinical encounters. Individual providers and practices displayed noticeable variation in their approaches to drug representatives and samples. We found formal strategies and policies in a minority of practices. Generally there was little structure in the organization and distribution of sample medications at the office level, and detailed patient education regarding these drugs was rarely observed in patient encounters. Nevertheless, samples were used in almost 20% of observed encounters, at times as starter dosages, but often as complete courses of treatment. The benefits derived from contact with the pharmaceutical industry varied substantially, but most often included free medication samples, meals, and patient education materials. Clinicians have a complex symbiosis with the pharmaceutical industry and need to critically evaluate their handling of samples and their contact with pharmaceutical representatives to optimize this relationship and ensure quality patient care. Clinics with specific policies for interactions with drug companies appear to derive more satisfaction from their encounters.


Breathlessness Beliefs and Related Factors in Male Patients with Chronic Obstructive Pulmonary Disease.
Dyspnea may be a debilitating factor for people with pulmonary problems as it may cause fear of movement. The aim of the present study was to determine the related factors with breathlessness beliefs, in other words, dyspnea-related fear of movement, in patients with chronic obstructive pulmonary disease. Male patients with chronic obstructive pulmonary disease were included in the study. Breathlessness beliefs (Breathlessness Belief Questionnaire), perceived dyspnea severity (modified Medical Research Council Dyspnea Scale and modified Borg Scale), pulmonary function tests (forced vital capacity, forced expiration volume in 1 second, and peak expiratory flow), emotional status (Hospital Anxiety and Depression Scale), fatigue (Fatigue Impact Scale and Fatigue Severity Scale), physical activity level (International Physical Activity Questionnaire-Short Form), disease-related quality of life (St. George Respiratory Questionnaire), and generic quality of life (Short-Form 36) were evaluated. A total of 70 patients were included. Significant correlations were detected between breathlessness beliefs and perceived dyspnea severity, pulmonary function tests, emotional status, fatigue, physical activity level, disease-related quality of life, and generic quality of life (P < .001). No correlations were detected between physical characteristics and dyspnea-related fear of movement (P > .05). Dyspnea-related fear of movement was found to be strongly related to perceived dyspnea severity, pulmonary function tests, emotional status, fatigue, physical activity level, and quality of life; thus, including breathlessness beliefs assessment into clinical examination may help clinicians to understand their patients' needs comprehensively.


Edoxaban, a Novel Oral Factor Xa Inhibitor.
To evaluate the current literature and potential clinical role of edoxaban (Savaysa) for stroke prevention in nonvalvular atrial fibrillation (NVAF) and treatment of deep-vein thrombosis and pulmonary embolism. A PubMed and Cochrane Central Register of Controlled trials search was conducted in February 2015 using the search terms edoxaban (ordu-176b) and atrial fibrillation, deep vein thrombosis, pulmonary embolism, or venous thromboembolism. Bibliographies of all retrieved articles were reviewed. All references included were published between 1998 and 2015. All studies that included humans and contained data describing the use of edoxaban for either stroke prevention in patients with NVAF or the treatment of venous thromboembolism (VTE) were reviewed. Edoxaban is a target-specific oral anticoagulant, specifically a factor Xa inhibitor. It has been studied in 4 major randomized controlled trials for the prevention of stroke and systemic embolism in patients with NVAF. One randomized controlled trial was conducted for the treatment of VTE. Edoxaban demonstrated noninferiority of the primary efficacy end point compared with warfarin for both approved indications. The most common adverse effect is bleeding, similar to other anticoagulants. A dosing limitation exists related to patients treated for NVAF with creatinine clearance >95 mL/min; these patients experienced decreased efficacy. Edoxaban is a safe and effective anticoagulant to reduce the risk of stroke in patients with NVAF and for the treatment of VTE.


[Prevalence and risk factors in diffuse idiopathic skeletal hyperostosis in a population sample in Hungary].
The aim of the study was to get some information on the epidemiology and etiology of DISH which is a frequent, chronic, benign musculoskeletal disease. In order to investigate the epidemiology of DISH the authors planned a population-based cross-sectional study and to investigate the etiology of the disease they planned a case-control study. The prevalence of DISH in Hungary in men over the age of 50 years is 5.8% and in women is 1.3%. In men DISH begins earlier in the lifetime and over the age of 65 years the prevalence increases rapidly in both sexes. In men throughout the life the disease is more common and more severe than in women. In the case-control study the authors investigated the association of the disease with risk factors as obesity, hyperuricemia, hypercholesterinemia, hypertriglyceridemia. Hyperuricemia was significantly more frequently found in DISH than in the control group. In the name of DISH the word "idiopathic" is questionable because apart from the known glucose metabolic imbalance other metabolic abnormalities (uric acid) could be found. There might be a complex metabolic disturbance in the etiology of DISH.


Cognitive function in DMD carriers: personal case series and literature review.
Improvement in clinical conditions allowed physicians to pay more attention to the cognitive function in DMD patients, leading to description of a cognitive impairment not only in affected males, but in female carriers as well. This study aimed to investigate the cognitive involvement in a cohort of DMD carriers and to summarize the current knowledge about the intellectual involvement and neuropsychological profile in DMD/BMD carriers. Our case series consisted of 22 carrier patients from two different centers (IRCCS Mondino, Pavia and Policlinico Gemelli, Rome), for whom we retrospectively collected cognitive, clinical and genetic data. For literature review, we selected 9 studies published in English language from 2011 to 2023 and cited in PubMed. We found that the average IQ of DMD carriers was lower (74; very low) than the average score on normal curve (100 as average standard score). Furthermore, about 50% of them fell in the "extremely low IQ" range, compared with 2-3% of general population. A higher incidence of intellectual disability was confirmed in symptomatic DMD carriers (mean IQ 66; extremely low) from IRCCS Mondino, but not in the asymptomatic ones (mean IQ 99; average), when compared to the general population. Current literature, albeit limited, seems to confirm the presence of a cognitive impairment in carriers, although milder than in affected males but with a similar neuropsychological profile. However, further studies are necessary to delve deeper into this issue and provide adequate educational support.


Characterization of novel peptide agonists of the alpha mating factor of Saccharomyces cerevisiae.
Alpha-factor [WHWLQLKPGQPMY], a secreted tridecapeptide pheromone, is required for mating between the a- and alpha-haploid mating types of Saccharomyces cerevisiae (MATa, MATalpha). New analogues of alpha-factor were synthesized and evaluated by morphogenesis assays and receptor binding studies. The Y(0)Nle(12)F(13) analogue [YWHWLQLKPGQPNleF] (MFN5) caused growth arrest and morphological alteration in MATa cells in a fashion identical to that of the native pheromone. Binding of (125)I-labeled MFN5 was saturable, and reversible as shown by equipotent label displacement by MFN5 and native alpha-mating factor. Scatchard analysis of equilibrium binding data on plasma membranes and intact cells indicated the existence of a single high-affinity binding site (K(d) = 6.4 x 10(-8)). Specific binding of (125)I-labeled MFN5 was significantly reduced by guanosine nucleotides. Affinity cross-linking of (125)I-labeled MFN5 to MATa cell membranes identified a specifically labeled 49-kDa protein. The novel synthetic alpha-factor analogue MFN5 can be easily iodinated and used as a probe for the alpha-factor receptor.