[An individual approach to the surgical treatment and medical rehabilitation of duodenal ulcer patients].
Since 1986 403 patients have been treated according to the following programme: successive preparation for surgery, the operative intervention chosen individually for each patient, the purposeful medical rehabilitation. Different types of vagotomy with draining operations were performed in 85.6% of the cases, stomach resection--in 14.4% of the patients. The mortality rate was 0%. The indications for various types of vagotomy, stomach resection and different types of draining operations were determined. Rehabilitation of 55% of the patients after the operative treatment took place at the gastroenterological department, the others--at an outpatient department. The indications for rehabilitation, its volume and time were established. The best remote results in the follow-up periods up to five years were obtained after truncal vagotomy and stomach resection. Ulcer recurrences were noted in 3.5% and 5.2% of the cases respectively. Recurrences of the disease were noted in 7.8% after combined vagotomy and in more than 20% after SPV. Nine patients out of 34 with recurrent ulcers were reoperated with good results, the others were successfully treated by conservative therapy.


Comparative study of dobutamine stress electron-beam computed tomography and exercise thallium scintigraphy in the diagnosis of patients with suspected coronary artery disease.
To evaluate the diagnostic value of dobutamine stress electron-beam computed tomography (EBCT) as compared with exercise stress thallium-201 single-photon emission computed tomography (201T1-SPECT) for the detection of myocardial ischemia, 10 patients with proven or suspected coronary artery disease underwent both tests. Nine of the 10 patients also underwent coronary angiography. EBCT images were analyzed objectively to evaluate systolic wall thickening and analyzed segmentally to determine the distribution of the coronary arteries. Dobutamine stress EBCT revealed the presence of ischemia in 59 segments, whereas exercise stress 201T1-SPECT revealed ischemia in 51 segments (agreement = 73%). The advantage of dobutamine stress EBCT was demonstrated in the inferior/posterior segments as compared with the results of exercise stress 201T1-SPECT. The overall sensitivity for detecting ischemic regions supplied by coronary arteries with significant stenosis (diameter stenosis > 50%) was 83% for dobutamine stress EBCT and 79% for exercise stress 201T1-SPECT (p = NS), with specificities of 75% and 82% (p = NS). Thus, dobutamine stress EBCT presents a reasonable alternative to exercise stress 201T1-SPECT for the objective assessment of patients with suspected coronary artery disease.


Anatomical changes of the ethmoid cavity after endoscopic sinus surgery.
Alteration of the bony architecture of the sinus cavities has been observed in chronic sinusitis. Plasticity of the ethmoid sinus framework after endoscopic surgery, however, is a newly described entity. The objective of this study was to determine the incidence and extent of changes in ethmoid size after ethmoidectomy. Retrospective review performed at an academic medical center. Computed tomography scans performed from 2006 through 2007 at the Massachusetts Eye and Ear Infirmary (n = 5,131) were reviewed to identify 100 consecutive patients who underwent sinus surgery and met inclusion criteria. Seven dimensions were measured for each pre- and postoperative scan (n = 200) using Voxar 3D software. Computed tomography scans performed before and 2 to 37 months after ethmoidectomy demonstrated a decrease of 1.1 +/- 1.6 mm in mean ethmoid cavity width at the level of the cribriform plate and posterior globe after surgery (P < .0001). Twenty-five patients (25%) had >1 mm decrease in mean ethmoid width, and six patients (6%) had a decrease of >2 mm (mean 3.1 +/- 0.9 mm). These findings seemed to be the result of postoperative bowing of the medial ethmoid walls with a corresponding increase in orbital volume. These volumetric changes resulted in a postoperative subclinical retrodisplacement (enophthalmos) of the globes (mean 0.2 +/- 0.8 mm, P = .008). The extent of surgery, including performance of frontal recess dissection (P = .007) and total ethmoidectomy (P = .021) were found to be independent predictors of the observed changes in sinus dimensions. Postsurgical plasticity of the ethmoid cavity is a new concept supported by observed changes in sinus dimensions after ethmoidectomy. These changes may reflect a loss of internal structural support and forces of contracture during the postoperative healing period.


A study of the growth of Pseudallescheria boydii isolates from sewage sludge and clinical sources on tributyrin, rapeseed oil, biodiesel oil and diesel oil.
The study compared the growth of Pseudallescheria boydii isolates from sewage sludge and from clinical sources on tributyrin, rapeseed oil, biodiesel oil and diesel oil agars. The isolates grew on all substrates tested. The highest growth was observed on rapeseed oil agar, while the lowest on diesel agar. On tributyrin agar, hydrolysis zones were observed around or underneath the colonies. On rapeseed oil agar, no hydrolysis zones were formed, while most isolates formed such a zone on biodiesel oil agar. Rapeseed oil and biodiesel oil stimulated the growth of P. boydii isolates, while tributyrin inhibited fungal growth. The stimulation or inhibition effect of diesel oil was dependent on the specified strain. In clinical isolates, fungal growth and activity were found to be more variable compared to sludge isolates. The data suggest that contamination of the environment with these oils could favor the growth of P. boydii. However, no association was found between the growth and oil utilization by this fungus and its pathogenicity.


Altered vascular permeability in the dental pulp of traumatised rat teeth.
A study was made of the vascular permeability changes occurring in the dental pulp of rat teeth subjected to trauma of the occlusal surface with a special steel burr. The vascular response was measured by leakage of 131I-labelled human serum albumin and of colloidal carbon. The effect of a variety of inhibitors of increased vascular permeability was observed. The results obtained support the hypothesis that in the model studied the vascular response of the dental pulp is mediated by the sequential release of histamine and 5-HT, kinins and prostaglandins.


Low molecular weight (7s) immunoglobulin M antibody against hepatitis B core antigen in the serum for differentiating acute from persistent hepatitis B virus infection.
Sera from persons infected with hepatitis B virus were fractionated into 19s and 7s moieties by high performance liquid chromatography and then tested for the antibody to hepatitis B core antigen (anti-HBc) of immunoglobulin M (IgM) class by radioimmunoassay. Sera from 17 patients with acute or fulminant hepatitis invariably showed a high activity of 19s IgM anti-HBc (sample/normal ratio 30.6 +/- 13.6). In addition, they all revealed a much lower activity of 7s IgM anti-HBc (4.1 +/- 3.4). In remarkable contrast, 7s IgM anti-HBc activity was higher than 19s IgM anti-HBc activity in the sera from 5 asymptomatic carriers (10.4 +/- 2.4 vs. 1.0 +/- 0.1), 4 patients with chronic persistent hepatitis (11.7 +/- 1.4 vs. 2.1 +/- 1.4), 13 with chronic active hepatitis (13.6 +/- 3.0 vs. 6.0 +/- 5.6), and 10 with liver cirrhosis (8.9 +/- 3.4 vs. 5.4 +/- 2.4). Among these 32 cases of persistent hepatitis B virus infection, there were only 2 (6.3%) in which the 7s IgM anti-HBc was lower than the 19s IgM anti-HBc. The proportion of patients who showed the value of 7s IgM anti-HBc exceeding that of 19s IgM anti-HBc was significantly higher for persistent (30 of 32) than for acute (0 of 17) hepatitis B virus infection (p less than 0.001). On the basis of these results, the determination of IgM anti-HBc in terms of 19s and 7s subpopulations would be useful for differentiating acute from chronic hepatitis B virus infection, especially when the titer of IgM anti-HBc is not high enough to exclude a persistent hepatitis B virus infection.


Human testis-expressed sequence 101 is limitedly distributed in germinal epithelium of testis and disappears in seminoma.
Testis-expressed sequence 101 (TEX101) was found to be highly expressed in testis and involved in acrosome reaction in previous studies. Recently, the metastasis suppressor function of TEX101 in cancer was disclosed, but the comprehensive investigation of its expression has rarely been reported. In this study, the expression features of TEX101 in normal human organs and seminoma were systematically analyzed. Immunohistochemistry demonstrated intense staining of TEX101 in human testis tissues; however, its expression in 27 other types of normal human organs, including the ovary, was negligible. Higher expression of TEX101 was observed in the spermatocytes and spermatids of the testis, but relatively lower staining was detected in spermatogonia. Western blotting showed a single TEX101 band of 38 kDa in human testis, but it did not correspond to the predicted molecular weight of its mature form at 21 KDa. Furthermore, we examined seminoma tissues by immunohistochemistry and found that none of the 36 samples expressed TEX101. Our data confirmed TEX101 to be a testis protein that could be related to the maturation process of male germ cells. The lack of TEX101 in seminoma indicated its potential role in tumor progression. This characteristic expression of TEX101 could provide a valuable reference for understanding its biological functions.


Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
Janus kinase (JAK) inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms, and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type I binding mode can lead to an increase in JAK activation loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type II inhibition acts in the opposite manner, leading to a loss of activation loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation loop may or may not be elicited.


Calcium preparations do not inhibit allergic reactions: a randomized controlled trial.
INTRODUCTION Massive consumption of dietary supplements, including vitamins and minerals, has recently become a serious health issue in Europe. Their use may negatively affect the pharmacological activity of various medications, including antiallergic drugs. Calcium preparations are commonly used in some European countries as a popular remedy for allergy‑related skin reactions, such as itching, erythema, and wheals, as well as insect bites. However, so far there have been no reliable studies to prove their action. OBJECTIVES The aim of this randomized, double‑blind, placebo‑controlled study was to investigate the efficacy of calcium salts in allergic reactions, using an allergen‑induced skin prick test (SPT). PATIENTS AND METHODS Forty adult volunteers with allergic rhinoconjunctivitis or asthma (or both) were recruited to receive oral calcium carbonate (1000 mg) or placebo 3 times a day for 3 days. SPTs were performed with 11 aeroallergen extracts at baseline and at 4 and 72 hours after drug administration. The wheal diameter was measured. We also used the visual analog scale to evaluate the intensity of pruritus. RESULTS There was no difference in the wheal size or pruritus between patients receiving calcium or placebo at any of the time points (P >0.05). Calcium preparations were well tolerated. CONCLUSIONS We found no evidence to support the efficacy of calcium preparations in allergy‑related skin reactions associated with itching and wheals. Calcium preparations do not suppress SPT responses; moreover, their use in allergic patients should be discouraged due to their possible interference with the absorption of antiallergic drugs.


Tobacco, Alcohol and Drug Use among Dental Undergraduates at One UK University in 2015.
The aim of this study was determine the prevalence of tobacco, alcohol and illicit substance use among dental undergraduates at one UK university in 2015. A cross-sectional survey of all 344 dental undergraduates using an anonymous self-report questionnaire was carried out. The response rate was 77%, of which 29% were male and 71% female. Tobacco smoking was reported by 23.6% of males and 12.2% of females, with only 1.6% of females reporting to smoke ≥10 cigarettes per day. Alcohol consumption was reported by 85.5% of males and 84% of females, and reported levels of alcohol consumption increased since becoming undergraduates. Binge drinking was reported by 35.3% of males and 41% of female students. Only 2.6% of males and 0.5% of females reported to be current regular users of cannabis. The vast majority of respondents claimed to have never used any illicit substance. The only other reported regularly used substances by males was Ecstasy (1.3%) and by females were LSD (0.5%), Ecstasy (1.5%), Cocaine (0.5%), Inhalants (0.5%) and Ketamine (0.5%). These results are encouraging. Fewer students reported smoking than in the general population, levels of binge drinking were considerably lower than previously reported figures, as were the numbers of regular users of cannabis and other illicit substances.


Predicting Time to Evaluation After Pediatric Concussion: Factors Affecting Specialty Concussion Care.
The timing of clinical evaluation after pediatric concussion represents an important and potentially modifiable clinical milestone for diagnosis, selection of appropriate treatment pathways, and recovery prognosis. Patient demographics, socioeconomic status, or medical history may affect the time to the initial evaluation and subsequently influence recovery outcomes. The purpose of this investigation was to evaluate the association of patient characteristics with the time to specialty evaluation after a concussion. It was hypothesized that patients with a history of concussion, a preexisting relationship with our specialty concussion program, or a higher ZIP code-based income estimate would present for care more quickly after a concussion than patients without these characteristics. Cross-sectional study; Level of evidence, 3. Included were patients with a concussion between 6 and 18 years old who were seen for care at a single sports medicine center between January 1 and December 31, 2019. Patient demographic, socioeconomic, injury, and clinical characteristics were collected through a retrospective review of the medical records. The primary outcome was the number of days between the date of the concussion and the patient's initial specialty evaluation. Overall, 220 patients (mean age, 14.4 ± 2.5 years; 46% female) were seen for care at a mean of 9.7 ± 5.6 days (range, 1-21 days) after concussion. A shorter time to specialty evaluation was associated with a history of concussion (β = -1.72 [95% CI, -3.24 to -0.20]; P = .03) and a prior clinical relationship with the treating clinical department (β = -1.85 [95% CI, -3.52 to -0.19]; P = .03). Referral by a primary care provider was associated with a longer time to evaluation (β = 3.86 [95% CI, 2.39-5.33]; P < .0001). A history of concussion and having a preexisting clinical relationship with the deparment were associated with a shorter time to evaluation after concussion. Referral from a primary care physician was associated with a longer time to evaluation. Issues may exist in the propensity to access care after an injury, resulting in delays for initiating early treatment.


The side effects of translational omics: overtesting, overdiagnosis, overtreatment.
High-throughput technologies such as next-generation genomics, transcriptomics and proteomics are capable of generating massive amounts of data quickly, and at relatively low costs. It is tempting to use this data for various medical applications including preclinical disease detection and for prediction of disease predisposition. Pilot projects, initiated by various research groups and Google, are currently underway, but results with not be available for a few years. We here summarize some possible difficulties with these approaches, by using examples from already tried cancer and other screening programs. Population screening, especially with multiparametric algorithms, will identify at least some false positive parameters and screening programs will identify abnormal results in otherwise healthy individuals. Whole genome sequencing will identify genetic changes of unknown significance and may not predict accurately future disease predisposition if the disease is also influenced by environmental factors. In screening programs, if the disease is rare, the positive predictive value of the test will be low, even if the test has excellent sensitivity and specificity. False positive results may require invasive procedures to delineate. Furthermore, screening programs are not effective if the cancer grows quickly, and will identify indolent forms of the disease with slow-growing tumors. It has also been recently shown that for some cancers, more intensive and radical treatments do not usually lead to better clinical outcomes. We conclude that new omics testing technologies should avoid overdiagnosis and overtreatment and need to be evaluated for overall clinical benefit before introduction to the clinic.


Effects of dopamine on photopic L-type S-potentials in the catfish retina.
Photopic L-type responses were recorded from the soma and the axon terminal of horizontal cells of the catfish (Ictalurus punctatus) retina in eye-cup preparations. The responses were produced by a spot of light with 100-micron diameter (intensity, 10 microW/cm2), which was flashed or steadily illuminated and swept along a 6-mm length over the retinal surface at a speed of 0.95 mm/sec. In some experiments, a traveling random bar stimulus was used instead of the sweeping spot. While recording the responses, dopamine (DA) was applied in a jet form via a nebulizer over the retinal preparation or as superfusate to the eye-cup preparation. DA increased the response amplitude by about 50% and markedly narrowed the spatial profile of the responses from the soma but not from the axon terminal. These DA effects were observed in both normal retinas and those from which DA cells had been deprived by prior intraocular injection of 6-hydroxydopamine. Deprival of DA cells from the retina resulted in a slightly wider spatial profile of the soma and axon terminal responses than that in normal retinas. The results indicate that the spatial properties of photopic L-type responses are modulated by DA at the soma level of horizontal cells.


Retrospective application of the Milan System for reporting salivary gland cytopathology: A Cancer Center experience.
The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) was recently proposed. Herein, we retrospectively applied this nomenclature system to salivary gland lesions sampled by ultrasound-guided fine-needle aspiration (FNA). All cases of salivary gland FNA with available surgical follow-up, in the period from 2014 to 2017 at our institution were reviewed and reclassified according to one of the six categories of the MSRSGC, blind to the surgical outcome. Overall sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated, as well as risks of neoplasm (RON) and risk of malignancy (ROM) for each of the proposed categories. There were 104 salivary gland lesions, with a female predominance (57.7%), most cases from the parotid gland (89.4%). Mean age was 53.2 years. Distribution of the specimens according to the Milan System was as follows: 19.2% nondiagnostic (ND), 8.7% non-neoplastic (NN), 9.6% atypia of undetermined significance (AUS), 40.4% benign neoplasm (BN), 14.4% salivary gland neoplasm of uncertain malignant potential (SUMP), 1.9% suspicious for malignancy (SFM), and 5.8% malignant. Sensitivity, specificity, PPV, and NPV using MSRSGC were calculated as 75%, 98.4%, 88.9%, and 95.3%, respectively. RON/ROM for each category were 60%/15% for ND, 44.4%/0% for NN, 90%/40% for AUS, 100%/9.5% for BN, 100%/13.3% for SUMP, 50%/50% for SFM and 100%/100% for malignant. The use of the Milan System proved to be a useful method to predict the risk of neoplasm and malignancy in the sample studied, with high sensitivity and specificity.


Age-dependent modulation of NF-kappaB expression in rat adrenal gland.
The current studies were initiated to examine the expression and regulation of an oxidative stress-responsive transcription factor, NF-kappa B, in rat adrenals during aging. NF- kappa B DNA-binding activity and expression of constituent proteins (Rel family of proteins and I kappa Bs) was measured in adrenal nuclear and cytoplasmic extracts from young mature (5 month) and old (24 month) Sprague-Dawley rats before and after treatment with LPS; the latter was used to further invoke oxidative stress. Administration of LPS to either young or old rats induced a dramatic activation of NF- kappa B DNA binding activity as assayed by EMSA. NF- kappa B hetero-dimers, RelA/NF- kappa B1 (p65/p50) accounted for the majority of proteins that bound to consensus NF- kappa B sequences in LPS-treated young and old animals. The intensity of DNA binding complexes was significantly reduced in old animals. The age-related decline in the activation of NF- kappa B could not be attributed to an alteration in the composition of constituent subunits or degradation of NF- kappa B inhibitory proteins (I kappa B alpha and I kappa B beta) but rather was due to selective down-regulation of RelA/p65 and NF- kappa B2/p52 proteins. No age-related or LPS-induced changes in the constitutively active transcription factors SP-1 and OCT-1 were detected. These data suggest that aberrancies in the activation of NF- kappa B DNA-binding activity may contribute to the excessive oxidative damage observed in adrenal tissue with aging and may adversely affect cellular processes crucial for intracellular cholesterol transport and steroid hormone production.


Evaluation of the nanostructure of cervical third cementum in health and chronic periodontitis: An in vitro study.
During the progression of periodontal disease, the cementum undergoes alterations in its structure and composition. Understanding the nanostructure of cementum, in terms of its mechanical properties, will provide an insight into the milieu that periodontal ligament cells encounter in health and chronic periodontitis. This study aims to analyze the nanomechanical properties of the cervical third of the cementum (transverse section) in health and chronic periodontitis. Twenty teeth (10 healthy and 10 periodontally diseased) were collected and the nanomechanical properties of the transverse section of the cervical third cementum were evaluated with depth-sensing nanoindentation technique under dry conditions. A total of 100 nanoindentations were performed to analyze the modulus of elasticity and hardness of cervical third of the cementum. The nanomechanical properties of the healthy cervical third cementum sections were significantly higher (P < 0.05) (hardness: 0.720 ± 0.305 GPa; modulus: 15.420 ± 3.902 GPa) than the diseased cementum section (hardness: 0.422 ± 0.157 GPa; modulus: 11.056 ± 3.434 GPa). The results of our study indicate that the hardness and modulus of elasticity of the cervical third cementum decreases significantly in chronic periodontitis.


Presence and estrogenicity of anthracene derivatives in coastal Japanese waters.
An analytical method was developed to measure levels of anthracene (ANT) and its derivative compounds 9,10-anthraquinone (ATQ) and eight hydroxy-anthraquinones (hATQs) in seawater from Tokyo Bay and Suruga Bay, Japan. The hATQs produced through photochemical reaction of ANT are known to be toxic. Seawater samples contained ANT at levels ranging from < 0.2 to 4.7 ng/L, ATQ from 3.9 to 200 ng/L, 1-hydroxyanthraquinone (1-hATQ) from < 0.9 to 5.3 ng/L, and 2-hATQ from 1.6 to 5.5 ng/L. The yeast two-hybrid system was also used to evaluate the estrogenic activity of these compounds. Estrogen agonist and antagonist tests with or without rat liver S9 were carried out. Some compounds showed estrogenic activity: The strongest (2-hydroxyanthraquinone) was of similar potency to p-nonylphenol. Concentrations of some estrogenic derivatives in the samples were higher than those of the parent ANT Polycyclic aromatic hydrocarbons (PAHs) such as ANT appear able to be transformed into toxic compounds in the environment when they are irradiated by sunlight, so it is important to monitor not only PAHs but also hydroxyl-PAH-quinones in the environment.


[Estrogen deficiency and urinary incontinence in menopausal women].
By analyzing relevant domestic and international literature and their own long-standing experience, the authors discuss the problem of urinary incontinence in the context of estrogen deficiency. They outline the conservative management of patients with mild incontinence and recurrent forms after plastic surgery with taking into account the morphological findings of paraurethral tissue.


The history of medicine teaching program in Croatia.
A history of medicine program was first introduced at the University of Zagreb, Croatia, in 1927 by the internist Lujo Thaller, who became the first lecturer on this subject at Zagreb. However, the development of the program did not go smoothly and medicohistorians in Croatia were engaged in a constant struggle for proper status and a permanent place for their program within the medical school curriculum. Today a 15-hour medical history course (offered in the last semester of the 6-year curriculum) is mandatory at all four Croatian medical schools. The course draws on historical, cultural, sociological, epistemological, and bioethical aspects of medicine, with the goal of broadening students' perspectives on the practice of medicine and thereby enabling them to better meet the demands they will face as practicing physicians.


Two cases of Legg-Perthes and intellectual disability in Tricho-Rhino-Phalangeal syndrome type 1 associated with novel TRPS1 mutations.
Tricho-Rhino-Phalangeal syndrome is a rare autosomal dominant genetic disorder caused by mutations in the TRPS1 gene. This malformation syndrome is characterized by distinctive craniofacial features including sparse scalp hair, bulbous tip of the nose, long flat philtrum, thin upper vermilion border, and protruding ears. Skeletal abnormalities include cone-shaped epiphyses at the phalanges, hip malformations, and short stature. In this report, we describe two patients with the physical manifestations and genotype of TRPS type I but with learning/intellectual disability not typically described as part of the syndrome. The first patient has a novel heterozygous two-base-pair deletion of nucleotides at 3198-3199 (c.3198-3199delAT) in the TRPS1 gene causing a translational frameshift and subsequent alternate stop codon. The second patient has a 3.08 million base-pair interstitial deletion at 8q23.3 (113,735,487-116,818,578), which includes the TRPS1 gene and CSMD3. Our patients have characteristic craniofacial features, Legg-Perthes syndrome, various skeletal abnormalities including cone shaped epiphyses, anxiety (first patient), and intellectual disability, presenting unusual phenotypes that add to the clinical spectrum of the disease.


Granulocyte-macrophage colony stimulating factor (GM-CSF) in the treatment of hematological malignancies.
Acute myeloid leukemic (AML) cells not only express receptors for various cytokines but also produce hemopoietic growth factors themselves. Thus, they are able to stimulate their own activation and proliferation, a phenomenon known as autocrine growth. The cell cycle kinetics of AML blast cells are susceptible to stimulation by a variety of cytokines, including granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin (IL)-3, granulocyte colony stimulating factor and stem cell factor. GM-CSF and IL-3 can markedly enhance the cytotoxicity of chemotherapeutic agents by increasing the proportion of AML cells in S-phase at any given time and by altering the metabolic status of the AML cells. A number of clinical studies involving the use of GM-CSF in association with chemotherapy in patients with AML are currently ongoing. In the next few years the first clinical results will become available indicating whether the use of cytokines holds any benefit for patients with AML.


Beta-2-microglobulin review: its relevance in clinical oncology.
Beta-2-microglobulin (beta 2-m) is an intrinsic part of the HLA system and is most probably involved in cell recognition. The levels of free beta 2-m in the blood and urine are influenced by beta 2-m production and its clearance and destruction in the kidney. Many tumors can be associated with an elevated serum beta 2-m, the reason is unknown. The most promising application of beta 2-m as a tumor marker would appear to be lymphoid malignancies, especially multiple myeloma and chronic lymphocytic leukemia.


Light-cured dimethacrylate-based resins and their composites: comparative study of mechanical strength, water sorption and ion release.
This study explored how resin type affects selected physicochemical properties of complex methacrylate copolymers and their amorphous calcium phosphate (ACP)-filled and glass-filled composites. Two series of photo-polymerizable resin matrices were formulated employing 2,2-bis[p-(2'-hydroxy-3'-methacryloxypropoxy)phenyl]propane (Bis-GMA) or an ethoxylated bisphenol A dimethacrylate (EBPADMA) as the base monomer, Unfilled copolymers and composites filled with a mass fraction with 40 %, 35 % and 30 %, respectively, of ACP or the un-silanized glass were assessed for biaxial flexure strength (BFS), water sorption (WS) and mineral ion release upon immersion in HEPES-buffered saline solution for up to six months. Substituting EBPADMA for Bis-GMA significantly reduced the WS while only marginally affected the BFS of both dry and wet copolymers. Independent of the filler level, both dry and wet ACP composites formulated with either BTHM or ETHM resins were mechanically weaker than the corresponding copolymers. The BFS of ACP composite specimens after 1 month in saline did not further decrease with further aqueous exposure. The BFS of glass-filled composites decreased with the increased level of the glass filler and the time of aqueous exposure. After 6 months of immersion, the BFS of glass-filled BTHM and ETHM composites, respectively, remained 58 % and 41 % higher than the BFS of the corresponding ACP composites. Ion release data indicated that a minimum mass fraction of 35 % ACP was required to attain the desired solution supersaturation with respect to hydroxyapatite for both the BTHM and ETHM derived composites.


Distribution of pesticide residues within homes in central New York State.
Residues for 17 pesticides were analyzed in 41 households in central New York State that represented farm, rural, and urban houses. Samples were taken in both summer and winter of 2000-2001 from the same households from four locations; family room carpet; adjacent smooth floor; flat tabletop surface; and settled dust collected in a Petri dish on a tabletop. Pesticide residues were analyzed to identity factors that influence both the transport into and the redistribution of pesticides in the indoor environment. Differences were observed between the various pesticides and pesticide classifications relative to location within and between households as well as by season. Variations in the pesticide residues were related to a number of factors. Higher residues were observed in the farm households, particularly in summer, with the highest amount observed for chloropyrifos in carpet (33 microg/m2). For many pesticides, the frequency of detection and the amount of residues were higher in summer, which relates to usage patterns in agriculture and horticulture; however, larger amounts of insecticides such as mecoprop, resmethrin, and tetramethrin were found on flat surfaces in winter, indicating household use and possible redistribution within the home. Distribution patterns suggest that routines within a household may cause high variation in residues; these practices include indoor pets and treatment for fleas and ticks, use of termiticides, and fastidiousness of occupants. Frequency of pesticide detection was highest in carpet for both summer and winter for all households, indicating that carpets hold pesticides over time. Adsorbent fibrous materials such as textiles hold pesticides by macro- and micro-occlusion in their complex structures. Amounts of pesticide residue were higher in carpets than on smooth floors, particularly for rural farm households where the farmer was a certified pesticide applicator. The maximum amount of pesticide residue on a smooth floor surface was 13.6 microg/m2 malathion while the maxima on wiped surfaces and in settled dust were 1.8 microg/m2 2, 4 D and 3 microg/m2 pendimethalin, respectively. Physical properties of individual pesticides such as vapor pressure influenced the distribution of the pesticide within the households. Evidence of volatilization of pesticides and redeposition on surfaces was observed, indicating that this is a mechanism for contamination of surfaces in addition to adsorption on airborne particles and tracking. High residues in winter are evidence that closure of households in winter that reduces ventilation results in redistribution of pesticides within households.


Heart transplantation in rapidly progressive end-stage heart failure associated with celiac disease.
Celiac disease is characterised by chronic immune-mediated malabsorption in genetically susceptible individuals induced by gluten proteins present in wheat, barley and rye. It occurs in adults and children at rates approaching 1% of the population. Cardiomyopathy associated with celiac disease is infrequent. The authors present here a first case of a severe progressive dilated cardiomyopathy that required heart transplantation in young woman with celiac disease.


Hemodynamic performances in patients treated with sotalol after electrical cardioversion of atrial fibrillation.
The negative inotropic effect of nearly all antiarrhythmic drugs, especially important in patients with impaired left ventricular function, represents a major drawback of medical therapy. The aim of this study is to evaluate the atrial and ventricular function and the exercise capacity in patients with mild heart failure treated with d,l-sotalol after electrical conversion of atrial fibrillation. The study included patients with persistent atrial fibrillation (for more than 2 weeks but less than 1 year) and mild heart failure (< or = class II NYHA). All patients had comparable basal echocardiographic findings, and received captopril. After successful cardioversion the patients were randomized in two groups: group 1 treated with sotalol (mean dose 240 mg q.d., max. 320 mg) and group 2--without sotalol. The drop-out criterion was the failure to maintain sinus rhythm. Finally, in the study remained 17 patients (10 men, 7 women, aged 41-60 years); group 1 included 10 patients and group 2-7 patients. They were assessed by quantitative echocardiography + Doppler and by standard ecg exercise test at less than 1 month but more than 2 weeks, and at 1, 3, and 6 months. When first evaluated (2 weeks-1 month), peak A wave velocity and atrial filling ratio were higher in group 2 than in group 1 (37 +/- 10 cm/s vs 20 +/- 5 cm/s and 23% +/- 7 vs 13% +/- 5, respectively) and group 1 had also a lower exercise tolerance (80 +/- 25 W vs 110 +/- 10 W). There were no significant differences between groups 1 and 2 in left atrial and left ventricular dimensions, ejection fraction and E wave deceleration time. After 1 month there were no significant differences in Doppler characteristics, echocardiographic parameters and exercise tolerance between the two groups. Group 1 remained at a lower heart rate and had a lower maximal double product (17250 mmHg/min vs 22100 mmHg/min) corresponding to a lower cardiac work. At 3 and 6 months there were no significant changes in all characteristics between the two groups. In conclusion, sotalol seems to be a well tolerated antiarrhythmic agent in patients with mild heart failure, after conversion of persistent atrial fibrillation. In this setting: 1. Sotalol could reversibly amplify the effect of atrial stunning after electrical cardioversion of atrial fibrillation, but this effect is brief. 2. Sotalol has no relevant negative inotropic effect, at least not in association with captopril. 3. Sotalol improves the effort capacity.


Reversal of P-glycoprotein-medicated multidrug resistance by LBM-A5 in vitro and a study of its pharmacokinetics in vivo.
The overexpression of P-glycoprotein (P-gp) in tumors leads to multidrug resistance (MDR), which is a significant obstacle in clinical cancer chemotherapy. The co-administration of anticancer drugs and MDR modulators is a promising strategy for overcoming this problem. Our study aimed to explore the reversal mechanism and safety of the MDR modulator LBM-A5 in vitro, and evaluate its pharmacokinetics and effects on doxorubicin metabolism in vivo. We evaluated an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of anticancer agents mediated by LBM-A5, the effect of LBM-A5 on rhodamine123 intracellular accumulation, and the efflux in K562/DOX cells to investigate the reversal mechanisms of LBM-A5. The results showed that LBM-A5 inhibits rhodamine123 efflux and increases intracellular accumulation by inhibiting the efflux pump function of P-gp. Furthermore, the therapeutic index and CYP3A4 activity analysis in vitro suggested that LBM-A5 is reasonably safe to use. Also, LBM-A5 (10 mg/kg body mass) achieved the required plasma concentration in sufficient time to reverse MDR in vivo. Importantly, the LBM-A5 treatment group shared similar doxorubicin (DOX) pharmacokinetics with the free DOX group. Our results suggest that LBM-A5 effectively reverses MDR (EC50 = 483.6 ± 81.7 nmol·L(-1)) by inhibiting the function of P-gp, with relatively ideal pharmacokinetics and in a safe manner, and so may be a promising candidate for cancer chemotherapy research.


Individual-specific changes in the human gut microbiota after challenge with enterotoxigenic Escherichia coli and subsequent ciprofloxacin treatment.
Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea in inhabitants from low-income countries and in visitors to these countries. The impact of the human intestinal microbiota on the initiation and progression of ETEC diarrhea is not yet well understood. We used 16S rRNA (ribosomal RNA) gene sequencing to study changes in the fecal microbiota of 12 volunteers during a human challenge study with ETEC (H10407) and subsequent treatment with ciprofloxacin. Five subjects developed severe diarrhea and seven experienced few or no symptoms. Diarrheal symptoms were associated with high concentrations of fecal E. coli as measured by quantitative culture, quantitative PCR, and normalized number of 16S rRNA gene sequences. Large changes in other members of the microbiota varied greatly from individual to individual, whether or not diarrhea occurred. Nonetheless the variation within an individual was small compared to variation between individuals. Ciprofloxacin treatment reorganized microbiota populations; however, the original structure was largely restored at one and three month follow-up visits. Symptomatic ETEC infections, but not asymptomatic infections, were associated with high fecal concentrations of E. coli. Both infection and ciprofloxacin treatment caused variable changes in other bacteria that generally reverted to baseline levels after three months.


Effects of Size and Stability of Native Fat Globules on the Formation of Milk Gel Induced by Rennet.
Rennet-induced gelation crucially impacts cheese structure. In this study, effects of the size and stability of native fat globules on the kinetics of rennet-induced coagulation were revealed by determining the caseinomacropeptide release rate and rheological properties of milk. Moreover, the mobility and stability of fat globules during renneting was revealed using diffusing wave spectroscopy and confocal laser scanning microscopy. By use of a 2-stage gravity separation combined centrifugation scheme, native fat globules were selectively separated into small (SFG, D4,3 = 1.87 ± 0.02 μm) and large fat globules (LFG, D4,3 = 5.65 ± 0.03 μm). The protein and fat content of SFG and LFG milk were then standardized to 3.2 g/100 mL and 1.2 g/100 mL, respectively. The milk containing different sized globules were then subjected to renneting experiments in the laboratory. Reduction of globule size accelerated the aggregation of casein micelles during renneting, giving a shorter gelation time and earlier 1/l* change. The gel produced from LFG milk was broken due to coalescent fat globules and generated coarser gel strands compared to the finer strands formed with SFG milk. Structural differences were also confirmed with a higher final storage modulus of the curd made from SFG milk than that from the LFG. In conclusion, the size of fat globules affects the aggregation of casein micelles. Moreover, fat globule coalescence and creaming during renneting, also affects the structure of the rennet gel. A better understanding of the size of globules effect on milk gelation could lead to the development of cheese with specific properties.


An empiric study of ecological inference.
Aggregate-level (macro) data are sometimes used when examining health care issues. Although they may be more accessible than individual (micro) observations, their interpretation is subject to ecological bias which in most cases is not measurable. This paper examines the implications of using aggregate-level data by conducting two separate analyses (micro and macro). Using as a database hospital episodes of care for the North Carolina Medicare aged population, regression models are developed from an examination of geographic grouping effects to explore the impact of extended care services, skilled nursing facility, and home health agency care on acute care hospital days. Specific problems encountered are: variable definition, collinearity , variance reduction, dilution of effect, spurious correlation, and observation influence. Stronger collinear (correlation among independent variables) relations occur at the macro-level than at the micro-level and spurious macro-correlations result from model specification and definition of interaction effects.


Fractal analysis of steady-state-flicker visual evoked potentials: feasibility.
Electrophysiological models of visual evoked potential recording have assumed that response variability is caused predominantly by random noise added to a true steady signal. Since neuronal geometry has a fractal structure, neural activity may demonstrate deterministic nonlinear dynamics, i.e., chaos. We recorded several-minute time-series traces of the visual evoked potential magnitude in response to full-field flicker from three glaucoma patients and one normal subject. When plotted in phase space, the steady-state response derived from a lock-in amplifier shows an apparent so-called strange attractor (extended nonrepeating loops) rather than the pattern expected from a signal-plus-noise model (a fuzzy dot). The fractal dimension of this attractor may be a more sensitive indicator of early optic-nerve damage than are visual evoked potential latency or amplitude measures.


A preventive therapy of the central nervous system complications in acute leukemias. Preliminary report.
A new therapeutic schedule for preventive therapy of the central nervous system (CNS) complications by intrathecal (i.t.) injections of methotrexate (MTX) was applied in two groups of 6 and respectively 13 adults with acute lymphoblastic or non-lymphoblastic leukemias. Instead of starting this treatment only in the remission stage, i.t. MTX was given from the very beginning of cytostatic therapy. In most of the patients this drug proved to be effective in preventing CNS involvement. In some cases, however, it was not well, tolerated owing probably to a neurotoxic effect. This suggested continuation of the study with Ara-C.


The prevention of colitis by E Prostanoid receptor 4 agonist through enhancement of epithelium survival and regeneration.
Inflammatory bowel disease (IBD) is often triggered and/or exacerbated by nonsteroidal anti-inflammatory drugs (NSAIDs). Among various prostanoids affected by NSAIDs, prostaglandin E2 (PGE2), in particular, seems to play critical roles in IBD via the EP4 receptor, one of the four PGE2 receptor subtypes (EP1-4). An EP4 agonist, [[3-[[(1R,2S,3R)-3-hydroxy-2-[(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl]-5-oxocyclopentyl]thio]propyl]thio]-acetic acid, C22H30O6S2 (ONO-AE1-329), for example, when topically applied, has been reported to ameliorate typical colitis symptoms by suppressing the production of cytotoxic cytokines in the dextran sodium sulfate (DSS)-induced colitis model. EP4 agonists are also known, however, for their ability to protect epithelial cells from apoptosis in vitro, which may contribute to the protection of mucosal barrier functions. To investigate this potential application, we have tested another EP4-selective agonist in the DSS-indomethacin mouse colitis model. 7-[2-(3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid methyl ester, C23H33NO4 (AGN205203), an analog from the 8-azapiperidinone series of EP4 agonists, is metabolically and chemically more stable than the ONO agonist, because of its lack of oxidizable sulfur atoms in the alpha-chain and of 11-OH group, a potential source of beta-elimination reaction. Treatment of mice subcutaneously with AGN205203 at 3 mg/kg/day minimized colitis symptoms, such as weight loss, diarrhea, and colonic bleeding. Further histological examination of colons revealed healthy surface columnar epithelial cells free of erosion and ulceration compared with those without the drug treatment. At cellular level, the drug treatment decreased colon epithelial apoptosis, prevented goblet cell depletion, and promoted epithelial regeneration. AGN205203 may be unique among known EP4 agonists for its metabolic and chemical stability, and it is amenable to systemic applications for the prevention and recovery of IBD.


Recent advances on extracellular vesicles in therapeutic delivery: Challenges, solutions, and opportunities.
Extracellular vesicles (EVs) are intrinsic mediators of intercellular communication in our body, allowing functional transfer of biomolecules (lipids, proteins, and nucleic acid) between diverse locations. Such an instrumental role evokes a surge of interest within the drug delivery community in tailoring EVs for therapeutic delivery. These vesicles represent a novel generation of drug delivery systems, providing high delivery efficiency, intrinsic targeting properties, and low immunogenicity. In the recent years, considerable research efforts have been directed toward developing safe and efficient EV-based delivery vehicles. Although EVs are shown to harbor great promise in therapeutic delivery, substantial improvements in exploring standardized isolation techniques with high efficiency and robust yield, scalable production, standard procedures for EV storage, efficient loading methods without damaging EV integrity, understanding their in vivo trafficking, and developing novel EV-based nanocarriers are still required before their clinical transformation. In this review, we seek to summarize the recent advance on harnessing EVs for drug delivery with focus on state-of-the-art solutions for overcoming major challenges.


Acute bronchoconstriction induced by cotton dust: dose-related responses to endotoxin and other dust factors.
Fifty-four healthy humans, selected for their acute airway responsiveness to cotton dust, had spirometric tests immediately before and after 6 hours of exposure to card-generated cotton dust from seven different cottons (of several grades and growing regions). During exposures, we measured airborne concentrations of viable fungi and bacteria (total and gram negative), vertically elutriated gravimetric dust, and vertically elutriated endotoxin. Correlation between each of these five exposure indices and exposure-related acute changes in forced expiratory volume in 1 s showed a statistically significant relationship between all of the indices except concentration of viable fungi. Of the other four indices, endotoxin was the most highly correlated (r = -0.94; p less than 0.00001), and gravimetric dust was the least correlated (r = -0.34; p less than 0.05). These findings suggest that gram-negative endotoxin may play a major role in the acute pulmonary response to inhaled cotton dust.


Longer intervals between SARS-CoV-2 infection and mRNA-1273 doses improve the neutralization of different variants of concern.
The humoral immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern elicited by vaccination was evaluated in COVID-19 recovered individuals (Rec) separated 1-3 months (Rec2m) or 4-12 months (Rec9m) postinfection and compared to the response in naïve participants. Antibody-mediated immune responses were assessed in 66 participants by three commercial immunoassays and a SARS-CoV-2 lentiviral-based pseudovirus neutralization assay. Immunoglobulin (Ig) levels against SARS-CoV-2 spike were lower in naïve participants after two doses than in Rec after a single dose (p < 0.05). After two doses in Rec, levels of total Ig to receptor-binding domain were significantly increased in Rec9m compared to Rec2m (p < 0.001). The neutralizing potency observed in Rec9m was consistently higher than in Rec2m against variants of concern (VOCs) Alpha, Beta, Delta, and BA.1 sublineage of Omicron with 2.2-2.8-fold increases. Increasing the interval between SARS-CoV-2 infection and the vaccination with messenger RNA-based vaccines to more than 3 months generates a more efficient heterologous humoral immune response against VOCs by allowing enough time to mount a strong recall memory B cell response.


Effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia.
Although ursodeoxycholic acid has been used to treat various cholestatic liver diseases in children, few data are available about its efficacy in biliary atresia. The aim of this study was to assess the effect of ursodeoxycholic acid treatment on liver function in children who underwent successful surgery for biliary atresia. We prospectively studied 16 children with biliary atresia who underwent successful portoenterostomies (postoperative conjugated bilirubin concentration: <34 micromol/L) and were treated with ursodeoxycholic acid for at least 18 months after surgery. Ursodeoxycholic acid treatment was then discontinued. Clinical and biological assessment was performed at the time of discontinuation of ursodeoxycholic acid treatment (T0), at follow-up (T1) and, if the clinical or biological status worsened, after resumption of ursodeoxycholic acid treatment (T2). Ursodeoxycholic acid treatment was resumed in 13 cases. In 1 patient, jaundice recurred after ursodeoxycholic acid therapy was discontinued but abated after resumption of treatment. In 13 children, liver function worsened significantly when ursodeoxycholic acid was discontinued. T1 versus T0 concentrations expressed as multiples of the upper limit of the normal range (in parentheses) were as follows: alanine aminotransferase, 3.0 xN (0.8-7.0) vs 1.5 xN (0.5-5.4); gamma glutamyl transpeptidase, 8.0 xN (1.8-30.2) vs 4.2 xN (0.5-27.4); and aspartate aminotransferase, 1.7 xN (0.7-6.0) vs 1.3 xN (0.6-3.4). When ursodeoxycholic acid treatment was resumed, liver function had improved in all patients by T2. Concentrations of endogenous bile acids tended to be elevated at T1 (not significant) and were significantly decreased at T2. Our study demonstrates the beneficial effect of ursodeoxycholic acid on liver function in children after successful surgery for biliary atresia.


[Advances in targeted therapy for childhood acute myeloid leukemia].
At present, acute myeloid leukemia (AML) accounts for about 15%-20% of childhood acute leukemia. Although overall survival rate is increasing with the help of risk stratification, stratification of chemotherapy, and supportive treatment, conventional pharmacotherapy still has a limited clinical effect and certain limitations in improving remission rate in previously untreated patients and reducing recurrence after remission. With the development of precision medicine, the mechanisms of targeted therapy, including abnormal activation of AML-related signaling pathways and epigenetic modification, have been found in recent years. Molecular-targeted drugs can therefore act on specific receptors and target genes to improve clinical effect and the prognosis of AML patients.


Mesoderm layer formation in Xenopus and Drosophila gastrulation.
During gastrulation, the mesoderm spreads out between ectoderm and endoderm to form a mesenchymal cell layer. Surprisingly the underlying principles of mesoderm layer formation are very similar in evolutionarily distant species like the fruit fly, Drosophila melanogaster, and the frog, Xenopus laevis, in which the molecular and the cellular basis of mesoderm layer formation have been extensively studied. Complementary expression of growth factors in the ectoderm and their receptors in the mesoderm act to orient cellular protrusive activities and direct cell movement, leading to radial cell intercalation and the spreading of the mesoderm layer. This mechanism is contrasted with generic physical mechanisms of tissue spreading that consider the adhesive and physical properties of the cells and tissues. Both mechanisms need to be integrated to orchestrate mesenchymal morphogenesis.


Intrapericardial administration of novel DNA formulations based on thermosensitive Poloxamer 407 gel.
Inherited cardiopathies are leading to life-threatening conditions such as heart failure. Moreover, treatments currently available fail in altering the cardiac phenotype. Thus, gene therapy appears as an attracting alternative to conventional treatments. However, gene delivery remains a major hurdle in achieving this goal. To obtain regional delivery of plasmid DNA, intrapericardial administration seems to be an interesting approach. In order to improve retention time at the site of injection, formulations based on a thermosensitive gel of Poloxamer 407 were assessed. Protection and condensation of plasmid DNA was initially performed through complexation with polyethyleneimine (PEI), a widely used polymer. Characterization of the size and zeta potential of the complexes suggested interactions between the polyplexes and the Poloxamer gel through significant increase of the size of the polyplexes and shielding of the surface charges. In vivo evaluation has highlighted the toxicity of PEI/DNA polyplexes toward the myocardium. However, feasibility of intrapericardial injection of Poloxamer based formulations as well as their very low toxicity has been established.


Hierarchical mechanochemical switches in angiostatin.
We wish to propose a novel mechanism by which the triggering of a biochemical signal can be controlled by the hierarchical coupling between a protein redox equilibrium and an external mechanical force. We have characterized this mechanochemical mechanism in angiostatin, and we have evidence that it can switch the access to partially unfolded structures of this protein. We have identified a metastable intermediate that is specifically accessible under thioredoxin-rich reducing conditions, like those met by angiostatin on the surface of a tumor cell. The structure of the same intermediate accounts for the unexplained antiangiogenic activity of angiostatin. These findings demonstrate a new link between redox biology and mechanically regulated processes.


Long vasodilator reflexes projecting through the myenteric plexus in guinea-pig ileum.
This study examined enteric neural reflexes activating submucosal cholinergic vasodilator motoneurons, which innervate the final resistance vessels regulating mucosal blood flow. Videomicroscopy was employed to monitor dilatation of submucosal arterioles in in vitro preparations from guinea-pig ileum. Balloon distension of intact lumen evoked reflex vasodilatation and flat sheet preparations were employed to separate mucosal mechanical stimulation from intestinal distension. Mucosal stroking and balloon distension of the orad segment evoked vasodilatations > 1.5 cm from the stimulating site. Mucosal stimulation was blocked by combined 5-HT3/5HT4 antagonists but distension-evoked responses were unaffected. Distension-evoked responses were also unaffected by nifedipine (5 microM) or nifedipine (1 microM) and wortmannin (300 nM), suggesting stretch activation rather than stretch-activated contraction was involved. Mucosal and distension-evoked responses were completely blocked when the myenteric plexus was surgically lesioned and were significantly inhibited by hexamethonium. The muscarinic antagonist 4-DAMP, which inhibits vasodilatations evoked by submucosal cholinergic vasodilator neurons, blocked dilatations elicited by mucosal stimulation and balloon distension. Maximal dilatations evoked with either sensory modality could be further enhanced when stimulated with the second modality. Dilatations evoked by stimulation of the aborad segment were similar to those elicited in the orad segment. In conclusion, sensory mechanisms in the mucosa and muscularis propria activate vasodilator pathways in the myenteric plexus which project for significant distances in both ascending and descending directions before innervating submucosal arterioles. These reflexes could co-ordinate mucosal blood flow during multiple motor events such as peristalsis and intestinal mixing between propulsive events.


[Objective surgery -- advanced robotic devices and simulators used for surgical skill assessment].
Robotic assistance became a leading trend in minimally invasive surgery, which is based on the global success of laparoscopic surgery. Manual laparoscopy requires advanced skills and capabilities, which is acquired through tedious learning procedure, while da Vinci type surgical systems offer intuitive control and advanced ergonomics. Nevertheless, in either case, the key issue is to be able to assess objectively the surgeons' skills and capabilities. Robotic devices offer radically new way to collect data during surgical procedures, opening the space for new ways of skill parameterization. This may be revolutionary in MIS training, given the new and objective surgical curriculum and examination methods. The article reviews currently developed skill assessment techniques for robotic surgery and simulators, thoroughly inspecting their validation procedure and utility. In the coming years, these methods will become the mainstream of Western surgical education.


Suppression of the intratesticular testosterone is associated with quantitative changes in spermatogonial populations in intact adult rats.
To investigate the interactions between testosterone and FSH on quantitative aspects of spermatogenesis, intact adult rats were implanted sc with 0.5- to 50-cm long testosterone-filled silastic capsules (TC) for 8 weeks. Serum testosterone levels were suppressed slightly in rats bearing 1-cm TC implants but were elevated 6- to 30-fold when 5 cm or longer TC implants were used. These changes in serum testosterone were associated with a biphasic, dose-dependent response in testicular testosterone concentrations, reaching a minimum of 10-15% of the control values in rats bearing the 1- or 5-cm TC implants, but rebounding to 80% when 50-cm long TC implants were used. Meanwhile, serum FSH was comparably suppressed by 40-70%. Complete spermatogenesis was observed in all experimental animals with the exception of three rats with 1-cm TC implants in which elongated spermatids were absent or reduced in number. Enumeration of various cell types in the basal compartment of whole mounted seminiferous tubules revealed a 20% increase in type A1 spermatogonia in rats with the 1-cm TC implants. On the other hand, a 15-20% reduction in type B spermatogonia and preleptotene spermatocytes was noted in rats receiving 5-cm or longer TC implants. These results demonstrate that complete spermatogenesis can be maintained in intact animals in the presence of 10-15% of the normal testicular testosterone concentration. Failure to maintain normal testis weight, testicular testosterone concentration, or germ cell number at a 30-fold increase in serum testosterone demonstrates that high levels of serum testosterone may not be beneficial for quantitative spermatogenesis. Furthermore, both quantitative and qualitative differences were observed in different phases of spermatogenesis in the presence of comparable serum FSH and testicular testosterone concentrations. These results suggest that factors other than these two hormones are also involved in the regulation of spermatogenesis.


[A case of embolism caused by metallic mercury in a drug addict].
We describe the case of pulmonary embolism from metallic mercury after an deliberate intravenous injection in a drug addict. Metallic mercury embolisation is extremely rare and it is very important to remark the role of elementary mercury in chronic poisoning. In most reported cases, including our patient, the clinical pathologic manifestations are not so important. The reported symptoms are chest pain, tachypnea, gastrointestinal-tract disorder and one case of bloody diarrhea. Intravenous injection causes a local endothelial damage. After embolization the mercury may remain within the pulmonary interstitium and the alveoli, where may develop in sterile abscesses and granulomatous foreign body reactions. The mercury may remain localized as a depot of elemental mercury or may be oxidized to the soluble mercuric ion and may be distributed to other body tissues and may produce chronic poisoning. This toxicity causes damages, particularly to the kidneys (glomerular-nephritis), but does not cause changes in renal function (follow-up 10 years).


[Improved metabolic state in insulin-tested diabetes. Self-testing of blood or urine glucose on 2 days per week].
Randomized serial tests of their metabolic state over four weeks, without self-testing and during daily urinary glucose-profile testing (4 tests) with the Diabur-Test or blood-glucose levels with the Haemo-Gluco-test 20-800 (5 tests daily) on two days weekly were undertaken on 27 unselected insulin-treated outpatient diabetes. HbA1, blood glucose, serum cholesterol, triglycerides and VLDL, LDL and HDL cholesterol were the target values. The following metabolic values were significantly reduced (P less than 0.05) during blood-glucose self-testing, compared with the results during the non-testing phase: HbA1 on average by 11%, blood-glucose (starving) by 20%, serum cholesterol by 9%, serum triglycerides by 13%. Self-testing of urinary glucose (compared with the test-free phase) brought little improvement in the metabolic state. The results of self-testing were the more impressive the worse the metabolic state during the phase without self-testing. Except for VLDL and HDL cholesterol, changes in HbA1 correlated well during all phases with changes in the other metabolic values (P less than 0.05).


Modification of a phospholipid stabilized emulsion interface by bile salt: effect on pancreatic lipase activity.
Lipase is activated by binding to an insoluble emulsified or aggregated substrate. The extent of binding is related to the physicochemical as well as the compositional structure of the interface, the quality of the interface. 'Quality' is as yet undefined but thought to contain contributions from electrostatic interactions, orientation of substrate, and hydration forces. To investigate the electrostatic and compositional factors we have used olive oil-in-water emulsions prepared with phosphatidylcholine and four bile salts of varying hydrophobicities. By measurement of the droplet zeta potential we have monitored semi-quantitatively the incorporation of bile salts within the interface. No correlation was found between droplet surface charge as monitored by the zeta potential and lag phase. The duration of the observed lag phase was found to be inversely related to the degree of incorporation of the bile salts. Simultaneously there was evidence of lipase binding to monomeric bile salts, reducing its availability for adsorption. Calcium ions reduced the surface charge but there was no correlation with lag phase duration. The evidence presented here agrees with a more specific role for calcium ions, i.e., the formation of a new catalytically active enzyme complex, (enzyme)-(mixed micelle)-(calcium ion).


Effect of disodiumcromoglycate on intestinal permeability changes and clinical response during cow's milk challenge.
Oral disodiumcromoglycate (DSCG) has been used for many years in the prevention of food allergic reactions. The reported effectiveness varies widely and little is known about the mode of action. The aim of this study was to evaluate the effect of DSCG pretreatment (2 x 100 mg) on intestinal permeability (IP), as measured with a sugar absorption test (SAT), in relation to the clinical response during food challenge in 30 children suspected of cow's milk allergy. In the SAT the urinary Lactulose/Mannitol (L/M) ratio was measured after oral administration of these compounds. DSCG pretreatment did not alter the number of clinically positive challenges. Children with clinically positive challenges showed a significant increase in the L/M ratio with placebo pretreatment as compared to children with clinically negative challenges (p = 0.0008). This difference was reduced to nonsignificant levels after DSCG pretreatment (p = 0.07). We conclude that DSCG in this dosage probably reduces the local intestinal response but does not prevent the extraintestinal reactions.


Does the use of personal electronic health records increase vaccine uptake? A systematic review.
Although Personal Electronic Health Records (PEHR) have been identified as innovative tools enabling the provision of patient-centered care and prevention, evidence on the impact of their use is scant. With PEHRs being more and more marketed as easily implementable and cost-effective instruments to provide people with direct control on their health, the question on whether their use might be associated with the priority to improve vaccine coverage arises. We conducted a systematic review following the PRISMA guidelines to retrieve, quantitatively pool and critically appraise the effectiveness of PEHR access on vaccine uptake. Analysis on PEHR effectiveness were carried out for the following comparison strata: i) PEHR access vs no intervention (standard care, no access to PEHR), ii) PEHR access only vs access to PEHR with additional features (e.g. health education materials, active reminders). Of 3114 identified citations, 8 studies were included, the majority published in the US and before 2015; 62% were randomized trials, the rest having an observational study design. Evidence suggests a moderate positive impact of PEHR access in increasing vaccine uptake, with data available for influenza and pneumococcal vaccines, diabetic patients and childhood immunization. Pooled data report the addition of digital communication features, i.e. the delivery of educational messages, reminders and availability of scheduling features might increase vaccine uptake, as compared to PEHR access alone. However, evidence is not conclusive. While immunization programs are struggling to achieve optimal coverage targets, it seems the potential of PEHRSs supporting informed adherence to vaccines recommendations is neither fully exploited nor explored. Which factors mediate the association between PEHRs access and vaccine uptake? Which PEHRs' design and functional components can maximize their impact? On which target populations? Which PEHR models works better for high-risk populations? Our findings can only partially answer those questions and further experimental research is needed.


Walleye dermal sarcoma virus reverse transcriptase is temperature sensitive.
Walleye dermal sarcoma virus (WDSV) is a piscine retrovirus that replicates naturally in fish at temperatures near 4 degrees C. The reverse transcriptase (RT) protein from virus particles isolated from walleye tumours was purified and biochemically characterized. Like the RT of the distantly related murine leukaemia virus, WDSV RT sediments as a monomer in the absence of template. It exhibits a K(m) of 22 microM for TTP in an assay with poly(rA) as a template and oligo(dT) as a primer. The enzyme is rapidly inactivated at temperatures greater than 15 degrees C. The ratio of RT activity at 15 degrees C to that at 4 degrees C is similar for WDSV and recombinant human immunodeficiency virus type 1, suggesting that, at least with this template, the fish enzyme is not specially adapted to function more efficiently in the cold.


Patterns of Eye Movement Impairment Correlate with Regional Brain Atrophy in Neurodegenerative Parkinsonism.
One common feature of neurodegenerative parkinsonism including Parkinson's disease (PD), multisystem atrophy (MSA), and progressive supranuclear palsy (PSP) is altered eye movement control. Characteristic regional structural atrophy patterns in MRI can be observed in PD, MSA, and PSP. To investigate the association between eye movement disturbances and regional brain atrophy in patients with PD, MSA, and PSP. High-resolution 3-dimensional T1-weighted MRI images and video-oculographic recordings (EyeLink®) were obtained from 39 PD, 32 PSP, and 18 MSA patients and 24 matched healthy control subjects. Automatic regional volumetric assessment was performed using atlas-based volumetry (ABV). The prevalence of saccadic intrusions as a measure of inhibitory control was significantly increased in PD patients compared to controls (p < 0.001) and negatively correlated with whole brain volume, cerebral brain volume, and occipital lobe volume (p = 0.0057, p = 0.0049, and p = 0.0059, respectively; all p values are false discovery rate corrected). In MSA, smooth pursuit was disturbed by characteristic "catch-up" saccades (p < 0.001) and it was significantly correlated with cerebellar volume (p = 0.004) and pontine volume (p < 0.001). The hallmark of PSP was pathologically slowed vertical peak eye velocities (p < 0.001); the lower the peak eye velocity, the more marked midbrain atrophy (p = 0.007). Foci of regional atrophy correlated with disease-specific eye movement alterations in all investigated parkinsonian syndromes. Oculomotor impairment in PD, predominantly the result of executive dysfunction, was linked to cerebral atrophy. Impairment in the corresponding oculomotor pathways was associated with atrophy of pontocerebellar oculomotor structures in MSA and midbrain atrophy in PSP.


The enigmatic function of chandelier cells.
Chandelier (or axo-axonic) cells are one of the most distinctive GABAergic interneurons in the brain. Their exquisite target specificity for the axon initial segment of pyramidal neurons, together with their GABAergic nature, long suggested the possibility that they provide the ultimate inhibitory control of pyramidal neuron output. Recent findings indicate that their function may be more complicated, and perhaps more interesting, than initially believed. Here we review these recent developments and their implications. We focus in particular on whether chandelier cells may provide a depolarizing, excitatory effect on pyramidal neuron output, in addition to a powerful inhibition.


Mode of delivery and peripartum outcome in women with heart disease according to the ESC guidelines: an Italian multicenter study.
The European Society of Cardiology (ESC) guidelines (GL) provide indications on the mode of delivery in women with heart disease. However available data suggests that the rate of Cesarean Delivery (CD) is high and widely variable among such patients. In this study, we aimed to investigate the degree of adherence to the ESC recommendations among women delivering in four tertiary maternity services in Italy and how this affects the maternal and neonatal outcomes. Retrospective multicenter cohort study including pregnant women with heart disease who gave birth between January 2014 and July 2020. Composite adverse maternal outcome (CAM) was defined by the occurrence of one or more of the following: major postpartum hemorrhage, thrombo-embolic or ischemic event, de novo arrhythmia, heart failure, endocarditis, aortic dissection, need for re-surgery, sepsis, maternal death. Composite Adverse Neonatal outcome (CAN) was defined as cord arterial pH <7.00, APGAR <7 at 5 min, admission to the intensive care unit, and neonatal death. We compared the incidence of CAM and CAN between the cases with planned delivery in accordance (group "ESC consistent") or in disagreement (group "ESC not consistent") with the ESC GL. Overall, 175 women and 181 liveborn were included. A higher frequency of CAN was found when delivery was not planned accordingly to the ESC guidelines [("ESC consistent" 9/124 (7.2%) vs "ESC not consistent" 13/57 (22.8%) p = 0.002 OR 3.74 (CI 95% 1.49-9.74) , while the occurrence of CAM was comparable between the two groups. At logistic regression analysis, the gestational age at delivery was the only parameter independently associated with the occurrence of CAN (p = 0.006). Among pregnant women with heart disease, deviating from the ESC guidelines scheduling cesarean delivery does not seem to improve maternal outcomes and it is associated with worse perinatal outcomes, mainly due to lower gestational age at birth.


Physical fitness of children and adolescents with insulin-dependent diabetes mellitus.
The physical working capacity (PWC170) of 84 children and adolescents with insulin-dependent diabetes mellitus (IDDM) and of 94 non-diabetic subjects was measured by a submaximal progressive exercise test. The age of the diabetic subjects ranged from 6.3 to 18.8 years and that of the control subjects from 8.5 to 18.8 years. The PWC170 of diabetic boys was lower than that of non-diabetic boys (p less than 0.01) while no difference was observed between diabetic and non-diabetic girls. PWC170 was inversely related to age (p less than 0.01) and concentration of hemoglobin A1 (p less than 0.025) in diabetic boys but not in diabetic girls. No relationship was observed between PWC170 and duration of diabetes in either boys or in girls. The results indicate that good physical fitness in boys is associated with a better metabolic control. Hence the study indirectly supports previous observations that physical activity improves the metabolic control of IDDM.


Arginase enzymes in isolated airways from normal and nitric oxide synthase 2-knockout mice exposed to ovalbumin.
Arginase has been suggested to compete with nitric oxide synthase (NOS) for their common substrate, l-arginine. To study the mechanisms underlying this interaction, we compared arginase expression in isolated airways and the consequences of inhibiting arginase activity in vivo with NO production, lung inflammation, and lung function in both C57BL/6 and NOS2 knockout mice undergoing ovalbumin-induced airway inflammation, a mouse model of asthma. Arginases I and II were measured by western blot in isolated airways from sensitized C57BL/6 mice exposed to ovalbumin aerosol. Physiological and biochemical responses - inflammation, lung compliance, airway hyperreactivity, exhaled NO concentration, arginine concentration - were compared with the responses of NOS2 knockout mice. NOS2 knockout mice had increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity. Both arginase I and arginase II were constitutively expressed in the airways of normal C57BL/6 mice. Arginase I was up-regulated approximately 8-fold in the airways of C57BL/6 mice exposed to ovalbumin. Expression of both arginase isoforms were significantly upregulated in NOS2 knockout mice exposed to ovalbumin, with about 40- and 4-fold increases in arginases I and II, respectively. Arginine concentration in isolated airways was not significantly different in any of the groups studied. Inhibition of arginase by systemic treatment of C57BL/6 mice with a competitive inhibitor, Nomega-hydroxy-nor-l-arginine (nor-NOHA), significantly decreased the lung inflammatory response to ovalbumin in these animals. We conclude that NOS2 knockout mice are more sensitive to ovalbumin-induced airway inflammation and its sequelae than are C57BL/6 mice, as determined by increased total cells in lung lavage, decreased lung compliance, and increased airway hyperreactivity, and that these findings are strongly correlated with increased expression of both arginase isoforms in the airways of the NOS2 knockout mice exposed to ovalbumin.


[Comparative study of the oral administration of flunitrazepam with oral pentobarbital and intramuscular administration of atropine and pethidine (meperidine) as premedication].
Thirty-four patients were allocated at random to treatment with 1 mg of flunitrazepam, orally, the night before operation, and 1 mg on the morning of operation (Group 1), and another 34 to treatment with 100 mg of pentobarbital, orally, the night before operation, followed by intramuscular atropine (0.01 mg/kg)+pethidine (meperidine 1 mg/kg) on the morning of operation (Group 2). The patients in both groups slept equally well. As far as apprehension and excitement (= anxiolytic effect) just before induction of anaesthesia were concerned, oral flunitrazepam proved to be markedly better than i.m. atropine+pethidine. There were no significant differences in cardiovascular variables between the two groups. From the anaesthesiologist's point of view, atropine had beneficial antisecretory effects, but, from the patients point of view, it caused only a subjective unwanted effect (dry mouth). In our opinion, oral flunitrazepam is a useful alternative agent for routine premedication. However, when used without i.m. atropine, excessive salivary secretion in some patients may occur and be disturbing, especially during extubation.


The functional significance of dental and mandibular reduction in Homo: A catarrhine perspective.
The reduction in dental size and mandibular robusticity is regarded as a major trend in human evolution, traditionally considered the result of the peculiar extra-oral food processing skills of Homo. The use of stone tools and fire would have allowed our ancestors to chew softer food in smaller bite size, thus relaxing the selective pressures to keep a large dentition and a robust lower jaw. This perspective assumes that differences in dental size and mandibular robusticity in hominins represent functional dissimilarities. This study uses a catarrhine comparative approach to test this fundamental assumption of the hypotheses on dental and mandibular reduction in Homo. A sample of extant catarrhines and fossil hominins was used to test for correlations between dental size, mandibular robusticity, and dietary proxies, the latter include diet quality, diet heterogeneity, feeding time, and microwear variables. The effects of phylogeny and body size were considered. Findings support the association between technological developments in Homo and reduction in incisor size and mandibular corpus robusticity, though not for premolar, molar size, and symphyseal robusticity. These results challenge the functional interpretation of postcanine reduction and symphyseal changes in the genus Homo.


[Hypoparathyroidism and pregnancy].
Any unrecognized or ill-controlled hypoparathyroidism, during pregnancy, may result in often severe fetal and neo-natal complications. Maintaining an accurate calcium-phosphorus balance is absolutely necessary to a good pregnancy in a woman with hypoparathyroidism. Alterations of the calcium-phosphorus metabolism, during pregnancy, make it more difficult to treat hypoparathyroidism. The treatment is based, essentially, on an appropriate vitamin D intake, with regular monitoring of the calcemia.


Culture and sun exposure in immigrant East Asian women living in Australia.
In this qualitative study, researchers examined cultural and attitudinal factors that might be related to sun-exposure behaviors among East Asian women living in Australia. Researchers asked Chinese (n = 20) and Korean (n = 16) immigrant women who participated in a larger cross-sectional quantitative study of vitamin D blood levels to volunteer to participate in an in-depth interview in 2010. These women reported a number of cultural factors related to their attitudes and behaviors with regard to sun exposure. They expressed preference for fair skin, a tradition of covering skin when outdoors, and no sunbathing culture. They believed that fair skin was more beautiful than tanned skin. They reported that beauty was the reason for active avoidance of sunlight exposure. Although they reported knowledge of the need for sun avoidance due to skin cancer risk, few reported knowledge about the benefits of sun exposure for adequate vitamin D levels. These findings may provide some reasons for vitamin D deficiency previously reported in these populations. Thus, researchers recommend that these attitudes of excessive sun protection and limiting sun exposure be further investigated as they may have implications for planning and delivery of health promotion programs to this growing population of immigrants in Australia.


Efficacy and safety of tadalafil in a pediatric population with pulmonary arterial hypertension: phase 3 randomized, double-blind placebo-controlled study.
This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient's current endothelin receptor antagonist therapy) study included pediatric patients aged <18 years with pulmonary arterial hypertension. Patients received tadalafil 20 mg or 40 mg based on their weight (heavy-weight: ≥40 kg; middle-weight: ≥25 to <40 kg) or placebo orally once daily for 24 weeks. Primary endpoint was change from baseline in six-minute walk distance in patients aged ≥6 years at Week 24. Sample size was amended from 134 to ≥34 patients, due to serious recruitment challenges. Therefore, statistical significance testing was not performed between treatment groups. Results showed that patient demographics and baseline characteristics (N = 35; tadalafil = 17; placebo = 18) were comparable between treatment groups; median age was 14.2 years (6.2-17.9 years) and majority (71.4%, n = 25) of patients were in the heavy-weight cohort. Least square mean (standard error) changes from baseline in six-minute walk distance at Week 24 was numerically greater with tadalafil versus placebo (60.48 (20.41) vs 36.60 (20.78) meters; placebo-adjusted mean difference (standard deviation) 23.88 (29.11)). Safety of tadalafil treatment was as expected without any new safety concerns. During study Period 1, two patients (one in each group) discontinued due to investigator's reported clinical worsening, and no deaths were reported. In conclusion, the statistical significance testing was not performed between the treatment groups due to low sample size; however, the study results show positive trend in improvement in non-invasive measurements, commonly utilized by clinicians to evaluate the disease status for children with pulmonary arterial hypertension. Safety of tadalafil treatment was as expected without any new safety signals.


Vascular and cardiac autonomic function and PM2.5 constituents among the elderly: A longitudinal study.
Although epidemiologic studies have shown an association between the total mass of particulate matter <2.5μm in aerodynamic diameter (PM2.5) and cardiovascular disease, few studies have examined PM2.5 constituents associated with vascular and cardiac autonomic dysfunction. In this longitudinal study, we investigated the relationship between PM2.5 constituents and blood pressure (BP), and markers of the autonomic nervous system. In 466 elderly subjects residing in communities in Seoul, Korea, we examined 16 constituents, seven sources, and total mass concentrations of PM2.5. We measured the BP, heart rate (HR), and indices of heart rate variability (HRV), such as the standard deviation of normal-to-normal intervals (SDNN), square root of the mean squared differences of successive NN intervals (rMSSD), and two frequency-domain variables (low frequency [LF] and high frequency [HF]). We used linear mixed effects models to assess the association of PM2.5 constituents and sources with cardiovascular markers. BP, HR, and rMSSD were associated with concentration of total mass of PM2.5. For each increase of the interquartile range in PM2.5 constituents, systolic and diastolic BP, and HR increased by 2.1-3.3mmHg, 1.2-2.3mmHg, and 1.2-1.9bpm, respectively, while the rMSSD, LF, and HF decreased by 8.1-9.3%, 16.6%, and 20.4%, respectively. Particularly, elemental carbon, sulfate, ammonium, lead, and strontium in the PM2.5 constituents and emissions from oil combustion and incineration were associated with increased BP, HR, and decreased HRV. Our results suggest an association between specific PM2.5 constituents and vascular and cardiac autonomic functions. These findings may provide supportive evidence for developing a pollution reduction plan to prevent cardiovascular diseases.


3D navigation in surgery of Eagle syndrome.
Eagle's syndrome is a rare condition caused by the elongation of the styloid process (> 4 cm) or calcification of the stylohyoid ligament. Patients with Eagle's syndrome typically present various clinical symptoms, such as headache, facial pain, neck pain, pulsating pain, sore throat, foreign body sensation, dysphagia, dysphonia, cough, voice changes, otalgia or vertigo. 3D printing refers to processes in which successive layers of material are formed from 3D computer tomography data to synthesize a three-dimensional object. This new diagnostic technique of rapid prototyping technology led to innovative new applications in biomedicine. The primary goal for this case study was to find out, whether the nowadays so popular 3D technology aids in the treatment of the Eagle syndrome or other similar craniofacial abnormalities during the surgical procedure. We report a case of a patient who initially presented a combination of symptoms like headache, sore throat, neck pain, which exacerbated with the movement of the head. This case report provides a brief review of the diagnosis and surgical management of the Eagle's syndrome with the help of 3D model navigation. Eagle's syndrome is difficult to diagnose due to its wide variability in symptoms. The inherent accuracy and other properties of 3D printing have allowed it to have exciting applications in anatomy education and surgery, with great benefit to the maxillofacial surgery. With the assistance of 3D technology, it is much easier for the surgeon to plan the surgical approach and the surgery, and significantly reduce the operation time (Fig. 3, Ref. 22).


Lipid Internal Dynamics Probed in Nanodiscs.
Nanodiscs offer a very promising tool to incorporate membrane proteins into native-like lipid bilayers and an alternative to liposomes to maintain protein functions and protein-lipid interactions in a soluble nanoscale object. The activity of the incorporated membrane protein appears to be correlated to its dynamics in the lipid bilayer and by protein-lipid interactions. These two parameters depend on the lipid internal dynamics surrounded by the lipid-encircling discoidal scaffold protein that might differ from more unrestricted lipid bilayers observed in vesicles or cellular extracts. A solid-state NMR spectroscopy investigation of lipid internal dynamics and thermotropism in nanodiscs is reported. The gel-to-fluid phase transition is almost abolished for nanodiscs, which maintain lipid fluid properties for a large temperature range. The addition of cholesterol allows fine-tuning of the internal bilayer dynamics by increasing chain ordering. Increased site-specific order parameters along the acyl chain reflect a higher internal ordering in nanodiscs compared with liposomes at room temperature; this is induced by the scaffold protein, which restricts lipid diffusion in the nanodisc area.


Functional MRI-specific alterations in frontoparietal network in mild cognitive impairment: an ALE meta-analysis.
Mild cognitive impairment (MCI) depicts a transitory phase between healthy elderly and the onset of Alzheimer's disease (AD) with worsening cognitive impairment. Some functional MRI (fMRI) research indicated that the frontoparietal network (FPN) could be an essential part of the pathophysiological mechanism of MCI. However, damaged FPN regions were not consistently reported, especially their interactions with other brain networks. We assessed the fMRI-specific anomalies of the FPN in MCI by analyzing brain regions with functional alterations. PubMed, Embase, and Web of Science were searched to screen neuroimaging studies exploring brain function alterations in the FPN in MCI using fMRI-related indexes, including the amplitude of low-frequency fluctuation, regional homogeneity, and functional connectivity. We integrated distinctive coordinates by activating likelihood estimation, visualizing abnormal functional regions, and concluding functional alterations of the FPN. We selected 29 studies and found specific changes in some brain regions of the FPN. These included the bilateral dorsolateral prefrontal cortex, insula, precuneus cortex, anterior cingulate cortex, inferior parietal lobule, middle temporal gyrus, superior frontal gyrus, and parahippocampal gyrus. Any abnormal alterations in these regions depicted interactions between the FPN and other networks. The study demonstrates specific fMRI neuroimaging alterations in brain regions of the FPN in MCI patients. This could provide a new perspective on identifying early-stage patients with targeted treatment programs. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432042, identifier: CRD42023432042.


Clinical Management of COVID-19 Patients - An Update.
SARS-CoV-2 virus may cause COVID-19 disease, which causes mild-to-moderate disease in 80% of laboratory-confirmed cases which may be community-managed. A considerable age-dependent mortality is seen among elderly and other at-risk populations but among young and healthy individuals it is < 0.5%. Long-term health issues have been reported following severe COVID-19 requiring hospitalization as well as after cases of mild COVID-19 without hospitalization. Upon receiving COVID-19 suspected patients at hospitals, patients should be isolated and PPE should be worn by all health staff when in contact with the patients. Additionally, patients are tested for the presence of SARS-CoV-2 RNA by PCR, and blood samples are drawn. Imaging is not pivotal for the diagnosis, but chest X-ray is a relevant examination for all and is used to determine severity and treatment need Abnormal findings on CT scans are found in most patients, most frequently peripheral ground-glass opacity and bilateral patchy shadowing are present. Patients are, according to their needs and risks, treated with oxygen therapy, anticoagulation therapy, steroids, antivirals, or immunosupressive drugs on special indications. Convalescent plasma therapy and monoclonal antibodies have a limited role in the treatment, mostly in severely immunocompromised patients. Patients with long-term sequelae should be evaluated in a post-COVID outpatient clinic. The most frequent reported symptoms include cognitive impairment, dyspnea, loss of smell and taste, and mental and physical fatigue although a wide spectrum of symptoms from other organ systems are also reported. The current treatment is based on symptom relief and rehabilitation as there is no documented specific medical treatment.


Circular RNAs: diversity of form and function.
It is now clear that there is a diversity of circular RNAs in biological systems. Circular RNAs can be produced by the direct ligation of 5' and 3' ends of linear RNAs, as intermediates in RNA processing reactions, or by "backsplicing," wherein a downstream 5' splice site (splice donor) is joined to an upstream 3' splice site (splice acceptor). Circular RNAs have unique properties including the potential for rolling circle amplification of RNA, the ability to rearrange the order of genomic information, protection from exonucleases, and constraints on RNA folding. Circular RNAs can function as templates for viroid and viral replication, as intermediates in RNA processing reactions, as regulators of transcription in cis, as snoRNAs, and as miRNA sponges. Herein, we review the breadth of circular RNAs, their biogenesis and metabolism, and their known and anticipated functions.


Survival of Human Neurofibroma in Immunodeficient Mice and Initial Results of Therapy With Pirfenidone.
Neurofibromatosis type I is a common tumor predisposing disease in humans. Surgical therapy can be applied only in selected patients with resectable masses. Hence, development of new therapies for this disease is urgent. We used human neurofibroma implants in mice with severe combined immunodeficiency (SCID) as a model to test the toxicity and potential efficacy of pirfenidone, a new therapeutic agent. Two hundred twelve human neurofibromas were transplanted into various locations in 59 experimental animals, and 30 mice with implants received oral pirfenidone for up to six weeks. Survival of neurofibromas in animals treated with pirfenidone was lower than in the control group $(P=.02)$. Tumors did not change histologic appearance or vascularization in response to pirfenidone. Treatment with pirfenidone, a new antifibrotic agent, inhibits survival of some tumors without causing toxicity in animals.


Impact of the aqueous extract of Eclipta alba on maternal aggression in rats.
Parturient females display impulsive behavior represented in the form of aggressive bouts when exposed to conspecifics. Prolonged aggression during the postpartum period could affect maternal care. Eclipta alba is traditionally known to induce neuropsychiatric alterations, however its ability to circumvent maternal aggression has not been elucidated. The present study was aimed to investigate the ability of the aqueous extract of Eclipta alba to suppress maternal aggression. In the single dose study, 100, 200 and 500 mg/kg body weight of the aqueous extract of Eclipta alba was administered to parturient females 30 minutes prior to maternal aggression testing against intruder males. In the multiple dose study, 100, 200 and 500 mg/kg of the extract were administered for 15 and 30 days and maternal aggression was quantified. Administration of the extract for 15 and 30 days in dose schedules of 200 and 500 mg/kg body weight significantly suppressed agonistic encounters by the dams and therefore had beneficial anti-aggressive activity.


The persistence of Shigella flexneri in the United States: increasing role of adult males.
The annual reported isolation rate of Shigella flexneri decreased from 1964 to 1973, but has remained constant since then at 1 per 100,000. Between 1975 and 1985, the median age of males from whom S. flexneri was isolated rose from 5 to 26 years. During this time, the isolation rate of S. flexneri rose more than five-fold among men, did not change in adult women, and decreased in children. By 1985, 23 per cent of reported S. flexneri isolates came from men aged 20-49. Increased male homosexual transmission of S. flexneri is a possible explanation for these findings.


Development of a chemical ionization ion trap mass spectrometric method for trace level determination of molecular halogens.
An ion trap mass spectrometric technique using negative ion chemical ionization has been developed for the quantitative determination of the molecular halogen species Br(2), Cl(2), and BrCl. The technique utilizes NO(2)(-) as a chemical ionization reagent in an electron-transfer reaction to form the corresponding molecular anions of the halogen species, lending excellent selectivity to the measurement. Reaction rate experiments performed in the ion trap yield a rate constant for Br(2) + NO(2)(-) --> Br(2)(-) + NO(2) of (1.4 +/- 0.6) x 10(-)(9) cm(3) molecule(-)(1) s(-)(1), determined relative to published data for Cl(2) + NO(2)(-) --> Cl(2)(-) + NO(2). This paper describes a mass spectrometer pinhole inlet design and cryogenic preconcentration system for detection of the molecular halogens at atmospherically relevant concentrations. Linear calibration curves were obtained for Cl(2) and Br(2) over 3 orders of magnitude and indicate limits of detection of 50 and 8 pmol for 3.8- and 5.1-L samples, respectively, corresponding to 220 and 50 parts per trillion (mole/mole). Quantitation is based on the total signal at m/z values of 70, 72, and 74 for Cl(2) and 158, 160, and 162 for Br(2). The effects of water vapor on the cryogenic preconcentration step are quantitatively assessed.