Determinants of temporal and areal variation in infant mortality in Germany, 1871-1933.
This article investigates how sociodemographic, economic, medical, and public health factors influence infant mortality by using data about German administrative areas from 1871 to 1933. Marital fertility has the largest impact on infant mortality, followed by illegitimacy, medical care, urbanization, and infant welfare centers. The variables considered here account for most of the variation in infant mortality. Some of the unexplained variance is due to factors associated with regions, such as breastfeeding patterns, and with time periods, such as national health insurance. The analyses found no evidence that advances in medical technology affected infant mortality or that the influence of economic development changed over time.


DNA methylation-based biomarkers in serum of patients with breast cancer.
Alterations of genetic and epigenetic features can provide important insights into the natural history of breast cancer. Although DNA methylation analysis is a rapidly developing field, a reproducible epigenetic blood-based assay for diagnosis and follow-up of breast cancer has yet to be successfully developed into a routine clinical test. The aim of this study was to review multiple serum DNA methylation assays and to highlight the value of those novel biomarkers in diagnosis, prognosis and prediction of therapeutic outcome. Serum is readily accessible for molecular diagnosis in all individuals from a peripheral blood sample. The list of hypermethylated genes in breast cancer is heterogeneous and no single gene is methylated in all breast cancer types. There is increasing evidence that a panel of epigenetic markers is essential to achieve a higher sensitivity and specificity in breast cancer detection. However, the reported percentages of methylation are highly variable, which can be partly explained by the different sensitivities and the different intra-/inter-assay coefficients of variability of the analysis methods. Moreover, there is a striking lack of receiver operating characteristic (ROC) curves of the proposed biomarkers. Another point of criticism is the fact that 'normal' patterns of DNA methylation of some tumor suppressor and other cancer-related genes are influenced by several factors and are often poorly characterized. A relatively frequent methylation of those genes has been observed in high-risk asymptomatic women. Finally, there is a call for larger prospective cohort studies to determine methylation patterns during treatment and follow-up. Identification of patterns specific for a differential response to therapeutic interventions should be useful. Only in this way, it will be possible to evaluate the predictive and prognostic characteristics of those novel promising biomarkers.


Birth trauma: incidence and predisposing factors.
The authors retrospectively studied 13,870 singleton full-term consecutive live births at a major teaching hospital and assessed the frequency of brachial plexus injury, clavicular fracture, and facial nerve injury in newborns delivered from January 1974 through December 1977 and from January 1979 through September 1981. Predisposing factors relating to mechanical birth trauma were defined, and a risk assessment profile was developed to identify the fetus at risk. Mechanical injuries were identified according to the International Classification of Diseases codes 761. The incidence of selected birth injuries in the study group were: brachial plexus injury, 2.6 per 1000 or 1 in 385 single full-term live births; fractured clavicle, 2.0 per 1000 or 1 in 495 single full-term live births; and facial nerve injury, 7.5 per 1000 or 1 in 133 single full-term live births. There were 162 full-term infants born with 168 injuries relevant to this study. Of the six infants who incurred more than one injury, three had a combined fractured clavicle-brachial plexus injury, and three had facial nerve-branchial plexus injuries. Logistic regression analysis of fetal, maternal, and intrapartum complications in labor and delivery revealed that midforceps , shoulder dystocia, low forceps, infants greater than 3500 g, and second stage labor exceeding 60 minutes were the predominant events associated with fetal injury. The authors then applied a risk assessment profile to successfully identify over 50% of the injured and 84% of the uninjured groups. From their results, the authors suggest that obstetricians should alert the pediatricians when these predisposing factors exist to aid in the recognition and early treatment of these birth injuries.


Metagenomes Reveal Global Distribution of Bacterial Steroid Catabolism in Natural, Engineered, and Host Environments.
Steroids are abundant growth substrates for bacteria in natural, engineered, and host-associated environments. This study analyzed the distribution of the aerobic 9,10-seco steroid degradation pathway in 346 publically available metagenomes from diverse environments. Our results show that steroid-degrading bacteria are globally distributed and prevalent in particular environments, such as wastewater treatment plants, soil, plant rhizospheres, and the marine environment, including marine sponges. Genomic signature-based sequence binning recovered 45 metagenome-assembled genomes containing a majority of 9,10-seco pathway genes. Only Actinobacteria and Proteobacteria were identified as steroid degraders, but we identified several alpha- and gammaproteobacterial lineages not previously known to degrade steroids. Actino- and proteobacterial steroid degraders coexisted in wastewater, while soil and rhizosphere samples contained mostly actinobacterial ones. Actinobacterial steroid degraders were found in deep ocean samples, while mostly alpha- and gammaproteobacterial ones were found in other marine samples, including sponges. Isolation of steroid-degrading bacteria from sponges confirmed their presence. Phylogenetic analysis of key steroid degradation proteins suggested their biochemical novelty in genomes from sponges and other environments. This study shows that the ecological significance as well as taxonomic and biochemical diversity of bacterial steroid degradation has so far been largely underestimated, especially in the marine environment.IMPORTANCE Microbial steroid degradation is a critical process for biomass decomposition in natural environments, for removal of important pollutants during wastewater treatment, and for pathogenesis of bacteria associated with tuberculosis and other bacteria. To date, microbial steroid degradation was mainly studied in a few model organisms, while the ecological significance of steroid degradation remained largely unexplored. This study provides the first analysis of aerobic steroid degradation in diverse natural, engineered, and host-associated environments via bioinformatic analysis of an extensive metagenome data set. We found that steroid-degrading bacteria are globally distributed and prevalent in wastewater treatment plants, soil, plant rhizospheres, and the marine environment, especially in marine sponges. We show that the ecological significance as well as the taxonomic and biochemical diversity of bacterial steroid degradation has been largely underestimated. This study greatly expands our ecological and evolutionary understanding of microbial steroid degradation.


Hepatoprotective activity of chrysin is mediated through TNF-α in chemically-induced acute liver damage: An in vivo study and molecular modeling.
Chrysin (5,7-dihydroxyflavone) is a naturally occurring flavonoid present at high levels in honey, propolis and numerous plant extracts. Chrysin is known to have hepatoprotective activity, however, the mechanisms by which it exerts this effect remain unclear. In the present study, the effects of chrysin in carbon tetrachloride (CCl4)-induced acute liver damage were investigated and the results used to infer a possible mechanism behind chrysin's hepatoprotective activity. Prior to an intraperitoneal injection of CCl4 (1 ml/kg) to induce acute liver damage, chrysin (50 mg/kg) was administered orally to mice for 7 days. The positive control group was given 50 mg/kg standardized silymarin, a well-studied hepatoprotective flavonoid. Twenty-four h following CCl4 administration, an increase in the activity levels of serum aspartate-amino-transferase and alanine-amino-transferase was found. This was accompanied by extended centrilobular necrosis, steatosis and an altered hepatocyte ultrastructure. In addition, CCl4-induced acute hepatotoxicity was associated with an increase in hepatic tumor necrosis factor-α (TNF-α) and α-smooth muscle actin (α-SMA) protein expression, which was significantly decreased in the livers of mice pre-treated with chrysin (P<0.001), similar to the results of the silymarin pre-treated group (P<0.001). Treatment with chrysin prior to CCl4 exposure significantly reduced the activity of enzymes used as biochemical markers of poor liver function compared with the group which did not receive pre-treatment (P<0.001). In addition, the results of histopathological and electron microscopy liver examination showed chrysin pre-treatment reduced the effects of CCl4 treatment. Molecular modeling results demonstrated that the hepatoprotective activity of chrysin is mediated through TNF-α, as it reduces soluble TNF-α generation via blocking TNF-α-converting enzyme activity. In conclusion, the results of the present study suggest that inflammatory pathways are activated in CCl4-induced acute liver damage, which are ameliorated by chrysin pre-treatment. This indicates that chrysin is a potent hepatoprotective agent, similarly to silymarin at the same dose, which has the potential to be a viable alternative to conventional hepatoprotective treatments.


Cystic Lesions of the Mediastinum.
Cystic lesions are commonly seen in the mediastinum, and they may arise from virtually any organ. The vast majority of these lesions are benign and result in no symptoms. When large, cysts may produce symptoms related to compression of adjacent structures. The most common mediastinal cysts are pericardial and foregut duplication cysts. Both computed tomography and magnetic resonance are routinely used to evaluate these lesions. Although computed tomography offers superior spatial resolution, magnetic resonance is useful in differentiating cysts that contain proteinaceous material from solid lesions. Occasionally, cysts arise from solid lesions, such as thymoma or teratoma. Although cysts are alike in appearance, location helps narrowing the differential diagnoses.


Systemic chemotherapy alters interleukin-1 beta and its receptor antagonist production by human alveolar macrophages in lung cancer patients.
The purpose of this study was to determine whether cytotoxic chemotherapy influences the number and function of alveolar macrophages (AM) in patients with lung cancer. AM were obtained by bronchoalveolar lavage from 24 patients with lung cancer and 17 control patients. The functional integrity of AM was determined by their ability to produce interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1ra) before and after platinum-containing systemic chemotherapy. The productions of IL-1 beta and IL-1ra were quantitated by enzyme immunoassays. The proportions of multinucleated cells among AM were significantly decreased after systemic chemotherapy in lung cancer patients. No significant difference in spontaneous and lipopolysaccharide (LPS)-stimulated IL-1 beta or IL-1ra production by AM was observed between lung cancer patients and control patients. Significant increase of IL-1 beta and significant decrease of IL-1ra production by AM were demonstrated in patients with small cell lung cancer who experienced response to systemic chemotherapy. These results suggest that systemic chemotherapy may influence functional roles of AM in the lung, and consideration of influence of systemic chemotherapy on host functions is important in cancer treatment.


The First National Summit on Women's Health: The Future of Obstetrics and Gynecology Training.
To identify the current challenges in obstetrics and gynecology residency education and propose solutions to overcome these obstacles. The American College of Obstetricians and Gynecologists (ACOG) hosted the first National Summit on Women's Health on May 31 and June 1, 2017, with a follow-up meeting December 20-21, 2017, at ACOG headquarters in Washington, DC. Invitees from 20 related societies briefly presented their organizations' perspectives and discussed focused questions about specific challenges, proposed solutions, and anticipated obstacles. Finally, participants summarized their top two recommendations to improve current residency training. Summit participants identified four primary areas of focus: 1) align curriculum with relevant topics to practice, 2) ensure faculty have the necessary resources and time to teach effectively, 3) consider using the final months of medical school to get a jump start on residency fund of knowledge and skills, and 4) use better assessments during the course of residency. Representatives of the Council on Resident Education in Obstetrics and Gynecology, the American Board of Obstetrics and Gynecology, and the Accreditation Council for Graduate Medical Education must work together to address these priorities and reach consensus on the curricular content of core training in obstetrics and gynecology.


Clostridium perfringens-Escherichia coli shuttle vectors that carry single antibiotic resistance determinants.
Two versatile Clostridium perfringens-Escherichia coli shuttle vectors were constructed. Each plasmid carried a single antibiotic resistance gene which was expressed in both organisms. The plasmid pJIR750 encoded resistance to chloramphenicol and pJIR751 encoded resistance to erythromycin. Each plasmid contained the pUC18-derived multiple cloning site and the lacZ' gene which enabled direct screening for recombinants in E. coli. These plasmids should prove invaluable for the genetic manipulation of C. perfringens.


Repairing Effect and Mechanism of Hydroxysafflor Yellow A and Sodium Hyaluronate for Knee Osteoarthritis in Rabbits.
KOA characterized by recurrent joint pain and progressive joint dysfunction. Is the present clinical common chronic progressive degenerative osteoarthropathy, how long the disease is difficult to cure and easy to relapse. Exploring new therapeutic approaches and mechanisms is important for the treatment of KOA. One of the main applications for sodium hyaluronate (SH) in the medical field is treatment of osteoarthritis. However, the effects of SH alone in the treatment of KOA are limited. Hydroxysafflor yellow A (HSYA) may have therapeutic effects for KOA. The study intended to investigate the therapeutic effects and possible mechanisms of action HSYA+SH for cartilage tissue of rabbits with KOA and to provide a theoretical basis for the treatment of KOA. The research team performed an animal study. The study that took place at Liaoning Jijia Biotechnology, Shenyang, Liaoning, China. The animals were 30 healthy, adult, New Zealand white rabbits, weighing 2-3 kg. The research team randomly divided the rabbits into three groups, with 10 rabbits in each group: (1) a control group, for which the research team didn't induce KOA and provided no treatment; (2) the HSYA+SH group, the intervention group, for which the research team induced KOA and injected the rabbits with the HSYA+SH treatment; and (3) the KOA group, for which the research team induced KOA and injected the rabbits with saline. The research team: (1) observed the morphological changes in the cartilage tissue using hematoxylin-eosin (HE) staining; (2) measured levels of serum inflammatory factors, including tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interferon gamma (IFN-γ), IL-6, and IL-17 using an enzyme-linked immunosorbent assay (ELISA); (3) measured cartilage-cell apoptosis using "terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling" (TUNEL); and (4) used Western Blot to detect the expression of proteins related to the "neurogenic locus notch homolog protein 1" (Notch1) signaling pathway. Compared with the control group, morphological changes had occurred to the cartilage tissue in the KOA group. Compared with the control group, that group's level of apoptosis was higher, the levels of serum inflammatory factors were significantly higher (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly higher (P < .05). The morphology of the cartilage tissue in the HSYA+SH was better than that of the KOA group but not as good as that of the control group. Compared with the KOA group, the HSYA+SH group's level of apoptosis was lower, the levels of serum inflammatory factors were significantly lower (P < .05), and the protein expression related to the Notch1 signaling pathway was also significantly lower (P < .05). HSYA+SH can reduce the cellular apoptosis in the cartilage tissue of rabbits with KOA, downregulate the levels of inflammatory factors, and protect against KOA-induced cartilage tissue injury, and the mechanism may be related to the regulation of the Notch1 signaling pathway.


Polydopamine film coated controlled-release multielement compound fertilizer based on mussel-inspired chemistry.
This work reports on a facile and reliable method to prepare a polydopamine film coated controlled-release multielement compound fertilizer (PCMCF) based on mussel-inspired chemistry for the first time. The polydopamine (Pdop) film was coated on double copper potassium pyrophosphate trihydrate, providing three essential nutrients (Cu, K, and P) by spontaneous oxidative polymerization of dopamine. The thickness of the polymer coating of the fertilizer was controlled by using the multistep deposition technique. The morphology and composition of the products were characterized by transmission electron microscopy, inductively coupled plasma emission spectrometer, a vis spectrophotometer, and a Kjeltec autoanalyzer. The controlled-release behavior of four elements, including nitrogen from Pdop, was evaluated in water and in soil (sterilized or not). The results revealed that the coated fertilizers had good slow-release properties, incubated in either water or soil. It is noted that the release rate of nutrients of PCMCF can be tailored by the thickness of the Pdop coating, and the Pdop coating can be biodegraded in soil. This coating technology will be effective and promising in the research and development of controlled-release fertilizer.


Pyrene-POSS nanohybrid as a dispersant for carbon nanotubes in solvents of various polarities: its synthesis and application in the preparation of a composite membrane.
In this study we report the preparation of nanohybrid dispersant molecules based on pyrene and polyhedral oligomeric silsesquioxanes for non-covalent functionalization of multi-walled carbon nanotubes (MWCNTs). The prepared dispersant improves the dispersion of MWCNTs in organic solvents with very different polarities such as tetrahydrofuran, toluene, and n-hexane. The functionalized MWCNTs were used to introduce conductivity into polydimethylsiloxane membranes which can be used for electrostatic discharge applications.


ATTACKS ON LINKING OR A DRIVE TO COMMUNICATE? TOLERATING THE PARADOX.
The notion of attacks on linking, as described by Bion, may depict a patient's drive to communicate the internalization of a destructive relationship between a primary object and an infant. This may be enacted between patient and analyst in the here and now of the analysis, whereby fragmentation and numbing of thinking may point to a primitive catastrophe relived in the psychoanalytic setting. The patient's material may seem incoherent, but incoherence might be the communication the patient is unconsciously trying to convey. Thus, the notion of attacks on linking depicts a paradoxical, caesural experience in which the attack on linking is itself a link.


Size-dependent crystalline fluctuation and growth mechanism of bismuth nanoparticles under electron beam irradiation.
Advanced nanofabrication requires accurate tailoring of various nanostructures with the assistance of electron or ion beam irradiation. However, evolution of the nanostructures under the beam irradiation significantly affects the fabrication process. It is thus of paramount importance to study the evolution behaviors and growth mechanism of the nanostructures. In this study, bismuth nanoparticles were selected to investigate crystalline fluctuation under electron beam irradiation via transmission electron microscopy. The results disclose size-dependent crystalline fluctuation of the nanoparticles. The particles exhibit crystalline and non-crystalline features for sizes of above 15 and below 4 nm, respectively, while a mixture of the two states is observed with sizes in between. The crystalline fluctuation facilitates the growth process of the particles when a crystalline particle is in contact with another non-crystalline one. This is promising for applications in nanofabrication where high quality interfaces are desired between two joining parts.


Choroideremia: melanopsin-mediated postillumination pupil relaxation is abnormally slow.
To investigate the rod-cone and melanopsin pupillary light response (PLR) pathways in choroideremia. Eight patients with choroideremia and 18 healthy age-matched controls underwent chromatic pupillometry by applying blue (463 nm) and red light (643 nm) at 100 lux intensity to the right eye while recording pupil diameters. Absolute baseline pupil size (mm), normalized maximal pupil constriction and the early and late postillumination pupillary dilation, from 0 to 10 seconds and 10 to 30 seconds after the end of illumination, respectively, were determined. Postillumination responses to blue light were considered to be primarily driven by melanopsin activation of the intrinsic photosensitive retinal ganglion cells. Baseline pupil diameters were comparable in patients with choroideremia and control subjects (p = 0.48). The maximum pupil constriction in patients with choroideremia was severely weakened in red light but only mildly weakened in blue light (p < 0.05). Postillumination dilation of the pupil was normal after red illumination but extremely protracted after blue illumination. Also, in contrast to healthy subjects, no abrupt change in the dilation curve was seen in the patients after the end of blue illumination, the early-phase dilation being completely abolished (p < 0.01). Rod-cone-driven pupil responses were decreased as expected in an outer retinal degeneration, and near-normal pupil constriction in blue light supports that the melanopsin system is normal. In contrast, the lack of brisk early-phase dilation after blue illumination in choroideremia is remarkable and may be interpreted to mean that the absence of photoreceptor inhibition promotes a tonic contraction of the pupil.


Uncommon clinical manifestations in a case of thyroid carcinoma.
A case of multiple, functional bone metastases from a previously operated follicular thyroid carcinoma is reported in an apparently euthyroid patient. Additional uncommon clinical manifestations encountered in this case were: 1) mandibular metastasis mimicking an intraoral arteriovenous malformation, 2) extensive, destructive, and expansive intraspinal metastases in the thoracic vertebral column protruding into the posterior mediastinum and causing severe spinal lesions, and 3) the precipitation of a fatal thyroid crisis following radioactive iodine treatment.


Sjögren's syndrome in children.
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the lacrimal and salivary glands; it eventually leads to keratoconjunctivitis sicca and xerostomia. The disease usually affects middle-aged women and is second to rheumatoid arthritis as the most commonly diagnosed connective tissue disorder. Surprisingly, only 31 cases have been reported in the pediatric population. The diagnosis should be considered, however, in children with a foreign body sensation in the eyes, chronic dryness of the eyes or mouth, or recurrent salivary gland enlargement. This has prompted us to describe our experience in treating five children with SS at Texas Children's Hospital, Houston. One 5-year-old child with no other evidence of connective tissue disease was diagnosed as having primary SS. The remaining four children either had juvenile rheumatoid arthritis or systemic lupus erythematosus in addition to SS, and the diagnosis of secondary SS was made. Other autoimmune disorders associated with SS include polyarteritis nodosa, scleroderma, and polymyositis. Interestingly, one child with secondary SS and chronic lymphocytic thyroiditis developed papillary carcinoma of the thyroid. Both forms of SS are probably more prevalent than the literature would suggest. Recognition of this fact is important if the immediate complications of corneal damage and severe dental decay are to be prevented. Symptomatic treatment with steroids, eyedrops, artificial saliva, and prophylactic fluoride treatments is available. With an adequate follow-up program the late morbidity associated with SS, such as malignant disease, can be minimized.


[The superoxide-scavenging activity of some amino acids in water solutions].
The superoxide-scavenging activity of a number of amino acids was revealed. The activity is comparable in effectiveness with known antioxidants. An original method for the estimation of antioxidant properties of amino acids was proposed. Quantum mechanical calculation of the interaction of lysine with superoxide anion was made. It was assumed that the mechanisms of the biological action of some physical factors, such as weak magnetic fields adjusted to the cyclotron frequency of ions of some amino acids, are associated with the modulation of the antioxidant activity of these molecules.


Operating Room Fires.
Operating room fires are rare but devastating events. Guidelines are available for the prevention and management of surgical fires; however, these recommendations are based on expert opinion and case series. The three components of an operating room fire are present in virtually all surgical procedures: an oxidizer (oxygen, nitrous oxide), an ignition source (i.e., laser, "Bovie"), and a fuel. This review analyzes each fire ingredient to determine the optimal clinical strategy to reduce the risk of fire. Surgical checklists, team training, and the specific management of an operating room fire are also reviewed.


Can we determine depressive conditions on the basis of somatic symptoms? A cross-sectional study of depressive conditions among Japanese patients at a university hospital general medicine clinic.
We evaluated the relationship between somatic symptoms and depressive conditions among patients visiting the general medicine clinic of a university hospital. We distributed interview forms to 332 consecutive patients who visited our clinic for the first time between March and July 2011. Somatic symptoms were rated using a symptom checklist, and depressive conditions were evaluated using the Zung Self-Rating Depression Scale (SDS). We categorized and compared 2 groups of patients: patients with an SDS score of more than 48 (depressive group) and patients with an SDS score of less than 48 (non-depressive group). A total of 284 (85.5%) patients returned the forms. The SDS scores were obtained from the forms of 182 patients (64.1%). The average age of these 182 patients was 46.5±18.04 years. The mean number of checked symptoms was 4.3±3.03, and the most common symptom was general fatigue (n=106; 58.2%). The number of checked symptoms in the survey was higher in the depressive group patients than in the non-depressive group patients. Multiple logistic regression analysis indicated that general fatigue, headache, and sleeping problems were significant dependent variables which were related to depressive conditions. We defined these 3 symptoms as depression-related somatic symptoms (DRSS). On a receiver-operating characteristic curve, the optimal cutoff scores were 2 of 3 DRSS and 4 of 20 somatic symptoms. General physicians should consider possible depressive conditions when patients have 2 or more DRSS or 4 or more somatic symptoms.


Results of long-continued cortisone administration in rheumatoid arthritis.
The administration of cortisone acetate to patients with rheumatoid arthritis usually produces prompt and often dramatic suppression of the disease manifestations. The effects of the hormone are not lasting, however, and after withdrawal relapse ensues. For sustained improvement in a chronic disease such as rheumatoid arthritis, it appears that cortisone must be given more or less continuously. This raises the question whether administration may be continued effectively and safely for long periods.Seventy-six patients with rheumatoid arthritis were given cortisone in the hope that treatment could be continued uninterruptedly for extended periods. For various clinical reasons it was necessary to discontinue treatment in 16 of these before six months, but the remaining 60 patients received the hormone uninterruptedly for six to 15 months. By using initial large suppressive amounts, then gradually reducing the dosage, and finally employing smaller maintenance doses, adequate degrees of rheumatic control were maintained in approximately two-thirds of the original 76 patients. The ability to sustain satisfactory improvement varied indirectly, in general, with the severity of the rheumatoid arthritis. The chief detriment to better results in the more severe cases was the intervention of adverse hormonal side effects which developed frequently when large or relatively large maintenance doses were required to support satisfactory improvement. Unwanted signs of hormonal excess developed in 40 per cent of cases at some time during the course of treatment. Most of them were mild or transient and disappeared or lessened when the dose of cortisone was reduced, but when the dose was reduced the degree of improvement often declined also. During prolonged cortisone therapy evidence of functional suppression of the adrenal cortices, as indicated by a decreased response of circulating eosinophils to exogenous ACTH, was present. The depression of cortical function was temporary, however. Whether irreversible damage may result when the drug is employed for longer periods cannot yet be answered.


Microvascular transplantation after acute myocardial infarction.
The primary objective of this study was to evaluate epicardial transplantation of an intact microvascular network for treatment of myocardial ischemia in a murine model of acute myocardial infarction. We describe transplantation of an intact microvascular network constructed from isolated microvascular segments stabilized in a 3-dimensional matrix to the epicardial surface after acute myocardial infarction. This microvascular graft was implanted as a patch on the epicardium of mice after left coronary artery ligation. After 14 and 28 days of implantation, left ventricular (LV) function was assessed and grafts evaluated via histology and cytochemistry. Inosculation of microvessels within the graft with host coronary microcirculation occurred as early as 7 days after initial tissue grafting. Morphologic evaluation of the grafts revealed arterioles, venules, capillaries, and erythrocytes within vascular lumina. Control grafts of collagen alone remained avascular. LV infarct size was smaller, and LV function improved in treated animals. Engraftment of whole microvascular units can be achieved to support cell-assisted vascular remodeling. Microvascular grafts may provide therapeutic benefit as a primary treatment or serve as a microvascular platform for cardiac repair and regeneration.


The value of stereotactic vacuum assisted breast biopsy in the investigation of microcalcifications. A six-year experience with 853 patients.
Vacuum Assisted Breast Biopsy (VABB) is a minimal invasive technique, in the diagnostic approach for non palpable lesions. The aim of this study was to evaluate the efficacy and accuracy of VABB in the investigation of breast microcalcifications, a significant mammographic sign of early breast cancer. The rate of histological underestimation and the false negative rate were assessed based on the follow up data and the histological examination of the surgical specimens. From January 2005 to November 2011, 853 women with mammographically detected microcalcifications, classified as BI-RADS 3-5, were referred to our Breast Unit for evaluation. During this 6-year period, 825 vacuum-assisted breast biopsies were performed, while 28 women (3.3%) were not submitted to VABB due to superficial location of microcalcifications. VABB histology revealed 594 benign (69.6%), 66 high risk (7.7%) and 164 malignant (19.2%) lesions. Twenty- nine cases were classified as non diagnostic, as in one case (0.1%) the sample of the biopsy was maladjusted and not suitable to undergo histopathological examination due to mechanical alterations and in 28 (3.3%) cases microcalcifications were located in proximity to the skin and open surgical excision was performed. The overall documented underestimation rate was 4.6%, the false negative rate was 2.4%. The sensitivity of the method was 98.2%, specificity 100%, positive predictive value 100% and negative predictive value 97.6%. VABB is a safe and accurate method for the evaluation of suspicious microcalcifications and diagnosis of early breast cancer.


Pre-eruptive movements of the mandibular third molar.
1. It would appear that the developing mandibular third molar is continually changing its angular position relative to the mandibular plane and adjacent teeth. 2. For normal uprighting and eruption to occur growth at the mesial root must dominate. 3. In the absence of sufficient space, uprighting movements of the mandibular third molar may result in mesioangular impaction. 4. Vertical and distoangular impactions can be explained by continued growth at the mesial root while the crown is prevented, at its distal surface, from erupting. 5. If growth at the distal root becomes more influential, severe mesioangular or horizontal impaction may occur.


[Interaction of the Humoral Agonist During the Platelets Activation in Patients with Chronic Cerebral Ischemia].
The aim of the study was to determine the effect of the standard drug therapy of 95 patients with chronic cerebral ischemia (CCI) on the functional status of platelets as possible participants of microcirculation of the brain. Platelets were isolated from peripheral blood by centrifugation and examined at 24 hours after initiation of standard medical therapy including aspirin (100 mg). The cells were stimulated in vitro using adenosine diphosphate (ADP), epinephrine, platelet activating factor (PAF) and serotonin in an effective concentration (EC50) inducing in healthy individuals platelet aggregation in the range of 50 ± 5%. A study of platelet aggregation was carried out on aggregometer Chrono-Log (USA). Research included 95 patients with CCI 1-2 Stage--82 patients taking antiplatelet and antihypertensive drugs before hospitalization (main group), 13--did not receive these drugs during 7 days prior to hospitalization (comparison group). After start conservative treatment, only ADP induced platelet aggregation, which was similar (p > 0.05) with values in healthy individuals. The pharmacological inhibition of the functional activity of platelets other investigated agonists reproduced hyporesponsiveness of platelets. Against this background, in 34 (41.5%) patients at 24 hours after initiation of therapy occurred potentiation effects of PAF and epinephrine in the test in vitro; whereas the summation of the effects of serotonin and epinephrine on platelets was detected in 12 (14.6%) patients. The basis of this phenomenon may be strengthening effect of ADP secreted from dense-granules, additional stimulation by Gi-protein signaling system by epinephrine and Gq-protein by the action of PAF and serotonin. Response to the combined action of platelet agonists may be predictor of the risk of thrombogenesis at CCI.


Vicious circle between progressive right ventricular dilatation and pulmonary regurgitation in patients after tetralogy of Fallot repair? Right heart enlargement promotes flow reversal in the left pulmonary artery.
The left pulmonary artery (LPA) contributes more than the right (RPA) to total pulmonary regurgitation (PR) in patients after tetralogy of Fallot (TOF) repair, but the mechanism of this difference is not well understood. This study aimed to analyze the interplay between heart and lung size, mediastinal geometry, and differential PR. Forty-eight Cardiovascular Magnetic Resonance (CMR) studies in patients after TOF repair were analyzed. In addition to the routine blood flow and ventricular volume quantification cardiac angle between the thoracic anterior-posterior line and the interventricular septum, right and left lung areas as well as right and left hemithorax areas were measured on an axial image. Statistical analysis was performed to compare flow parameters between RPA and LPA and to assess correlation among right ventricular volume, pulmonary blood flow parameters and lung area. There was no difference between LPA and RPA diameters. The LPA showed significantly less total forward flow (2.49 ± 0.87 L/min/m(2) vs 2.86 ± 0.89 L/min/m(2); p = 0.02), smaller net forward flow (1.40 ± 0.51 vs 1.89 ± 0.60 mL/min/m(2); p = <0.001), and greater regurgitant fraction (RF) (34 ± 10 % vs 43 ± 12 %; p = 0.001) than the RPA. There was no difference in regurgitant flow volume between RPA and LPA (p = 0.29). Indexed right ventricular end-diastolic volume (RVEDVi) correlated with LPA RF (R = 0.48, p < 0.001), but not with RPA RF (p = 0.09). Larger RVEDVi correlated with a more leftward cardiac axis (R = 0.46, p < 0.001) and with smaller left lung area (R = -0.58, p < 0.001). LPA RF, but not RPA RF, correlated inversely with left lung area (R = -0.34, p = 0.02). The follow-up CMRs in 20 patients showed a correlation of the rate of RV enlargement with the rates of LPA RF worsening (R = 0.50, p = 0.03), and of increasing left lung compression (R = -0.55, p = 0.012). An enlarged and levorotated heart is associated with left lung compression and impaired flow into the left lung.


Fabrication of a microresonator-fiber assembly maintaining a high-quality factor by CO₂ laser welding.
We demonstrate fabrication of a microtoroid resonator of a high-quality (high-Q) factor using femtosecond laser three-dimensional (3D) micromachining. A fiber taper is reliably assembled to the microtoroid using CO2 laser welding. Specifically, we achieve a high-Q-factor of 2.12 × 10(6) in the microresonator-fiber assembly by optimizing the contact position between the fiber taper and the microtoroid.


Microarray Integrated Analysis of a Gene Network for the CD36 Myocardial Phenotype.
CD36 is a multifunctional membrane-type receptor glycoprotein that reacts with oxidized low-density lipoprotein and long-chain fatty acid (LCFA). However, much remains to be understood about the molecular mechanism of the cardio-myopathy observed in CD36-KO mice. In this study, we identify different genes pathways involved in response to CD36 cardio-myopathy phenotype by identifying the differences among biological processes, molecular pathways and networks of interactions that emerge from knocking CD3 and using different bioinformatics tools such as STRING, GeneMANIA and Cytoscape. We were able list all the CD36-regulated genes, their related function and their specific networks. Data analysis showed that CD36-regulated genes differentially expressed are involved in biological processes such as FA metabolism, angiogenesis/apoptosis and cell structure. These results provide the first look at mechanisms involved in CD36 deficiency and development of cardio-myopathy and the opportunity to identify new therapeutic targets.


Tirzepatide: A Novel Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist for the Treatment of Type 2 Diabetes: The First Twincretin.
Tirzepatide is a dual-action glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GLP-1) receptor agonist and the first drug in a new class known as twincretins. It is similar to GLP-1 receptor agonists but provides a synergistic enhancement of the incretin effect to control blood glucose levels and reduce weight. Across the SURPASS research program trials, tirzepatide lowered A1C by 1.7-2.4% from baseline. The proportion of patients using tirzepatide who achieved an A1C <7% ranged from 91 to 97%. Patients in the treatment groups averaged a weight loss of 5.44-11.34 kg (12-25 lb). Across all trials, patients on tirzepatide 15 mg lost 8.8-12.9 kg (19.4-28.44 lb) or 9.17-13.7% body weight. In the SURMOUNT-1 trial, maximum weight loss was 23.6 kg (52 lb) or 22.5% body weight. Tirzepatide is a potent new weapon in the arsenal against diabetes.


A novel surgery-like strategy for droplet coalescence in microchannels.
We report an innovative and efficient surgery-like strategy for achieving the coalescence of surfactant-stabilized droplets in microchannels. As pairs of preformed droplets flow across a micro-lancet, with a suitable surface wettability, in a converging microchannel simultaneously, their surfaces are scratched by the micro-lancet, which causes temporarily local scattering of surfactants, and thus induces their coalescence by joining up their scratched wounds. Our approach shows highly controllable flexibility and stability. We demonstrate this by controlling the coalescence of emulsion droplets with different numbers and complex structures. This surgery-like strategy is totally passive and has great potential in myriad applications including micro-reaction, high-throughput injection, and multiple emulsion formation, etc.


Ranaviruses Bind Cells from Different Species through Interaction with Heparan Sulfate.
Ranavirus cross-species infections have been documented, but the viral proteins involved in the interaction with cell receptors have not yet been identified. Here, viral cell-binding proteins and their cognate cellular receptors were investigated using two ranaviruses, Andrias davidianus ranavirus (ADRV) and Rana grylio virus (RGV), and two different cell lines, Chinese giant salamander thymus cells (GSTC) and Epithelioma papulosum cyprinid (EPC) cells. The heparan sulfate (HS) analog heparin inhibited plaque formation of ADRV and RGV in the two cell lines by more than 80% at a concentration of 5 μg/mL. In addition, enzymatic removal of cell surface HS by heparinase I markedly reduced plaque formation by both viruses and competition with heparin reduced virus-cell binding. These results indicate that cell surface HS is involved in ADRV and RGV cell binding and infection. Furthermore, recombinant viral envelope proteins ADRV-58L and RGV-53R bound heparin-Sepharose beads implying the potential that cell surface HS is involved in the initial interaction between ranaviruses and susceptible host cells. To our knowledge, this is the first report identifying cell surface HS as ranavirus binding factor and furthers understanding of interactions between ranaviruses and host cells.


[A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954].
A Multi-arm Placebo-controlled Study with Glutamic Acid Conducted in Rostock in 1953/1954 Glutamic acid was commonly used in the treatment of intellectually disabled children in the 50s. Koch reported first results of an observation of 140 children treated with glutamic acid in 1952. In this line is the multi-arm placebo-controlled study reported here. The original study protocols were available. 58 children with speech problems who attending a school of special needs received glutamic acid, or vitamin B, or St.-John's-wort. The effect of glutamic acid was in few cases an improvement of attention. On the other hand restlessness and stutter increased. The majority of all reported a weight loss. The treatment with vitamin B showed a positive effect concerning concentration. The treatment with St.-John's wort was stopped caused by headache and vomiting in eight of nine cases. The results of the study reported here are unpublished. The reason may be that until the 60s the effects of glutamic acid in the treatment of intellectually disabled children were in generally overestimated.


[Cardiovascular risk factors in the elderly patients in primary care].
Aim of the study was to assess cardiovascular risk in the elderly patients during single visit to primary care (PC) offices. The study was performed in 256 units of PC in 2004 and 2005 year. Demographic data, history of diabetes and smoking habit were obtained from patients older than 60 years old, who visited general practitioners. Moreover, blood pressure, pulse, weight and height used to calculate body mass index (BMI), waist circumference and glucose strip tests were performed. Blood pressure levels were classified according to the guidelines, BMI > or = 30 kg/m2 was considered as obesity, waist > or = 88 cm for women and > or = 102 cm for men were criterions of visceral obesity. Passing glucose > 125 mg/dl (6,9 mmol/l) was noted. Mean values and the performance of studied parameters were compared between three age groups: 61-70, 71-80, and > 80 years and reference to gender. 26 801 patients aged between 61 and 102 years were examined, 59.5% were women, 81.9% were hypertensives, more often men. Isolated systolic hypertension (ISH) was diagnosed in 1/4 of subjects, more often in women. Along with age, the frequency of ISH and severe stages of hypertension increased. 39.8% subjects had visceral obesity, more often women (51.8% vs. 21.9%). Frequency of visceral obesity decreased along with age but constantly was significantly greater among women than men. Diabetes and glucose > 125 mg/dl was stated in 26.0% and 26.3%, respectively. Frequency of smokers was 19.3%, more frequent in men (30.9% vs. 11.5%), and decreased with age. Increased cardiovascular risk of primary care elderly patients was mainly connected with high frequency of hypertension, especially ISH in the oldest. Among elderly men additional risk resulted from widespread smoking habit, while among women from high frequency of obesity, especially visceral.


Hyperthermophilic Archaeon Thermococcus kodakarensis Utilizes a Four-Step Pathway for NAD+ Salvage through Nicotinamide Deamination.
Many organisms possess pathways that regenerate NAD+ from its degradation products, and two pathways are known to salvage NAD+ from nicotinamide (Nm). One is a four-step pathway that proceeds through deamination of Nm to nicotinic acid (Na) by Nm deamidase and phosphoribosylation to nicotinic acid mononucleotide (NaMN), followed by adenylylation and amidation. Another is a two-step pathway that does not involve deamination and directly proceeds with the phosphoribosylation of Nm to nicotinamide mononucleotide (NMN), followed by adenylylation. Judging from genome sequence data, the hyperthermophilic archaeon Thermococcus kodakarensis is supposed to utilize the four-step pathway, but the fact that the adenylyltransferase encoded by TK0067 recognizes both NMN and NaMN also raises the possibility of a two-step salvage mechanism. Here, we examined the substrate specificity of the recombinant TK1676 protein, annotated as nicotinic acid phosphoribosyltransferase. The TK1676 protein displayed significant activity toward Na and phosphoribosyl pyrophosphate (PRPP) and only trace activity with Nm and PRPP. We further performed genetic analyses on TK0218 (quinolinic acid phosphoribosyltransferase) and TK1650 (Nm deamidase), involved in de novo biosynthesis and four-step salvage of NAD+, respectively. The ΔTK0218 mutant cells displayed growth defects in a minimal synthetic medium, but growth was fully restored with the addition of Na or Nm. The ΔTK0218 ΔTK1650 mutant cells did not display growth in the minimal medium, and growth was restored with the addition of Na but not Nm. The enzymatic and genetic analyses strongly suggest that NAD+ salvage in T. kodakarensis requires deamination of Nm and proceeds through the four-step pathway.IMPORTANCE Hyperthermophiles must constantly deal with increased degradation rates of their biomolecules due to their high growth temperatures. Here, we identified the pathway that regenerates NAD+ from nicotinamide (Nm) in the hyperthermophilic archaeon Thermococcus kodakarensis The organism utilizes a four-step pathway that initially hydrolyzes the amide bond of Nm to generate nicotinic acid (Na), followed by phosphoribosylation, adenylylation, and amidation. Although the two-step pathway, consisting of only phosphoribosylation of Nm and adenylylation, seems to be more efficient, Nm mononucleotide in the two-step pathway is much more thermolabile than Na mononucleotide, the corresponding intermediate in the four-step pathway. Although NAD+ itself is thermolabile, this may represent an example of a metabolism that has evolved to avoid the use of thermolabile intermediates.


Sequencing of methylase-accessible regions in integral circular extrachromosomal DNA reveals differences in chromatin structure.
Although extrachromosomal DNA (ecDNA) has been intensively studied for several decades, the mechanisms underlying its tumorigenic effects have been revealed only recently. In most conventional sequencing studies, the high-throughput short-read sequencing largely ignores the epigenetic status of most ecDNA regions except for the junctional areas. Here, we developed a method of sequencing enzyme-accessible chromatin in circular DNA (CCDA-seq) based on the use of methylase to label open chromatin without fragmentation and exonuclease to enrich ecDNA sequencing depth, followed by long-read nanopore sequencing. Using CCDA-seq, we observed significantly different patterns in nucleosome/regulator binding to ecDNA at a single-molecule resolution. These results deepen the understanding of ecDNA regulatory mechanisms.


Sphingomonas ginsengisoli sp. nov., isolated from soil of a ginseng field.
A Gram-reaction-negative, oxidase- and catalase-positive, non-gliding motile bacteriun, designated DCY58(T), was isolated from a ginseng field in Pocheon Province, South Korea. Colonies of strain DCY58(T) were circular, 0.5-1.5 mm in diameter, yellow, and convex on an R2A agar plate after 2 days. The 16S rRNA gene sequence analysis revealed that strain DCY58(T) belongs to the family of the Sphingomonadaceae and is most closely related to the species of genus Sphingomonas with similarity levels of 95.7-96.4%. Strain DCY58(T) contained Q-10 as the predominant ubiquinone. The major cellular fatty acids included Summed Feature 8 (containing C(18:1ω)6c and/or C(18:1ω)7c), C(14:0) 2-OH and C(16:0). The DNA G+C content was 65.1 mol%. Furthermore, strain DCY58(T) differed from other related Sphingomonas species by a number of phenotypic characteristics. On the basis of the evidence presented in this study, strain DCY58(T) is described as a novel species of genus Sphingomonas, for which the name Sphingomonas ginsengisoli sp. nov., is proposed. The type strain is DCY58(T) (=KCTC 23762(T) =JCM 18016(T)).


[Hepatitis B vaccination in patients on chronic hemodialysis].
Patients on chronic haemodialysis (PCHD) respond less well to vaccination with recombinant hepatitis B virus superficial antigen (HbsAg) because of immunity disorders in uraemic patients. Today many schemes and vaccination modification for nonresponding PCHD are proposed. The reaction on vaccination with HbsAg is weaker in those PCHD who had diabetes, older age and insufficient nutritive parameters. In those patients some alternative schemes of vaccinating for nonrespondering PCHD must be considered, especially one of the proposed intradermal ways of vaccine inoculation.


Controlled arrangement of nanoparticle arrays in block-copolymer domains.
This Review describes recent results on the precise spatial distribution control of metal and semiconductor nanoparticles into domains of microphase-separated block copolymers. Specific focus is directed towards selective incorporation into a specific microphase of a block copolymer. Details on theoretical aspects concerning nanoparticle incorporation as well as practical examples are given. Furthermore, examples on applications and technological aspects of the resulting nanoparticle/polymer nanocomposites are provided.


Dissected peripancreatic tissue margin is a critical prognostic factor and is associated with a K-ras gene mutation in pancreatic ductal adenocarcinoma.
We previously reported that the dissected pancreatic tissue margin (DPM) and the preoperative serum level of carbohydrate antigen 19-9 (preCA19-9) were independent prognostic factors in pancreatic ductal adenocarcinoma (PDAC). In the current study, the prognostic relevance of these factors, including their molecular associations, were validated. A total of 161 patients with PDAC underwent a pancreatectomy between 1986 and 2013, and a multivariate Cox proportional hazards model and a propensity score-based model validated the prognostic importance of DPM. The prognostic factors were compared with the mutation profiles of the K-ras and TP53 genes. Univariate prognostic analysis of disease-specific survival (DSS) demonstrated that DPM (P<0.0001), preCA19-9 (P<0.0001) and Union for International Cancer Control (UICC) stage (P<0.0001), were all significantly associated with poor outcome in PDAC. A multivariate Cox proportional hazards model confirmed that preCA19-9 (P=0.0002) and DPM (P=0.0002) remained as prognostic factors independent of UICC stage (P=0.0015). The combination of preCA19-9 and DPM to predict prognosis could accurately identify the long-term survivors of PDAC (70% 5-year DSS), and a multivariate logistic regression model identified that DPM was the most effective predictor of mortality. The prognostic relevance of DPM was also confirmed (P=0.0008) through propensity score-based background adjustment of patient bias. K-ras gene mutation was significantly associated with DPM (P=0.0002), and DPM-positive patients demonstrated recurrence of distant metastasis in 67% of cases. Therefore, DPM is a critical prognostic indicator in PDAC. In combination with preCA19-9, DPM may be useful to identify long-term survivors of PDAC. Furthermore, to the best of our knowledge, the current study was the first to discover that DPM can represent a poor prognosis based putatively on its association with the K-ras gene mutation.


Mitral valve prolapse in rheumatic mitral stenosis.
Four adult women with histories of rheumatic fever and clinical findings of mitral stenosis and regurgitation had echocardiograms demonstrating moderately severe mitral stenosis (EF slope less than 20 mm/sec, mean left atrial size 3.0 cm/m2, mean anterior mitral leaflet excursion 25 mm) as well as typical mitral valve prolapse. Three patients underwent cardiac catheterization which confirmed the presence of mitral stenosis, as well as systolic prolapse and excessive scalloping of the mitral valve with no visible mitral calcium and no coronary artery disease. One patient had associated mild aortic stenosis and regurgitation. Two patients underwent mitral valve surgery which revealed anterior and posterior commissural fusion consistent with rheumatic disease and intact chordal apparatus. Both leaflets were large and the anterior leaflets were redundant. There were no vegetations. Pathology revealed myxomatous degeneration of the valve leaflets. In the absence of heavy calcification and thickening, the presence of mitral stenosis with commisural fusion does not exclude the possibility of a redundant mitral valve. When these entities coexist, systolic clicks may be absent.


Differential chromatin profiles partially determine transcription factor binding.
We characterize how genomic variants that alter chromatin accessibility influence regulatory factor binding with a new method called DeltaBind that predicts condition specific factor binding more accurately than other methods based on DNase-seq data. Using DeltaBind and DNase-seq experiments we predicted the differential binding of 18 factors in K562 and GM12878 cells with an average precision of 28% at 10% recall, with the prediction of individual factors ranging from 5% to 65% precision. We further found that genome variants that alter chromatin accessibility are not necessarily predictive of altering proximal factor binding. Taken together these findings suggest that DNase-seq or ATAC-seq Quantitative Trait Loci (dsQTLs), while important, must be considered in a broader context to establish causality for phenotypic changes.


TeaCoN: a database of gene co-expression network for tea plant (Camellia sinensis).
Tea plant (Camellia sinensis) is one of the world's most important beverage crops due to its numerous secondary metabolites conferring tea quality and health effects. However, only a small fraction of tea genes (especially for those metabolite-related genes) have been functionally characterized to date. A cohesive bioinformatics platform is thus urgently needed to aid in the functional determination of the remaining genes. TeaCoN, a database of gene co-expression network for tea plant, was established to provide genome-wide associations in gene co-expression to survey gene modules (i.e., co-expressed gene sets) for a function of interest. TeaCoN featured a comprehensive collection of 261 high-quality RNA-Seq experiments that covered a wide range of tea tissues as well as various treatments for tea plant. In the current version of TeaCoN, 31,968 (94% coverage of the genome) tea gene models were documented. Users can retrieve detailed co-expression information for gene(s) of interest in four aspects: 1) co-expressed genes with the corresponding Pearson correlation coefficients (PCC-values) and statistical P-values, 2) gene information (gene ID, description, symbol, alias, chromosomal location, GO and KEGG annotation), 3) expression profile heatmap of co-expressed genes across seven main tea tissues (e.g., leaf, bud, stem, root), and 4) network visualization of co-expressed genes. We also implemented a gene co-expression analysis, BLAST search function, GO and KEGG enrichment analysis, and genome browser to facilitate use of the database. The TeaCoN project can serve as a beneficial platform for candidate gene screening and functional exploration of important agronomical traits in tea plant. TeaCoN is freely available at http://teacon.wchoda.com .


[Sensitivity and specificity of sonographic diagnosis of the lymph nodes in malignant melanoma].
A total of 213 melanoma patients were checked perioperatively with a 5-MHz sonographic scanner in order to detect lymph-node metastases; they were also checked in the scope of tumor follow-up. Of the 415 sonographic results, the method yielded a 97% accuracy. The soundness of lymph-node sonography has been proved histologically and/or through clinical observation. Compared to the other diagnostic techniques available for checking surface and subsurface lymph-node groups, lymph-node sonography is an advantageous combination of diagnostic practicability, accuracy, economic feasibility, and patient acceptance. The possible therapeutic implications are also discussed in this paper.


A case of Erdheim Chester disease with central nervous system involvement.
Erdheim Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, commonly involving the musculoskeletal system. Other tissue can also be involved, including the central nervous system with wide spectrum of clinical features, at times being nonspecific. This can cause diagnostic dilemmas with delay in diagnosis and initiation of therapy. Here we describe a 63-year-old man who had presented with ataxia and behavioral changes, bony pains, weight loss, and fatigue. His computed tomography (CT), 99Tc scintigraphy and histopathological features on bone biopsy were consistent with ECD. Thus, ECD should be considered as a differential diagnosis in patients presenting with bony pain and nonspecific features of multiorgan involvement.


Spin excitations of the spin-polarized electron gas in semimagnetic quantum wells.
Collective and single-particle spin-flip excitations of a two-dimensional electron gas in a semimagnetic Cd(1-x)Mn(x)Te quantum well are observed by resonant Raman scattering. Application of a magnetic field splits the spin subbands and a spin polarization is induced in the electron gas. Above 1 T the collective modes, which disperse with the in-plane wave vector, dominate the spectra. The local spin-density approximation provides a good description of our results and enables us to confirm that the energy of the low wave vector collective mode is given by the bare Zeeman energy.


Bile resistance mechanisms in Lactobacillus and Bifidobacterium.
Probiotics are live microorganisms which when administered in adequate amounts confer a health benefit on the host. Most of the probiotic bacteria currently available in the market belong to the genera Lactobacillus and Bifidobacterium, and specific health-promoting activities, such as treatment of diarrhea or amelioration of gastrointestinal discomfort, have been attributed to them. In order to be able to survive the gastrointestinal transit and transiently colonize our gut, these bacteria must be able to counteract the deleterious action of bile salts, which are the main components of bile. Bile salts are detergent-like biological substances synthesized in the liver from cholesterol. Host enzymes conjugate the newly synthesized free bile acids in the liver with the amino acids glycine or taurine, generating conjugated bile salts. These compounds are stored in the gall bladder and they are released into the duodenum during digestion to perform their physiological function, which is the solubilization of fat coming from diet. These bile salts possess strong antimicrobial activity, since they are able to disorganize the structure of the cell membrane, as well as trigger DNA damage. This means that bacteria inhabiting our intestinal tract must have intrinsic resistance mechanisms to cope with bile salts. To do that, Lactobacillus and Bifidobacterium display a variety of proteins devoted to the efflux of bile salts or protons, to modify sugar metabolism or to prevent protein misfolding. In this manuscript, we review and discuss specific bile resistance mechanisms, as well as the processes responsible for the adaptation of bifidobacteria and lactobacilli to bile.


Multichannel Doppler transmission grating spectrometer at the Alcator C-Mod tokamak.
Upgrades to an existing transmission grating spectrometer for visible light used for Doppler velocity and temperature measurements at the Alcator C-Mod tokamak are given. These include a new Princeton Instruments Photonmax 512B charge-coupled device and a four channel fiber optic input. These together allow improvements to the signal level, time resolution, and the number of spatial channels. The fiber optic input allows four simultaneous spatial channels each of which offers a larger percentage of input light flux when compared to the standard fiber slit combination. The "on chip" amplification combined with versatile pixel binning further increases the signal to noise ratio allowing a continuous acquisition of spectra every 8 ms. The error bars for extracted velocity and temperature values are potentially smaller owing to the smaller pixel size and increased light flux which allow a more detailed line shape and simplifies line fitting. Examples of time and space resolved spectra are shown and further improvements are discussed.


Optimizing clinical outcomes of transcatheter aortic valve implantation patients with comorbidities.
Transcatheter aortic valve implantation (TAVI) has revolutionized the management of high-risk or inoperable patients presenting with symptomatic severe aortic stenosis (AS). There are several factors to consider to optimize patient outcomes from TAVI. Before TAVI, patient selection is key and an understanding the effects of common comorbidities on outcomes after TAVI is critical. Some comorbidities share common risk factors with AS (e.g. coronary artery disease), others are directly or indirectly caused or exacerbated by severe AS (e.g. atrial fibrillation, pulmonary hypertension, mitral regurgitation, tricuspid regurgitation and right ventricular dysfunction), whereas others are not directly related to severe AS (e.g. chronic kidney disease and chronic lung disease). Choice of transcatheter heart valve prosthesis, vascular access route and mode of anesthesia are important considerations during TAVI. New onset conduction disturbances and arrhythmias remain a vexing issue after TAVI. The aim of the present review is to provide an overview of these issues.


Cross-linked polyhemoglobin-superoxide dismutase-catalase supplies oxygen without causing blood-brain barrier disruption or brain edema in a rat model of transient global brain ischemia-reperfusion.
In strokes, myocardial infarctions, severe sustained hemorrhagic shock, and donor organs, inadequate blood supply results in lack of oxygen to the tissue (ischemia). If ischemia is sustained, reperfusion with the needed oxygen can result in tissue injury (ischemia-reperfusion injury) due to formation of reactive oxygen species. We are studying an oxygen-carrying solution with anitoxidant activity formed by cross-linking hemoglobin, superoxide dismutase, and catalase to form PolyHb-SOD-CAT. The present report studies its effect on the blood-brain barrier and cerebral edema when used in a transient global brain ischemia-reperfusion rat model. We compare this solution to sham-control, oxygenated saline, stroma-free hemoglobin (SF-Hb), polymerized hemoglobin (PolyHb), and a mixture of SF-Hb, SOD, and CAT in free solution. The results show that the cross-linked PolyHb-SOD-CAT solution, unlike the other solutions, can supply oxygen to ischemic tissues without causing reperfusion injury in the transient global brain ischemia-reperfusion model.


Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis.
Iron homeostasis is dysregulated in primary myelofibrosis (PMF), given the high prevalence of anemia, need for red blood cell (RBC) transfusions, and disease-associated inflammatory state. We measured plasma hepcidin levels in 203 consecutive PMF patients at the time of first referral; hepcidin levels were significantly higher as compared to healthy controls (P < 0.0001), and were correlated with hemoglobin of <10 g/dL, RBC transfusion requirement, serum ferritin of >500 µg/L, higher dynamic international prognostic scoring system (DIPSS)-plus risk category, the presence of circulating blasts, age of >65 years, and leukocyte count of <4 × 10(9) /L. Increased hepcidin levels predicted for inferior survival independent of six out of the eight DIPSS-plus prognostic parameters (hazard ratio [HR] = 1.8; P = 0.02), but not when RBC transfusion requirement, hemoglobin of <10 g/dL, or increased serum ferritin were included in the Cox model. Multivariable analysis that considered the four overlapping prognostic variables revealed that increased hepcidin (HR = 1.9; P = 0.03) and increased ferritin (HR = 2.3; P = 0.04), but not hemoglobin of <10 g/dL or RBC transfusion requirement, independently retained their significance for predicting survival. Accordingly, increased levels of both hepcidin and serum ferritin (seen in 29% of patients) predicted inferior survival independent of DIPSS-plus or increased inflammatory cytokine levels (HR = 2.4; P = 0.002), and could be considered in future prognostic models for PMF.


Neurogenic pulmonary oedema.
Two young patients with head injuries subsequently developed neurogenic pulmonary oedema. The origin and pathways of the reflex response to cerebral trauma are discussed, with emphasis on the role of raised intracranial pressure and the sympathetic division of the autonomic nervous system in precipitating movement of systemic circulatory volume into the pulmonary circulation. Therapeutic measures are discussed which correct the progression of this condition by reducing intracranial pressure and blocking the systemic effects of autonomic reflex activity. This leads to the basis of a simple regime to treat future cases.


A genetically encoded fluorescent sensor of ERK activity.
The activity of the ERK has complex spatial and temporal dynamics that are important for the specificity of downstream effects. However, current biochemical techniques do not allow for the measurement of ERK signaling with fine spatiotemporal resolution. We developed a genetically encoded, FRET-based sensor of ERK activity (the extracellular signal-regulated kinase activity reporter, EKAR), optimized for signal-to-noise ratio and fluorescence lifetime imaging. EKAR selectively and reversibly reported ERK activation in HEK293 cells after epidermal growth factor stimulation. EKAR signals were correlated with ERK phosphorylation, required ERK activity, and did not report the activities of JNK or p38. EKAR reported ERK activation in the dendrites and nucleus of hippocampal pyramidal neurons in brain slices after theta-burst stimuli or trains of back-propagating action potentials. EKAR therefore permits the measurement of spatiotemporal ERK signaling dynamics in living cells, including in neuronal compartments in intact tissues.


Clients' Willingness to Pay for Immunization Services in the Urban and Rural Primary Health Centers of Enugu State, Nigeria.
Our study aims at determining the pattern of willingness of clients to pay for childhood immunization services in urban and rural primary health centers of Enugu state, Nigeria. Using a cross-sectional design, 800 clients who presented with their children/wards to receive childhood immunization services were selected at the primary health center in rural and urban local government areas of the state. The mean age was 28.9±4.5 and 26.7±5.1 years in the urban and rural areas respectively. About 54.5% of clients in the urban and 55.3% in the rural area were willing to pay for immunization services. The clients willingness to pay was influenced by: non satisfaction with immunization services, (OR=0.3, 95%CI: 0.2-0.5), younger age, (OR=1.4, 95%CI: 1.0-2.0) marital status (OR=2.8, 95%CI: 1.2-6.5), proximity to health centers (OR=0.6, 95%CI: 0.4-0.8), and delivering in a private health facility (OR=0.4, 95%CI: 0.1-0.9). The study suggests that the economic value that clients give to immunization services was similar in the rural and urban areas, and this could be increased by improving the level of clients' satisfaction for the services among others.


Potency of descending pain modulatory system is linked with peripheral sensory dysfunction in fibromyalgia: An exploratory study.
Fibromyalgia (FM) is characterized by chronic widespread pain whose pathophysiological mechanism is related to central and peripheral nervous system dysfunction. Neuropathy of small nerve fibers has been implicated due to related pain descriptors, psychophysical pain, and neurophysiological testing, as well as skin biopsy studies. Nevertheless, this alteration alone has not been previously associated to the dysfunction in the descending pain modulatory system (DPMS) that is observed in FM. We hypothesize that they associated, thus, we conducted a cross-sectional exploratory study.To explore small fiber dysfunction using quantitative sensory testing (QST) is associated with the DPMS and other surrogates of nociceptive pathways alterations in FM.We run a cross-sectional study and recruited 41 women with FM, and 28 healthy female volunteers. We used the QST to measure the thermal heat threshold (HTT), heat pain threshold (HPT), heat pain tolerance (HPT), heat pain tolerance (HPTo), and conditional pain modulation task (CPM-task). Algometry was used to determine the pain pressure threshold (PPT). Scales to assess catastrophizing, anxiety, depression, and sleep disturbances were also applied. Serum brain-derived neurotrophic factor (BDNF) was measured as a marker of neuroplasticity. We run multivariate linear regression models by group to study their relationships.Samples differed in their psychophysical profile, where FM presented lower sensitivity and pain thresholds. In FM but not in the healthy subjects, regression models revealed that serum BDNF was related to HTT and CPM-Task (Hotelling Trace = 1.80, P < .001, power = 0.94, R = 0.64). HTT was directly related to CPM-Task (B = 0.98, P = .004, partial-η = 0.25), and to HPT (B = 1.61, P = .008, partial η = 0.21), but not to PPT. Meanwhile, BDNF relationship to CPM-Task was inverse (B = -0.04, P = .043, partial-η = 0.12), and to HPT was direct (B = -0.08, P = .03, partial-η = 0.14).These findings high spot that in FM the disinhibition of the DPMS is positively correlated with the dysfunction in peripheral sensory neurons assessed by QST and conversely with serum BDNF.


[Aarno Snellman, the pioneer of modern neurosurgery in Finland and the founder of the Neurosurgical Clinic of Helsinki University Hospital].
Aarno Snellman, M.D., (1893-1964) was the pioneer of modern neurosurgery in Finland and the founder of the Neurosurgical Clinic of Helsinki University Hospital. In 1932, at the initiative of Marshal Mannerheim, the Finnish Red Cross Hospital started functioning at Helsinki, with trauma as its focus of activity. From the outset, the main task of the hospital was to treat the brain injuries caused by traffic accidents in the capital and its environment. With a view to improving the prognosis of the patients, the medical staff took an active interest in the achievements of foreign neurosurgeons. Assistant Surgeon Aarno Snellman had been working at Prof. Herbert Olivecrona's Neurosurgical Clinic in Stockholm. After his return in 1935, he was the first to perform a craniotomy in Helsinki. When the war began in 1939, the development of neurosurgery was delayed by the lack of staff. On the other hand, the war provided a strong incentive for the development of independent neurosurgery. The military authorities favoured the Finnish Red Cross Hospital, all wounds to the brain, spinal cord and peripheral nervous system being referred to its wards, which were superintended by Snellman. After the conclusion of peace, these wards were gradually transformed into an independent neurosurgical clinic led by Snellman. He was appointed Personal Professor of Neurosurgery at the University of Helsinki in 1947. He retired from his post as Head of the clinic in 1961. Aarno Snellman's abundant achievements include the organization of treatment and after-care of the brain-injured war veterans in Finland.


[Effects of dissolved organic matter derived from hyperaccumulator Sedum alfredii Hance rhizosphere on Zn adsorption and desorption in soil].
The study with pot experiment and simulation test showed that after planted hyperaccumulator Sedum alfredii Hance on mining soil, the water soluble Zn and NH4OAc extractable Zn in rhizosphere were decreased obviously, while the available Zn in non-rhizosphere had less change. The pH value of rhizosphere soil was decreased by 0. 3 units, whereas the organic matter and dissolved organic matter (DOM) contents were increased by 13.6% and 20.9%, respectively, compared with the soil without S. alfredii. The effects of DOM from S. alfredii rhizosphere on Zn absorption and desorption varied with the kinds of test soils. After the addition of rhizosphere DOM, the maximal absorption capacity (Xm) of mining soil, quaternary red clay soil, and fluavio-marine yellow loamy soil was reduced by 17.8%, 21.9% and 27.7%, respectively, whereas the addition of non-rhizosphere DOM had no effects on Zn absorption. The Zn desorption in the three soils, especially in fluavio-marine yellow loamy soil, was promoted by the addition of rhizosphere DOM. It was indicated that the DOM from S. alfredii rhizosphere could reduce the maximal absorption capacity and accelerate the desorption of adsorbed Zn, and thus, increase the Zn mobility and bioavailability.


Behavioral and neurochemical changes produced by postnatal pretreatments with methamphetamine in rats.
Male neonates of Wistar strain rats were given s.c. 1-4 mg/kg/day of methamphetamine (MAP) for 7 successive days from days 6 to 12 after birth. The acquisition processes of the discriminative lever-press avoidance response were investigated from day 60 after birth. Effects of the postnatal pretreatments with MAP on saturation constants for specific bindings of 3H-spiperone (SPP) and 3H-WB4101, respectively, in 8 brain regions were also investigated at 100-120 days after birth. In addition, dopamine, noradrenaline and the levels of their metabolites were measured in the brain. No significant difference was detected in body weight, gross behaviors and avoidance learning between saline- and MAP-pretreated groups. However, effects of MAP and apomorphine on the locomotor activity significantly increased in the MAP-pretreated group. Significant decreases in Bmax and Kd values of 3H-SPP binding sites in the striatum were detected in the MAP-pretreated group, while significant decreases in Bmax values of 3H-WB4101 binding sites in the cortex and hippocampus as well as those in Kd values in the hippocampus were found in the treated group. Dopamine and noradrenaline levels significantly decreased in the MAP-pretreated group, but on the contrary, their metabolites levels significantly increased. These results suggest that postnatal pretreatments with MAP produce long-lasting behavioral changes associated with an impaired development of catecholaminergic neurons in the rat brain after maturity.


Optical-resolution photoacoustic microscopy of oxygen saturation with nonlinear compensation.
Optical-resolution photoacoustic microscopy (OR-PAM) of oxygen saturation (sO2) offers high-resolution functional information on living tissue. Limited by the availability of high-speed multi-wavelength lasers, most OR-PAM systems use wavelengths around 532nm. Blood has high absorption coefficients in this spectrum, which may cause absorption saturation and induce systematic errors in sO2 imaging. Here, we present nonlinear OR-PAM that compensates for the absorption saturation in sO2 imaging. We model the absorption saturation at different absorption coefficients and ultrasonic bandwidths. To compensate for the absorption saturation, we develop an OR-PAM system with three optical wavelengths and implement a nonlinear algorithm to compute sO2. Phantom experiments on bovine blood validate that the nonlinear OR-PAM can improve the sO2 accuracy by up to 0.13 for fully oxygenated blood. In vivo sO2 imaging has been conducted in the mouse ear. The nonlinear sO2 results agree with the normal physiological values. These results show that the absorption saturation effect can be compensated for in nonlinear OR-PAM, which improves the accuracy of functional photoacoustic imaging.


Revolutionizing Inflammatory Bowel Disease Management: A Comprehensive Narrative Review of Innovative Dietary Strategies and Future Directions.
This comprehensive narrative review delves into the intricate interplay between diet and inflammatory bowel disease (IBD), shedding light on the potential impact of dietary interventions in disease management. By analyzing nutritional interventions, risks, challenges, and future perspectives, this review serves as a vital resource for clinicians, researchers, and patients alike. The amalgamation of evidence underscores the significance of customizing dietary strategies for individual patients, considering disease phenotype and cultural factors. Through an exploration of dietary components' effects on IBD, including exclusive enteral nutrition and omega-3 fatty acids, this review offers pragmatic implementation advice and outlines avenues for further research. Bridging the gap between research findings and clinical applications, the review facilitates informed decision-making and patient-centric care. In the face of escalating IBD prevalence, this review emerges as an indispensable guide for healthcare professionals, empowering them to navigate the complexities of dietary management while enabling patients to actively participate in their care trajectory. Ultimately, this narrative review advances the understanding of diet's pivotal role in IBD management, fostering a more integrated approach to patient care and paving the way for improved research and policy initiatives in the field of inflammatory bowel diseases.


Healing course of primate ulna segmental defects treated with osteogenic protein-1.
Twelve African green monkeys were implanted with recombinant human osteogenic protein-1 (rhOP-1) placed on a bovine bone-derived Type I collagen carrier to characterize healing in an ulna segmental bone defect model at 1, 3, 12, and 20 weeks postoperative. Defect healing was evaluated by plain film radiography, computed tomography (CT), magnetic resonance imaging (MRI), bone mineral density (BMD), and histologic analysis. Radiographically, new bone formation was observed as early as 3 weeks postoperative. By 6 weeks, new bone was visible in five of six defects. Increased quantity and mineralization of the new bone were apparent by 12 weeks. Reformation of the medullary cavity with appearance of marrow elements was demonstrated by CT and MRI at 20 weeks. BMD studies revealed a significant increase in the presence of bone with time. Histology at 1 week demonstrated that the implant material was well contained in the defect, and a proliferation of cells occurred at the defect borders. At 3 weeks cell proliferation continued and cell phenotype differentiation was recognized. By 12 weeks substantially less residual carrier was found in the defects, and calcifying tissues with plump chondrocytes, osteoblasts, and immature woven bone were observed. Areas of lamellar and woven bone were identified at 12 weeks, with advanced remodeling and revascularization observed at 20 weeks. The use of osteoinductive implants may provide an alternative to autologous and allogeneic bone tissue in the therapeutic approach to bone defects and promotion of fusion by eliminating the donor site morbidity associated with autogenous bone and the decreased efficacy and potential for disease transmission associated with allogeneic bone.


Prevalence and risk factors of multi-drug resistant tuberculosis in Dalian, China.
Objectives To investigate the prevalence and risk factors associated with multi-drug resistant tuberculosis (MDR-TB) in Dalian, China. Methods This was a retrospective review of data from patients attending a TB clinic in Dalian, China between 2012 and 2015. Demographic and drug susceptibility data were retrieved from TB treatment cards. Univariate logistic analysis was used to assess the association between risk factors and MDR-TB. Results Among the 3552 patients who were smear positive for Mycobacterium tuberculosis (MTB), 2918 (82.2%) had positive MTB cultures and 1106 (31.1%) had isolates that showed resistance to at least one drug. The overall prevalence of MDR-TB was 10.1% (359/3552; 131/2261 [5.8%] newly diagnosed and 228/1291 [17.7%] previously treated patients). Importantly, 75 extensively drug-resistant TB isolates were detected from 25 newly treated and 50 previously treated patients. In total, 215 (6.1%) patients were infected with a poly-resistant strain of MTB. Previously treated patients and older patients were more likely to develop MDR-TB. Conclusions The study showed a high prevalence of MDR-TB among the study population. History of previous TB treatment and older age were associated with MDR-TB.


Prognostic scores in status epilepticus: A systematic review and meta-analysis.
The performance of prognostic scores of status epilepticus (SE) has been reported in very heterogeneous cohorts. We aimed to provide a summary of the available evidence on their respective performance. PubMed and EMBASE were searched for relevant articles. Studies were reviewed for eligibility for meta-analysis of the area under the receiver-operating characteristic curve (AUC) and for meta-analysis of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) in predicting in-hospital mortality with scores in which at least two external evaluations had been published. This study was registered with PROSPERO (international prospective register of systematic reviews) (CRD42022325766). Study quality was assessed using Prediction model Risk Of Bias ASsessment Tool (PROBAST). In the meta-analysis of AUC, 21 studies were pooled for STESS (Status Epilepticus Severity Score), five for EMSE-EAC (Epidemiology-based Mortality Score in Status Epilepticus - Etiology, Age, level of Consciousness), five for EMSE-EACE (EMSE - Etiology, Age, level of Consciousness, EEG), and two for ENDIT (Encephalitis, nonconvulsive status epilepticus, Diazepam resistance, Imaging abnormalities, Tracheal intubation). The pooled AUC of STESS, EMSE-EAC, EMSE-EACE, and ENDIT was 0.74 (95% CI: 0.71-0.78), 0.68 (95% CI 0.63-0.72), 0.77 (95% CI: 0.72-0.81), and 0.78 (95% CI: 0.70-0.87), respectively. The pooled sensitivity of STESS-3, STESS-4, EMSE-EACE-64, and ENDIT-4 was 0.83 (95% CI: 0.80-0.86), 0.60 (95% CI: 0.55-0.65), 0.76 (95% CI: 0.67-0.83), and 0.70 (95% CI: 0.55-0.82), respectively. Their pooled specificity was 0.50 (95% CI: 0.48-0.52), 0.74 (95% CI: 0.72-0.76), 0.63 (95% CI: 0.59-0.67), and 0.65 (95% CI: 0.61-0.70), respectively. Their pooled PPV was 0.27 (95% CI: 0.24-0.30), 0.35 (95% CI: 0.29-0.41), 0.33 (95% CI: 0.24-0.43), and 0.20 (95% CI: 0.13-0.27). Their pooled NPV was 0.94 (95% CI: 0.93-0.96), 0.90 (95% CI: 0.89-0.92), 0.89 (95% CI: 0.80-0.98), and 0.95 (95% CI: 0.92-0.98). Variations in performance were observed in patients' subgroups, such as critically ill patients and refractory cases. Investigated scores only have acceptable AUC, sensitivity, and specificity for predicting in-hospital mortality, with the EMSE-EAC having a lower discriminative power. STESS-3 has the highest sensitivity, and STESS-4 the highest specificity, but neither combines acceptable sensitivity and specificity. All these scores had high NPV but very low PPV. Caution should be exercised in their clinical use. Further studies are required to develop more accurate scores.


Successful surgical closure and continence rate of obstetric fistula in Africa: systematic review and meta-analysis.
A female genital fistula is an abnormal connection between a woman's reproductive tract and her urinary tract or rectum. While numerous studies have aimed to determine the success rate of obstetric fistula closure in different health settings, there remains a significant scarcity of data on closure success rates and incontinence rates for various types of fistulas at the regional and sub-regional levels. The success rate reflects the continent's healthcare setup in regard to the World Health Organization standards. Thus, this study aims to determine the success of surgical closure and the continence rate of obstetric fistula in Africa. This systematic review and meta-analysis review includes studies conducted up to February 2023. Search engines like EMBBASE, Medline, Google, PubMed, Google Scholar, African Journals Online, and ScienceDirect databases were utilized to find articles. The Joanna Briggs Institute critical evaluation checklist was used to evaluate the quality of our review, which was conducted in accordance with PRISMA criteria. Heterogeneity was indicated by a p-value for I2 statistics of less than 0.05. Publication bias was assessed using the Egger regression asymmetry test. Data were entered into Microsoft Excel and analyzed using STATA 16. This review includes 85 studies. A total of 24 countries from East, West, Central, North, and Southern African sub-regions were included. The overall pooled estimated rate of successful obstetric fistula closure is 86.15 (95% CI: 83.88-88.42). Moreover, the pooled estimated rate of successfully closed vesico-vaginal fistulas but with ongoing or residual incontinence (wet) was revealed as 13.41% (95% CI: 11.15-15.68). The pooled estimated rate of successfully closed rectovaginal fistulas and combined VVF and RVF are 91.06% (95% CI: 86.08-96.03) and 62.21% (95% CI: 48.94-75.49), respectively. The rate of successful obstetric fistula closure in Africa is 86.15, which is higher than the WHO target. However, the surgical closure rate of a combined VVF and RVF is 62.2%, which is significantly lower than the WHO target.


Studies on the interactions of MPTP(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) with the cytochrome P-450 enzyme system--clues to a possible aetiological factor in Parkinson's disease.
Idiopathic Parkinson's disease has been postulated to result from exposure to environmental toxins similar to the parkinsonism-causing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This study examines the interactions of MPTP with the cytochrome P-450 system--an enzyme system which is known to be involved in the detoxication of MPTP. In vitro studies, using control hepatic microsomes, studied changes in cytochrome P-450 content and enzyme activity with varying concentrations of MPTP and substrates. In vivo liver and brain studies were conducted using groups of 4 animals treated intraperitoneally with varying doses of MPTP and sacrificed at varying time intervals after treatment. Changes in cytochrome P-450 enzyme contents and activities were determined using standard analytical procedures. MPTP was found from in vitro studies to cause a mixed non-competitive inhibition of cytochrome P-450 dependent ethoxyresorufin O-dealkylase activity with an inhibition constant (Ki) of 0.06 mM. Two binding sites of MPTP to hepatic cytochrome P-450 were found by spectral perturbation studies--the higher affinity site binding about a hundred times more avidly to MPTP than the other. In vivo studies showed a depression of cytochrome P-450 content and activity in a dose-dependent manner. Cytochrome P-450 levels were lowest 3 to 6 hours after treatment with MPTP. MPTP was also found to cause a dose-dependent decrease in the cytochrome P-450 enzyme activities bufuralol hydroxylase (buf) and aryl hydrocarbon hydroxylase (AHH) in the brain. Bufuralol hydroxylase activity was found to be about 2000 times more sensitive than aryl hydrocarbon hydroxylase to the effects of MPTP.(ABSTRACT TRUNCATED AT 250 WORDS)


Nitrogen Reduction to Ammonia on a Fe16 Nanocluster: A Computational Study of Catalysis.
The sequence of elementary steps leading to reductive ammonia formation from N2 and H2 catalyzed by a Fe16 cluster is studied using generalized gradient approximation density functional theory and an all-electron basis set of triple-ζ quality. The computational methods are validated by comparison to experimental data such as binding energies where possible. First, the associative and dissociative attachment of N2 to Fe16 is considered, followed by exploration of the pathways leading to distal (Fe16-N-NH2) and enzymatic (NFe16-NH2) formation of an amino group. Next, the pathways leading to NH3 formation in both distal and enzymatic cases are examined. Two mechanisms for NH3 detachment have been discovered. An interesting peculiarity of the pathways is that they often proceed with total spin fluctuations, which are related to the rupture and formation of bonds on the surface of the catalyst over the course of the reactions. The reaction Fe16 + N2 + 2H2 → Fe16NH + NH3 is found to be exothermic by 1.02 eV (93.8 kJ/mol).


Electrode-assisted acetoin production in a metabolically engineered Escherichia coli strain.
This paper describes the metabolic engineering of Escherichia coli for the anaerobic fermentation of glucose to acetoin. Acetoin has well-established applications in industrial food production and was suggested to be a platform chemical for a bio-based economy. However, the biotechnological production is often hampered by the simultaneous formation of several end products in the absence of an electron acceptor. Moreover, typical production strains are often potentially pathogenic. The goal of this study was to overcome these limitations by establishing an electrode-assisted fermentation process in E. coli. Here, the surplus of electrons released in the production process is transferred to an electrode as anoxic and non-depletable electron acceptor. In a first step, the central metabolism was steered towards the production of pyruvate from glucose by deletion of genes encoding for enzymes of central reactions of the anaerobic carbon metabolism (ΔfrdA-D ΔadhE ΔldhA Δpta-ack). Thereafter, the genes for the acetolactate synthase (alsS) and the acetolactate decarboxylase (alsD) were expressed in this strain from a plasmid. Addition of nitrate as electron acceptor led to an anaerobic acetoin production with a yield of up to 0.9 mol acetoin per mol of glucose consumed (90% of the theoretical maximum). In a second step, the electron acceptor nitrate was replaced by a carbon electrode. This interaction necessitated the further expression of c-type cytochromes from Shewanella oneidensis and the addition of the soluble redox shuttle methylene blue. The interaction with the non-depletable electron acceptor led to an acetoin formation with a yield of 79% of the theoretical maximum (0.79 mol acetoin per mol glucose). Electrode-assisted fermentations are a new strategy to produce substances of biotechnological value that are more oxidized than the substrates. Here, we show for the first time a process in which the commonly used chassis strain E. coli was tailored for an electrode-assisted fermentation approach branching off from the central metabolite pyruvate. At this early stage, we see promising results regarding carbon and electron recovery and will use further strain development to increase the anaerobic metabolic turnover rate.


Persistent organic pollutants induced protein expression and immunocrossreactivity by Stenotrophomonas maltophilia PM102: a prospective bioremediating candidate.
A novel bacterium capable of growth on trichloroethylene as the sole carbon source was identified as Stenotrophomonas maltophilia PM102 by 16S rDNA sequencing (accession number of NCBI GenBank: JQ797560). In this paper, we report the growth pattern, TCE degradation, and total proteome of this bacterium in presence of various other carbon sources: toluene, phenol, glucose, chloroform, and benzene. TCE degradation was comparatively enhanced in presence of benzene. Densitometric analysis of the intracellular protein profile revealed four proteins of 78.6, 35.14, 26.2, and 20.47 kDa while the extracellular protein profile revealed two distinct bands at 14 kDa and 11 kDa that were induced by TCE, benzene, toluene, and chloroform but absent in the glucose lane. A rabbit was immunised with the total protein extracted from the bacteria grown in 0.2% TCE + 0.2% peptone. Antibody preadsorbed on proteins from peptone grown PM102 cells reacted with a single protein of 35.14 kDa (analysed by MALDI-TOF-mass-spectrometry) from TCE, benzene, toluene, or chloroform grown cells. No reaction was seen for proteins of PM102 grown with glucose. The PM102 strain was immobilised in calcium alginate beads, and TCE degradation by immobilised cells was almost double of that by free cells. The beads could be reused 8 times.


Adaptive evolution of highly mutable loci in pathogenic bacteria.
Bacteria have specific loci that are highly mutable. We argue that the coexistence within bacterial genomes of such 'contingency' genes with high mutation rates, and 'housekeeping' genes with low mutation rates, is the result of adaptive evolution, and facilitates the efficient exploration of phenotypic solutions to unpredictable aspects of the host environment while minimizing deleterious effects on fitness.


Truncated protein tyrosine phosphatase receptor type O suppresses AKT signaling through IQ motif containing GTPase activating protein 1 and confers sensitivity to bortezomib in multiple myeloma.
Proteasome inhibitors are an important part of our chemotherapeutic armamentarium against multiple myeloma, but the vast majority of patients eventually develop drug-resistant disease through incompletely understood mechanisms. Comparison of gene expression profiles (GEPs) of bortezomib-resistant (BR) myeloma cell lines with their drug-naïve counterparts revealed decreased expression of truncated Protein tyrosine phosphatase receptor-type O (PTPROt) in BR cells. Over-expression of wild-type PTPROt in drug-naïve and BR cells reduced myeloma cell proliferation, induced apoptosis, and sensitized cells to bortezomib and to alkylating agents. PTPROt expression reduced AKT phosphorylation and activity, and sensitized to pharmacologic AKT pathway inhibitors, but this was not the case for a substrate-trapping catalytic domain-inactivating mutant. Co-immunoprecipitation and mass spectrometry studies identified IQ motif containing GTPase activating protein 1 (IQGAP1) as a PTPROt binding partner, and PTPROt reduced tyrosine phosphorylation of IQGAP1, providing a link to AKT activity. Analysis of clinically annotated GEP databases identified high PTPROt expression as being related to an increased likelihood of achieving complete remission with bortezomib therapy, while low expression was linked to a greater likelihood of disease progression. Finally, high PTPROt expression associated with prolonged median overall survival in patients receiving bortezomib-based therapy in the front-line or relapsed and/or refractory settings. Taken together, these data identify PTPROt suppression as a novel mechanism of myeloma resistance to bortezomib in myeloma cell lines, and also support the possibility that PTPROt expression could be used as a biomarker to predict outcomes with bortezomib, and by which to select patients for therapy with AKT inhibitors.