Expression of human T cell receptor-gamma delta structural forms.
The human TCR-gamma delta occurs in three biochemically distinct forms (forms 1, 2bc, and 2abc). A 40-kDa TCR gamma-chain is disulfide-linked to the TCR delta-chain in form 1, whereas 40-kDa or 55-kDa TCR-gamma polypeptides are noncovalently associated with the TCR delta-chain in forms 2bc and 2abc, respectively. Sequence analysis of TCR-gamma cDNA clones indicates that form 1 utilizes the C gamma 1 gene segment, whereas forms 2bc and 2abc appear to use allelic C gamma 2 gene segments containing either two copies (b and c) or three copies (a, b, and c) of the CII exon, respectively. We transfected TCR-gamma cDNA encoding form 1 or form 2abc into the MOLT-13 cell line that expresses form 2bc. The transfected TCR gamma-chains associate with the resident MOLT-13 TCR-delta, normally part of form 2bc, to yield CD3-associated TCR-gamma delta heterodimers identical to those seen on the donor cell lines (form 1 or 2abc). These transfection experiments show directly that, 1) when a single TCR-delta subunit is available, the presence or absence of disulfide linkage between TCR gamma- and TCR delta-chains is controlled by the TCR gamma-chain, and 2) the difference in the amount of N-linked carbohydrate attached to the transfected TCR-gamma proteins of form 2bc vs form 2abc is influenced by the presence or absence of CII exon copy "a" which appears to alter the secondary and/or tertiary structure of these TCR gamma-chain constant regions, thereby affecting the attachment of N-linked glycans. In contrast to the similar structure and usage of C beta 1 and C beta 2, TCR-gamma delta forms show striking differences in structure and are not equally represented in peripheral blood. Although the role of each form is unknown, it is possible that variable or joining-gene segment selection events or functional differences account for their unequal usage.


Early limited internal fixation of diaphyseal extensions in select pilon fractures: upgrading AO/OTA type C fractures to AO/OTA type B.
Fractures of the tibial pilon may present an array of problems and potential complications. Staged treatment with initial spanning external fixation of the ankle has proven to be a successful strategy for the treatment of these difficult fractures in many cases. A subset of the tibial pilon fractures, with an oblique extension to the diaphysis may constitute a treatment problem, as these long fractures may be difficult to reduce at the time of definitive fixation, often 1-3 weeks post-injury due to interposed soft tissues, hematoma and/or early callus. Anatomic reduction of this fracture may thus require more extensive dissection than might be desirable in this injury. We offer a technique to assist in the treatment of the subset of these difficult fractures. In appropriate cases, a small fragment plate may be applied to the diaphyseal component of the fracture in an anti-glide type plate application, through a small incision proximal to the area of greatest injury. This re-establishes the length, rotation and alignment of this fragment which is commonly attached to either the Chaput anterolateral or the Volkmann posterolateral fragment. It additionally provides the intimate contact that may favor early union or minimize the need for secondary procedures. The fracture is thereby converted from a complete articular AO/OTA 43-C type pattern to a partial articular, or AO/OTA 43-B type pattern.


Health and housing in Savannah.
St. Joseph's/Candler, a two-hospital system in Savannah, GA, and Mercy Housing East (MHE), Atlanta, a regional subsidiary of the Denver organization, collaborate on housing projects in southeastern Georgia. In Savannah, the partners transformed two local landmarks, a former hospital and a former school, into an 88-apartment development for low-income, predominantly African-American residents. St. Joseph's/Candler also provides health services to the community. As a result of their work, MHE and St. Joseph's/Candler have helped restore a historic city neighborhood. In Pembroke, GA, MHE (with support from St. Joseph's/Candler) has constructed a two-story, 30-unit, independent-living apartment development for senior citizens. Last year, St. Joseph's/Candler opened a health care facility in Pembroke.


3D Printing of Antibacterial, Biocompatible, and Biomimetic Hybrid Aerogel-Based Scaffolds with Hierarchical Porosities via Integrating Antibacterial Peptide-Modified Silk Fibroin with Silica Nanostructure.
Scaffold-mediated tissue engineering has become a golden solution for the regeneration of damaged bone tissues that lack self-regeneration capability. A successful scaffold in bone tissue engineering comprises a multitude of suitable biological, microarchitectural, and mechanical properties acting as different signaling cues for the cells to mediate the new tissue formation. Therefore, careful design of bioactive scaffold macro- and microstructures in multiple length scales and biophysical properties fulfilling the tissue repair demands are necessary yet challenging to achieve. Herein, we have developed an antibacterial and biocompatible silica-silk fibroin (SF) gel-based ink through novel yet simple chemical approaches of sol-gel and self-assembly followed by processing the obtained gels as three-dimensional (3D) hybrid aerogel-based scaffolds exploiting the advanced materials design approaches of micro-extrusion-based 3D printing, and directional freeze-casting/drying approaches. As the main constituent of the hybrid biocompatible scaffold of this study, we used the SF extracted from Bombyx mori silkworm cocoon. However, to increase the cell responsivity and bactericidal efficiency of the final scaffold, thiol-ended antimicrobial and cell adhesive peptide sequence (SH-CM-RGD) was conjugated to silica-SF hybrid gels via covalent attachment using a spacer molecule through either preprint (prior to sol-gel) or during the post-printing steps on the previously printed silica-SF gel. In the next step, the hybrid Silica-SF-CM-RGD hydrogel ink was 3D-printed into the construct with interconnected porous structure with hierarchically organized porosity and a combination of several promising properties. Namely, due to the covalent linkage of the antibacterial peptide to the SF, the scaffold shows potent bactericidal efficiency toward Gram-positive and Gram-negative bacteria. Moreover, nanostructured silica components in the 3D-printed composites could intertwine with SF-CM-RGD to support the mechanical properties in the final scaffold and the final osteoconductivity of the scaffold. This study supports the promising properties of 3D-printed silica-SF-based hybrid aerogels constructs for repairing bone defect.


Complication profile of the Berlin Heart EXCOR biventricular support in children.
In chronic cardiomyopathy, mechanical circulatory support (MCS) plays an increasingly important role for children as the shortage of suitable donor hearts increases waiting time on the transplant list. We report our experience with the paracorporal Berlin Heart EXCOR System (Berlin Heart AG, Berlin, Germany) used as a biventricuclar assist device (BVAD). Nine patients with a BVAD EXCOR system were treated between 2006 and 2012; out of these patients, four were less than 18 years old (6, 14, 14, and 17 years old). Their diagnoses were postcardotomy failure (n = 1), dilatative cardiomyopathy (n = 2), and terminal heart failure (n = 1). Overall survival, waiting time for heart transplantation (HTx) and complication profile for the BVAD were analyzed retrospectively. Thirty days' mortality was 25% (n = 1). One child died after 84 days on support due to cerebral bleeding. Mean support time was 218.75 days (4, 84, 262, and 525 days). Pump chamber exchange was necessary three times due to pump chamber thrombosis (n = 2) and partial pump chamber membrane rupture (n = 1). Complications included: sepsis (n = 1), drive line infection requiring intravenous antibiotics (n = 2), and recurrent epistaxis (n = 3). Two children were successfully transplanted after 262/525 days on BVAD; they are currently at home (follow-up: 1.9 and 2.3 years). The EXCOR is a life-saving MCS system suitable for long-term paracorporeal biventricular assistance.


Pulmonary benign metastasizing leiomyoma associated with intravenous leiomyomatosis of the uterus: clinical behavior and genomic changes supporting a transportation theory.
Benign metastasizing leiomyoma is a rare lesion characterized by benign-appearing smooth muscle tumor most frequently involving the lung and usually associated with a benign leiomyoma or intravenous leiomyomatosis of the uterus. The pathogenetic mechanism of the tumor has not been clarified, but the possibilities including hormone-sensitive in situ proliferations of smooth muscle bundles, mechanical displacement or intravascular spread of preexisting benign uterine tumor tissue, and metastasized very low-grade uterine leiomyosarcoma have been proposed. We described a case of pulmonary benign metastasizing leiomyoma associated with a uterine intravenous leiomyomatosis in a 46-year-old woman with a result of comparative genomic hybridization study. The 2 lesions showed significantly overlapping, if not identical, complex genomic changes in the comparative genomic hybridization, suggesting that the 2 lesions are closely related to each other. Unresected pulmonary nodules were left untreated for 13 months after the hysterectomy and wedge biopsy of 3 pulmonary nodules to show no further growth, suggesting clinical behavior of nonmalignant tumor in our case. Benign metastasizing leiomyomas may comprise a heterogeneous group of tumors in terms of their malignant potential and pathogenetic mechanism.


Indian hedgehog signaling promotes chondrocyte differentiation in enchondral ossification in human cervical ossification of the posterior longitudinal ligament.
Histological, immunohistochemical, and immunoblot analyses of the expression of Indian hedgehog (Ihh) signaling in human cervical ossification of the posterior longitudinal ligament (OPLL). To examine the hypothesis that Ihh signaling in correlation with Sox9 and parathyroid-related peptide hormone (PTHrP) facilitates chondrocyte differentiation in enchondral ossification process in human cervical OPLL. In enchondral ossification, certain transcriptional factors regulate cell differentiation. OPLL is characterized by overexpression of these factors and disturbance of the normal cell differentiation process. Ihh signaling is essential for enchondral ossification, especially in chondrocyte hypertrophy. Samples of ossified ligaments were harvested from 45 patients who underwent anterior cervical decompressive surgery for symptomatic OPLL, and 6 control samples from patients with cervical spondylotic myelopathy/radiculopathy without OPLL. The harvested sections were stained with hematoxylin-eosin and toluidine blue, examined by transmission electron microscopy, and immunohistochemically stained for Ihh, PTHrP, Sox9, type X, XI collagen, and alkaline phosphatase. Immunoblot analysis was performed in cultured cells derived from the posterior longitudinal ligaments in the vicinity of the ossified plaque and examined for the expression of these factors. The ossification front in OPLL contained chondrocytes at various differentiation stages, including proliferating chondrocytes in fibrocartilaginous area, hypertrophic chondrocytes around the calcification front, and apoptotic chondrocytes near the ossified area. Immunoreactivity for Ihh and Sox9 was evident in proliferating chondrocytes and was strongly positive for PTHrP in hypertrophic chondrocytes. Mesenchymal cells with blood vessel formation were positive for Ihh, PTHrP, and Sox9. Cultured cells from OPLL tissues expressed significantly higher levels of Ihh, PTHrP, and Sox9 than those in non-OPLL cells. Our results indicated that overexpression of Ihh signaling promotes abnormal chondrocyte differentiation in enchondral ossification and enhances bone formation in OPLL.


PKC-independent signal transduction pathways increase SERCA2 expression in adult rat cardiomyocytes.
Catecholamines seem to play a major role in the initial response of the heart to pressure overload. The mechanisms by which alpha(1A)-adrenoceptor stimulation increases protein synthesis and subsequently cell size have been worked out in the past. However, little is known about the functional consequence of this type of hypertrophy. Recent transgenic work seems to indicate an adaptive character of this response, but mechanistic insights have yet to be established. The present study investigates whether chronic (overnight) exposure of cardiomyocytes to phenylephrine, an alpha-adrenoceptor agonist, modifies the expression of calcium-handling proteins and identifies key elements of signal transduction pathways leading to such alterations. Cardiomyocytes exposed to phenylephrine had elevated expression of SR-calcium ATPase (SERCA), but not of the sodium-calcium exchanger (NCX). SERCA induction persisted in the presence of protein kinase C (PKC) inhibitors, but required an increase in diastolic cell calcium levels via activation of the sodium-proton exchanger (NHE) and the reverse mode of the NCX. Downstream of an increase in resting cell calcium concentrations an activation of the calcineurin/NFAT pathway was found to be responsible for SERCA2 induction. Transfection of cardiomyocytes with decoys directed against NFAT activity inhibited the increase in SERCA2 expression. Decoys did not inhibit the concomitant PKC-dependent increase in hypertrophic growth. In the absence of SERCA up-regulation, hypertrophied cardiomyocytes were unable to maintain normal, load-free cell shortening. In conclusion, our data give mechanistic insights into the adaptional process during alpha-adrenoceptor-dependent myocardial hypertrophy.


Enhancement of the Catalytic Activity of Hammerhead Ribozymes by Organic Cations.
Catalytic turnover is important for the application of ribozymes to biotechnology. However, the turnover is often impaired because of the intrinsic high stability of base pairs with cleaved RNA products. Here, organic cations were used as additives to improve the catalytic performance of hammerhead ribozyme constructs that exhibit different kinetic behaviors. Kinetic analysis of substrate cleavage demonstrated that bulky cations, specifically tetra-substituted ammonium ions containing pentyl groups or a benzyl group, have the ability to greatly increase the turnover rate of the ribozymes. Thermal stability analysis of RNA structures revealed that the bulky cations promote the dissociation of cleaved products and refolding of incorrectly folded structures with small disruption of the catalytic structure. The use of bulky cations is a convenient method for enhancing the catalytic activity of hammerhead ribozymes, and the approach may be useful for advancing ribozyme technologies.


Preoperative ultrasonographic features of papillary thyroid carcinoma predict biological behavior.
Although ultrasound (US) features of papillary thyroid carcinoma (PTC) are well established, little is known regarding biological behavior according US features. We investigated whether there was a difference in biological behavior between PTCs that did and did not meet malignant US criteria. We retrospectively reviewed clinical records and histological and US findings of the index tumors in 488 patients who underwent surgery for PTC. Benign-looking PTC (B-PTC) was defined as showing none of the accepted US criteria for malignancy. Malignant-looking PTCs (M-PTCs) and B-PTCs were compared in terms of patients' age, sex, tumor size, histological subtype, multifocality, lymph node (LN) metastasis, extrathyroidal extension, stage, recurrence, and distant metastasis. B-PTCs accounted for 74 (15%) of all 488 PTCs. Mean tumor size was not significantly different between the groups, with 1.10 cm for M-PTC and 1.11 cm for B-PTC (P = .947). Univariate and multivariate analysis indicated that M-PTC more frequently had LN metastasis, extrathyroidal extension, and a higher stage than B-PTC (all P < .05). The results were significant in tumors ≥1.0 cm, whereas there were no significant differences in tumors <1 cm. As the number of malignant US features increased, multifocality, extrathyroidal extension, LN metastasis, and a higher stage were more likely. PTCs that did not meet malignant US criteria had better prognostic indicators than PTCs that met US criteria. Therefore, US features at the time of diagnosis can serve as a useful tool for predicting biological behavior in PTC.


Intrapartum stress and lipid status of term infants: relation to fetal adrenal production of dehydroepiandrosterone sulphate.
Evaluate the effect of acute intrapartum stress on umbilical cord plasma levels of cholesterol, triglyceride and dehydroepiandrosterone sulphate (DS) in term infants. Umbilical cord plasma levels of cholesterol, triglyceride and DS were measured in 176 infants that delivered >or=37 weeks' gestation. Eighty-eight infants experienced acute intrapartum stress while the remaining infants were non-stressed controls who were case-matched by gestational age and delivery method. The umbilical cord plasma levels of cholesterol in the stressed infants (71.7 +/- 16.1 mg/dL, mean +/- SD) were similar to those of the control infants (70.9 +/- 16.0 mg/dL). Triglyceride levels in stressed infants were significantly higher (p = 0.003) than those of control infants. Both stressed and control infants with increased triglyceride levels had normal DS levels; however, those with increased cholesterol levels had reduced umbilical cord plasma levels of DS. Stressed infants with increased cholesterol levels had significantly lower DS levels than control infants (p = 0.008). Intrapartum stress leads to increased fetal plasma levels of triglycerides; yet, cholesterol levels are usually unaffected. Infants with increased cholesterol levels also have reduced DS levels, suggesting that the rise in cholesterol was due to a reduction in fetal adrenal utilisation of plasma cholesterol as substrate for steroid formation.


[The guidelines for the diagnosis and management of multiple myeloma in China(2020 revision)].
Multiple myeloma (MM) is a clonal plasma cell disorder, the second most hematological malignancy. MM mainly develops in elderly people and remains incurable at present. With the development of novel agents and advances of laboratory evaluation, the diagnosis and treatment of MM have been significantly improved. In this version, an anti-CD38 monoclonal antibody, Daratumumab, based regimens and related concerns were appended. The chimeric antigen receptor T cell (CAR-T) immunotherapy was updated in the section of relapse and refractory myeloma. Again, autologous stem cell transplantation (ASCT) is still the standard consolidation after front-line therapy for transplant candidates with MM.


Rapid (24-hour) reaccumulation of brain organic osmolytes (particularly myo-inositol) in azotemic rats after correction of chronic hyponatremia.
It was recently demonstrated that renal failure and exogenous urea prevent myelinolysis induced by rapid correction of experimental hyponatremia. To determine why elevated blood urea levels favorably affect brain tolerance to osmotic stress, the changes in brain solute composition that occur when chronic hyponatremia is rapidly corrected were studied in rats with or without mercuric chloride-induced renal failure. After 48 h of hyponatremia, the brains of azotemic and nonazotemic animals became depleted of sodium, potassium, and organic osmolytes. Twenty-four hours after rapid correction of hyponatremia, the brains of animals without azotemia remained depleted of organic osmolytes, with little increase in myo-inositol or taurine contents above those observed in animals with uncorrected hyponatremia; brain electrolytes were rapidly reaccumulated, increasing the brain sodium content to a level 17% higher than values for normonatremic control animals. In contrast, within 2 h after correction of hyponatremia, brain myo-inositol contents in azotemic rats returned to control levels and brain taurine levels were significantly higher than those in azotemic animals with uncorrected hyponatremia (16.5 versus 9 micromol/g dry weight). There was no "overshooting" of brain sodium and water contents after rapid correction in the azotemic animals. Rapid reaccumulation of brain organic osmolytes after correction of hyponatremia could explain why azotemia protects against myelinolysis.


Comparing the concentration curves directly in a pharmacokinetics, bioavailability/bioequivalence study.
In a traditional pharmacokinetics (PK), bioavailability (BA) /bioequivalence (BE) study, the same number of time points and sampling times are used for each subject. Often, an indirect inference is then made on some PK parameters such as area under the plasma concentration curve (AUC), maximum plasma concentration (C(max)), time to maximum plasma concentration (T(max)) or half-life. However, since these PK parameters are summarized from repeated measurements, a lot of information can be lost. The indirect inferences on some PK parameters are not always accurate. Taking the repeated measurements of the concentration curve into consideration, a functional linear model has been developed to compare concentration curves directly instead of the PK parameters. Considering the nature of repeated measurements, a multiple testing procedure is proposed to assess the equality of two concentration curves. A real data set is used to demonstrate the proposed procedure.


[Enhanced expression of human vimentin intermediate filaments in hepatocellular carcinoma cells decreases their proliferative and invasive abilities in vitro].
Expression of vimentin in carcinoma cells is a marker for poor prognosis in patients. The aim of this investigation was to assess the influence of vimentin on the characteristics of carcinoma cells. The full-length vimentin gene open reading frame (1401 base pairs) was cloned into the plasmid vector pcDNA 3.1 (+), and these vectors were used to stably transfect the human hepatocellular carcinoma HepG2 cell line. Vimentin gene expression was evaluated by RT-PCR and Western blot. Proliferative activity and invasive potential of tumor cells were determined by the CellTiter 96 aqueous one solution cell proliferation assay and BioCoat GFR Matrigel invasion chamber, respectively. DNA sequencing and restriction endonuclease digestion analysis demonstrated that the recombinant vector was correctly cloned. The stable cell line demonstrated a higher vimentin RNA and protein expression. However, both proliferative and invasive abilities of the cells were reduced in vitro ( P < 0.05). A recombinant plasmid pcDNA3. 1-VIM is successfully constructed and a carcinoma cell line HepG2-pV highly expressing vimentin is obtained. Recombinant vimentin protein suppresses the proliferative and invasive abilities of HepG2 cells, suggesting that it might decrease malignant phenotype of tumor cells in vitro. This work makes a foundation for further study on the relationship between vimentin and biological phenotype of carcinoma cells.


Controlled growth of organic 2D layered material thin films via interfacial methods.
The isolation of graphene from graphite triggered enormous interest in the study of 2D materials due to their remarkable physical properties. These 2D materials feature many unique properties, such as atomically thin flakes, a layered structure, a long-range order and a dangling bond-free surface, which are promising for broad applications in various fields including (opto)electronics, spintronics, catalysis and so on. Specially, organic 2D layered materials have the prominent advantage of their designable and tailorable chemical structure at the atomic level. The preparation of organic 2D layered material thin films has become a very hot research topic in the materials fields because of their great potential to be integrated into advanced nanodevices. Considering the lack of large single crystal samples, it is not possible to obtain large-scale films from the traditional top-down exfoliation methods. Various groups and our previous studies prove the efficiency of interfacial synthesis methods for high-quality organic 2D layered material thin film preparation by restricting the reaction at the two-phase boundary area within a plane. As the performance of resultant films is highly related to their "quality" in aspects of continuity, crystallinity, uniformity, and thickness, the selection of interfaces and conditions is vitally important. Until now, many interfacial synthesis methods have been developed and modified for the controlled growth of high-quality organic 2D layered material thin films. This feature article reviews the recent advances in organic 2D layered material thin film preparation by interfacial methods. First, how the features of the interface affect the growth behavior of organic 2D layered materials is analyzed. Then, varieties of organic 2D layered material thin films with different chemical structures grown at various interfaces are discussed. Finally, the challenges and prospects in the interfacial synthesis of high-quality organic 2D layered materials are also explored.


Glycolic acid peel therapy - a current review.
Chemical peels have been time-tested and are here to stay. Alpha-hydroxy peels are highly popular in the dermatologist's arsenal of procedures. Glycolic acid peel is the most common alpha-hydroxy acid peel, also known as fruit peel. It is simple, inexpensive, and has no downtime. This review talks about various studies of glycolic acid peels for various indications, such as acne, acne scars, melasma, postinflammatory hyperpigmentation, photoaging, and seborrhea. Combination therapies and treatment procedure are also discussed. Careful review of medical history, examination of the skin, and pre-peel priming of skin are important before every peel. Proper patient selection, peel timing, and neutralization on-time will ensure good results, with no side effects. Depth of the glycolic acid peel depends on the concentration of the acid used, the number of coats applied, and the time for which it is applied. Hence, it can be used as a very superficial peel, or even a medium depth peel. It has been found to be very safe with Fitzpatrick skin types I-IV. All in all, it is a peel that is here to stay.


Involucrin-like proteins in non-primates.
A monoclonal and two polyclonal antibodies to human involucrin were used to look for involucrin epitopes in other species. All antibodies react strongly with the same proteins of monkey, and both polyclonal antibodies react with specific proteins of cow and dog. One of the polyclonal antibodies also reacts with proteins of sheep, guinea pig, rat, and finback whale. The immunoreactive proteins from cow and dog could be purified using a procedure developed for human involucrin. The reaction with the purified dog protein could be blocked by purified human involucrin. The results suggest that involucrin-like proteins have a wider species distribution than originally appreciated.


Fully spin-polarized Weyl fermions and in/out-of-plane quantum anomalous Hall effects in a two-dimensional d0 ferromagnet.
The quantum anomalous Hall effect (QAHE) in intrinsic ferromagnets has attracted considerable attention recently. Previously, studies of the QAHE have mostly focused on the default assumption of out-of-plane magnetization. In fact, the QAHE can also be achieved via in-plane magnetization, but such candidate materials are very scarce. Here, we find that two-dimensional (2D) YN2 not only possesses the previously reported out-of-plane QAHE, but it also possesses a tunable in-plane QAHE. More importantly, unlike the previously reported in-plane QAHE in d/f-type ferromagnets, here we report the effect in a 2D d0 ferromagnet, namely YN2, for the first time. In the ground state, a YN2 monolayer has a half-metal band structure, and manifests six pairs of fully spin-polarized Weyl points at the Fermi level. When spin-orbit coupling is included, the YN2 monolayer can realize multiple topological phases, determined based on the magnetization direction. Under in-plane magnetization, the YN2 monolayer shows either the Weyl state or in-plane QAHE state. Remarkably, the Chern number (±1) and the propagating direction of QAHE edge channels can be continuously switched via shifting the direction of the in-plane magnetic field. When magnetization is applied out-of-plane, the YN2 monolayer realizes an out-of-plane QAHE phase with a high Chern number of 3. The nontrivial edge states for all the topological phases in the YN2 monolayer have been clearly identified. This work suggests that 2D YN2 is an excellent candidate for investigating in-plane QAHE phases in d0 ferromagnets.


William G. Lennox: a remembrance.
William G. Lennox, author of Epilepsy and Related Disorders, had a lasting effect on our understanding of this illness. He postulated that epilepsy was not a unitary condition and that neuronal chemistries differed from one form of the disease to another. A leader in the use of electroencephalography in epilepsy, he described the first nearly pathognomonic EEG pattern and demonstrated specific features for each of the three most common types of seizure. His pioneering investigations into the biochemical basis of epilepsy helped to identify pathological mechanisms in epileptic attacks. Lennox stood alone in his belief, now generally accepted, that the genetics of epilepsy could be understood only through a multifactorial mode of inheritance. The author presents an affectionate portrait of the physician, the teacher and the man, the founder of the Seizure Unit and the unifying force in the study of epilepsy by both professionals and lay persons.


Angioleiomyoma of the Auricle: An Unusual Tumor on a Rare Location.
Cutaneous angioleiomyomas (ALMs) (also known as vascular leiomyomas or angiomyomas) are unusual benign tumors of the skin deriving from the muscle layer of dermal blood vessels. They usually manifest as tender subcutaneous nodules, mostly encountered on the legs of adult women in their fifth or sixth life decade. ALMs rarely develop on the head/neck area, and even more rarely (<3% of all cases) on the auricle. Head/neck (including ear) ALMs differ from their more usual leg counterparts in that they are usually painless and do not show a female predominance. The diagnosis is clinically difficult, and most cases are diagnosed by histopathologic examination. A new case of an auricular ALM in a 40-year-old Caucasian man is reported herein, and a brief literature review on this unusual tumor is presented.


[Mixed and palatal salivary secretion in denture-wearing healthy people and in patients with Sjogren syndrome].
Denture retention is related to forces necessary to completely remove the denture from its basal seat. The liquid-joint model for explaining denture retention is accepted by most of the authors. According to this model retentive force is a function of saliva surface tension, liquid film thickness, surface of contact and the liquid-denture contact angle. Based upon the literature, mucosa covered with the least amount of saliva exists at the area of the palate and the upper lip, consequently at the area of the upper denture retention. Dryness is dependent on the volume of saliva present on the oral mucous membranes and the rate of its evaporation of them. However, the hard palate contains few minor glands and it is an area of high evaporation. Based on the above mentioned facts, patients with xerostomia might have problems with the stability of the complete dentures. To verify it, authors investigated 24 healthy people and 11 patients with Sjögren's syndrome (SS). Further aim of the authors was to determine how the new dentures influence the whole resting and the palatal saliva flow rate. According to the results whole resting saliva flow rate is decreased in SS because of the focal inflammation of the salivary glands, but surprisingly the palatal secretion rate does not change in SS related to the initial values of the healthy people. Although every patient had xerostomia (WRS < or = 0.1 ml/min), none of them complained about denture instability. Based upon this study, authors agree with the statement of the literature, that palatal mucous saliva can help to stabilize the maxillary denture. Results suggest that whole resting and palatal saliva flow rates are not influenced by the placement of new dentures in healthy complete denture wearers.


Neurobiological effects of bisphenol A may be mediated by somatostatin subtype 3 receptors in some regions of the developing rat brain.
Considerable attention has been focused on environmental disruptors such as the xenoestrogen bisphenol A, which influences reproductive, developmental, and cognitive activities through its interaction with specific neuromediating systems in an estrogen-like fashion. In the present study, the effects of this xenoestrogen proved to be preferentially directed toward hypothalamic and extrahypothalamic somatostatin receptor subtype 3, which displayed a higher binding affinity of its specific nonpeptide agonist L-796-778 than that of L-779-976 (subtype 2). One type of action, with respect to animals treated with vehicle alone, consisted of a very strong (p < 0.001) decrease of somatostatin receptor subtype 3 mRNA levels in layer V of the frontoparietal cortex of adult rats (Sprague-Dawley) after transplacental and lactational exposure to bisphenol A (400 microg/kg/day). Similarly, such treatment in 7-day-old rats was responsible for a very strong reduction of the subtype 3 mRNA levels in the hypothalamic periventricular nuclei and a strong (p < 0.01) increase of the subtype 3 mRNA levels in the ventromedial nuclei. Moreover, even greater upregulated and downregulated activities were reported when subtype 3 mRNA levels were determined in the presence of receptor agonists specific for distinct alpha GABA(A) receptor subunits (alpha(1,5)). The predominant effects of bisphenol A on somatostatin receptor subtype 3 mRNA levels occurring in an alpha GABA(A) subunit-dependent manner tend to suggest the early modulatory importance of this environmental disruptor on cross-talking mechanisms that are implicated in the plasticity of neural circuits, with consequential influence on neuroendocrine/sociosexual behaviors.


Quality of life in quadriplegic adults: a focus group study.
This article describes a study whose purpose was to provide additional information about the components of quality of life for quadriplegic individuals. A focus group technique was used to determine subjects' opinions about what constitutes an acceptable quality of life. Three focus groups with a total of 14 subjects met to discuss the topic. Transcripts of the interviews were analyzed to determine themes and to identify components of quality of life for these individuals. Findings indicate that the factors influencing quality of life for quadriplegics include inner strength/survival, finances, relationships, job/productivity, health, level of activity, assertiveness, and independence/dependence. These findings will provide health professionals and policymakers with information about what factors quadriplegics consider important to maintaining an acceptable quality of life. This knowledge is necessary for public policy development, resource allocation, and interventions that will enhance the quality of life for people affected by quadriplegia.


[Echocardiography in athletes].
Echocardiography of athletes focuses on the left ventricle: in many cases, the interpretation is difficult, showing features of either dilated of hypertrophic cardiomyopathy. Accurate analysis requires careful recording of the left ventricle in the fundamental mode. Diagnostic errors by excess are common: overestimation of the chamber size (inadequate incidence), overestimation of wall thickness (failure to recognise right ventricular bands or false tendons). The body size of the individual must be considered when interpreting the chamber dimensions. The diastolic left ventricular dimension is often < 60 mm but it may attain 70 mm. In these cases, left ventricular function must be accurately determined and shown to be normal, which may prove difficult as the resting left ventricular ejection fraction is physiologically lower in trained athletes. The use of stress echo (exercise left ventricular ejection fraction) and Doppler tissue imaging (left ventricular filling) are often indispensable. Left ventricular wall thickness is rarely > 13 mm. a situation where the possibility of hypertrophic cardiomyopathy has to be assessed. Left atrial dilatation is inconstant and aortic root dilatation is very unusual. The right heart chambers are usually globally dilated and the inferior vena cava may seem abnormally dilated.


Neonatal myasthenia gravis. Anti-acetylcholine receptor antibodies in the amniotic fluid.
Neonatal myasthenia gravis (NMG) with mild arthrogryposis was observed at birth in the newborn infant of a myasthenic mother. Anti-acetylcholine receptor (anti-AChR) antibodies were present in the serum of both mother and child, in umbilical cord serum and in the amniotic fluid. The presence of anti-AChR antibodies in the amniotic fluid may be one of the causes of the NMG.


The biological effects of simple tandem repeats: lessons from the repeat expansion diseases.
Tandem repeats are common features of both prokaryote and eukaryote genomes, where they can be found not only in intergenic regions but also in both the noncoding and coding regions of a variety of different genes. The repeat expansion diseases are a group of human genetic disorders caused by long and highly polymorphic tandem repeats. These disorders provide many examples of the effects that such repeats can have on many biological processes. While repeats in the coding sequence can result in the generation of toxic or malfunctioning proteins, noncoding repeats can also have significant effects including the generation of chromosome fragility, the silencing of the genes in which they are located, the modulation of transcription and translation, and the sequestering of proteins involved in processes such as splicing and cell architecture.


The temporal distribution of directional gradients under selection for an optimum.
Temporal variation in phenotypic selection is often attributed to environmental change causing movements of the adaptive surface relating traits to fitness, but this connection is rarely established empirically. Fluctuating phenotypic selection can be measured by the variance and autocorrelation of directional selection gradients through time. However, the dynamics of these gradients depend not only on environmental changes altering the fitness surface, but also on evolution of the phenotypic distribution. Therefore, it is unclear to what extent variability in selection gradients can inform us about the underlying drivers of their fluctuations. To investigate this question, we derive the temporal distribution of directional gradients under selection for a phenotypic optimum that is either constant or fluctuates randomly in various ways in a finite population. Our analytical results, combined with population- and individual-based simulations, show that although some characteristic patterns can be distinguished, very different types of change in the optimum (including a constant optimum) can generate similar temporal distributions of selection gradients, making it difficult to infer the processes underlying apparent fluctuating selection. Analyzing changes in phenotype distributions together with changes in selection gradients should prove more useful for inferring the mechanisms underlying estimated fluctuating selection.


Amino Acid Substitution K470R in the Nucleoprotein Increases the Virulence of H5N1 Influenza A Virus in Mammals.
H5N1 is a highly pathogenic influenza A virus (IAV) and poses a major threat to the public health. The nucleoprotein (NP) has a multiple functions during the viral life cycle, however, the precise role of NP mutants in viral replication and pathogenicity is not completely understood. Here, we attempted to identify five residues in NP that may contribute to viral replication or pathogenicity. Of these, K227R, K229R, and K470R viruses were successfully rescued by reverse genetic, but the K91R and K198R viruses were not viable. A mini-genome assay demonstrated that the NP mutations K91R and K198R significantly decreased the polymerase activity. Moreover, these two mutations resulted in disrupted cellular localization in mammalian cells. Importantly, mutation at position 470 of NP significantly increased its virulence in vitro and in vivo. These findings demonstrated that the NP protein plays a major role in influenza virulence and pathogenicity, which adds to the knowledge of IAV virulence determinants and may benefit IAV surveillance.


FOXA1 Reprogramming Dictates Retinoid X Receptor Response in ESR1-Mutant Breast Cancer.
Estrogen receptor alpha (ER/ESR1) mutations occur in 30% to 40% of endocrine resistant ER-positive (ER+) breast cancer. Forkhead box A1 (FOXA1) is a key pioneer factor mediating ER-chromatin interactions and endocrine response in ER+ breast cancer, but its role in ESR1-mutant breast cancer remains unclear. Our previous FOXA1 chromatin immunoprecipitation sequencing (ChIP-seq) identified a large portion of redistributed binding sites in T47D genome-edited Y537S and D538G ESR1-mutant cells. Here, we further integrated FOXA1 genomic binding profile with the isogenic ER cistrome, accessible genome, and transcriptome data of T47D cell model. FOXA1 redistribution was significantly associated with transcriptomic alterations caused by ESR1 mutations. Furthermore, in ESR1-mutant cells, FOXA1-binding sites less frequently overlapped with ER, and differential gene expression was less associated with the canonical FOXA1-ER axis. Motif analysis revealed a unique enrichment of retinoid X receptor (RXR) motifs in FOXA1-binding sites of ESR1-mutant cells. Consistently, ESR1-mutant cells were more sensitive to growth stimulation with the RXR agonist LG268. The mutant-specific response was dependent on two RXR isoforms, RXR-α and RXR-β, with a stronger dependency on the latter. In addition, T3, the agonist of thyroid receptor (TR) also showed a similar growth-promoting effect in ESR1-mutant cells. Importantly, RXR antagonist HX531 blocked growth of ESR1-mutant cells and a patient-derived xenograft (PDX)-derived organoid with an ESR1 D538G mutation. Collectively, our data support the evidence for a stronger RXR response associated with FOXA1 reprograming in ESR1-mutant cells, suggesting development of therapeutic strategies targeting RXR pathways in breast tumors with ESR1 mutation. It provides comprehensive characterization of the role of FOXA1 in ESR1-mutant breast cancer and potential therapeutic strategy through blocking RXR activation.


Computer-based ophthalmotropes.
The versatility of a computer-based display of the extraocular muscles is demonstrated by comparing two different assumptions as to the paths of the muscles over the globe.


A clinicopathologic study of thrombotic microangiopathy in the setting of IgA nephropathy.
IgA nephropathy is the most common glomerulonephritis in the world. Thrombotic microangiopathy occurs in a number of clinical settings, including but not limited to thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, malignant hypertension, anti-phospholipid antibody syndrome and radiation nephropathy. Renovascular complications, such as thrombotic microangiopathy, in the setting of IgA nephropathy may be overlooked and their significance as a concomitant histologic finding is unclear. We conducted a clinicopathologic study to understand the possible relationship between IgA nephropathy and a concurrent thrombotic microangiopathy injury process. We identified 10 patients with an established diagnosis of IgA nephropathy and concurrent findings of thrombotic microangiopathy based on their renal biopsies. Six patients presented with malignant hypertension, while three others had severe hypertension (> or = 100 mmHg, diastolic). Five patients had nephrotic-range proteinuria. Seven patients had occasional arteriolar thrombi identified by light microscopy and prominent glomerular subendothelial space widening by electron microscopy, while three patients demonstrated only ultrastructural features of thrombotic microangiopathy. Other possible etiologic causes of thrombotic microangiopathy were not identified with the available clinical information. Our study suggests that a thrombotic microangiopathy injury, when present, is usually found in advanced stages of IgA nephropathy and can be associated with severe proteinuria. Although other possible causes of thrombotic microangiopathy, such as anti-phospholipid antibody syndrome, were excluded in only two patients, the thrombotic microangiopathy injury process may be a cause or a consequence of the severe hypertension encountered in most of the patients which, in turn, may be a consequence of the disease progression of IgA nephropathy.


Loss of Growth Hormone Gene (gh1) in Zebrafish Arrests Folliculogenesis in Females and Delays Spermatogenesis in Males.
As a master hormone controlling growth and metabolism, GH is also known to regulate reproduction. Studies in mammals have shown that mutations in GH or its receptor (GHR) not only result in retardation in body growth but also reproductive dysfunctions in both sexes. However, the roles of GH in reproduction of other vertebrates are poorly defined. In this study, we created two zebrafish GH (gh1) mutant lines using CRISPR/Cas9. The mutant developed normally up to 14 days postfertilization (dpf); however, a high rate of mortality was observed afterward in both lines, and only a small number of mutant fish could survive to adult stage. The body growth of the mutants was significantly retarded in both sexes in a gene dose-dependent manner compared with their wild-type siblings. A severe dysfunction of gonadal development was observed in survived mutant females, with ovarian folliculogenesis being arrested completely at primary growth stage until 100 dpf. Interestingly, the folliculogenesis in the mutant resumed after months of delay with a certain number of follicles entering vitellogenic growth. As for male reproduction, although the spermatogenesis in mutant males seemed normal in adults, the GH-insufficient heterozygote showed an obvious delay of spermatogenesis (puberty onset) at early developmental stages. The adult mutant males could not breed with wild-type females through natural spawning; however, the sperm isolated from the mutant testes could fertilize eggs through artificial fertilization. This study provides further genetic evidence for the dependence of puberty onset on somatic growth, but not age, in fish.


Undecaprenyl pyrophosphate phosphatase confers low-level resistance to bacitracin in Enterococcus faecalis.
Undecaprenyl pyrophosphate phosphatases (UppPs) have been implicated in bacitracin resistance in some bacterial genera and the aim of this study was to determine the role of UppPs in mediating low-level bacitracin resistance in Enterococcus faecalis. The uppP gene was identified in the genomes of laboratory (JH2-2) and clinical (V583) strains of E. faecalis. Gene fusions (uppP-lacZ) and 5'-RACE were used to study uppP expression. The uppP gene in both strains was inactivated and mutants were studied for antimicrobial susceptibility and their susceptibilities to various stress agents. The UppP protein from E. faecalis showed high sequence identity to the Escherichia coli BacA-type UppP and was predicted to be a hydrophobic protein with eight transmembrane helices. The expression of uppP-lacZ was constitutive and not affected by bacitracin or cell wall-active antimicrobials. E. faecalis uppP mutants showed no significant changes in growth rate, colony morphology and biofilm formation. The uppP mutants exhibited increased susceptibility to bacitracin (MICs=3-6 mg/L) relative to the isogenic wild-type (MICs=32-48 mg/L). When uppP was expressed in a wild-type background, the MIC of bacitracin increased to 128-≥256 mg/L. The MICs of cefoxitin, teicoplanin, vancomycin, gentamicin, enrofloxacin and d-cycloserine were unaltered in the uppP mutant relative to the wild-type, as were susceptibilities to other stress agents (glycine, lysozyme, NaCl, SDS, low and high pH, oxidative stress and ethanol). The results demonstrate that low-level bacitracin resistance in E. faecalis is mediated by a BacA-type UppP.


Gene Deletion in Barley Mediated by LTR-retrotransposon BARE.
A poly-row branched spike (prbs) barley mutant was obtained from soaking a two-rowed barley inflorescence in a solution of maize genomic DNA. Positional cloning and sequencing demonstrated that the prbs mutant resulted from a 28 kb deletion including the inflorescence architecture gene HvRA2. Sequence annotation revealed that the HvRA2 gene is flanked by two LTR (long terminal repeat) retrotransposons (BARE) sharing 89% sequence identity. A recombination between the integrase (IN) gene regions of the two BARE copies resulted in the formation of an intact BARE and loss of HvRA2. No maize DNA was detected in the recombination region although the flanking sequences of HvRA2 gene showed over 73% of sequence identity with repetitive sequences on 10 maize chromosomes. It is still unknown whether the interaction of retrotransposons between barley and maize has resulted in the recombination observed in the present study.


Kinetic analysis of cephalosporin biosynthesis in Streptomyces clavuligerus.
A kinetic model describing the cephalosporin biosynthesis in Streptomyces clavuligerus was developed. Using previously reported kinetic data of biosynthetic enzymes, we examined the kinetics of cephalosporin production. The predicted time profile of the specific production rate during a batch culture parallels that of experimental observation. Sensitivity analysis reveals that delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) synthetase is the rate-limiting enzyme. The effect of amplifying ACV synthetase on the specific production rate was analyzed theoretically. Increasing ACV synthetase enhances the production rate initially until ACV synthetase enhances the production rate initially until deacetocycephalosporin C hydroxylase becomes rate-limiting. Such kinetic analysis can provide a rational basis for modifying the biosynthetic machinery of cephalosporin through gene cloning.


A critical analysis of computational protein design with sparse residue interaction graphs.
Protein design algorithms enumerate a combinatorial number of candidate structures to compute the Global Minimum Energy Conformation (GMEC). To efficiently find the GMEC, protein design algorithms must methodically reduce the conformational search space. By applying distance and energy cutoffs, the protein system to be designed can thus be represented using a sparse residue interaction graph, where the number of interacting residue pairs is less than all pairs of mutable residues, and the corresponding GMEC is called the sparse GMEC. However, ignoring some pairwise residue interactions can lead to a change in the energy, conformation, or sequence of the sparse GMEC vs. the original or the full GMEC. Despite the widespread use of sparse residue interaction graphs in protein design, the above mentioned effects of their use have not been previously analyzed. To analyze the costs and benefits of designing with sparse residue interaction graphs, we computed the GMECs for 136 different protein design problems both with and without distance and energy cutoffs, and compared their energies, conformations, and sequences. Our analysis shows that the differences between the GMECs depend critically on whether or not the design includes core, boundary, or surface residues. Moreover, neglecting long-range interactions can alter local interactions and introduce large sequence differences, both of which can result in significant structural and functional changes. Designs on proteins with experimentally measured thermostability show it is beneficial to compute both the full and the sparse GMEC accurately and efficiently. To this end, we show that a provable, ensemble-based algorithm can efficiently compute both GMECs by enumerating a small number of conformations, usually fewer than 1000. This provides a novel way to combine sparse residue interaction graphs with provable, ensemble-based algorithms to reap the benefits of sparse residue interaction graphs while avoiding their potential inaccuracies.


Custom-made micro applicators for high-dose-rate brachytherapy treatment of chronic psoriasis.
In this study, we present the treatment of the psoriatic nail beds of patients refractory to standard therapies using high-dose-rate (HDR) brachytherapy. The custom-made micro applicators (CMMA) were designed and constructed for radiation dose delivery to small curvy targets with complicated topology. The role of the HDR brachytherapy treatment was to stimulate the T cells for an increased immune response. The patient diagnosed with psoriatic nail beds refractory to standard therapies received monthly subunguinal injections that caused significant pain and discomfort in both hands. The clinical target was defined as the length from the fingertip to the distal interphalangeal joint. For the accurate and reproducible setup in the multi-fractional treatment delivery, the CMMAs were designed. Five needles were embedded into the dense plastic mesh and covered with 5 mm bolus material for each micro applicator. Five CMMAs were designed, resulting in the usage of 25 catheters in total. The prescription dose was planned to the depth of the anterior surface of the distal phalanx, allowing for the sparing of the surrounding tissue. The total number of the active dwell positions was 145 with step size of 5 mm. The total treatment time was 115 seconds with a 7.36 Ci activity of the 192Ir source. The treatment resulted in good pain control. The patient did not require further injections to the nail bed. After this initial treatment, additional two patients with similar symptoms received HDR brachytherapy. The treatment outcome was favorable in all cases. The first HDR brachytherapy treatment of psoriasis of the nail bed is presented. The initial experience revealed that brachytherapy treatment was well-tolerated and resulted in adequate control of the disease. A larger cohort of patients will be required for additional conclusions related to the long-term clinical benefits.


Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons.
Valosin-containing protein (VCP), also called p97, is an evolutionarily conserved and ubiquitously expressed ATPase with diverse cellular functions. Dominant mutations in VCP are found in a late-onset multisystem degenerative proteinopathy. The neurological manifestations of the disorder include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In these patients, long motor neuron axons could be particularly susceptible to defects in axonal transport. However, whether VCP has a physiological function in maintaining axonal transport and whether this role is impaired by disease-causing mutations remains elusive. Here, by employing live-imaging methods in Drosophila larval axons and performing genetic interaction experiments, we discover that VCP regulates the axonal transport of mitochondria. Downregulation of VCP enhances the retrograde transport of mitochondria and reduces the density of mitochondria in larval axons. This unidirectional motility phenotype is rescued by removing one copy of the retrograde motor dynein heavy chain (DHC), or elevating Miro which facilitates anterograde mitochondrial movement by interacting with the anterograde motor kinesin heavy chain (KHC). Importantly, Miro upregulation also significantly improves ATP production of VCP mutant larvae. We investigate human VCP pathogenic mutations in our fly system. We find that expressing these mutations affects mitochondrial transport in the same way as knocking down VCP. Our results reveal a new role of VCP in mediating axonal mitochondrial transport, and provide evidence implicating impaired mitochondrial motility in the pathophysiology of VCP-relevant neurodegenerative diseases.


A meta-analysis of 20 case-control studies of the glutathione S-transferase M1 (GSTM1) status and colorectal cancer risk.
Glutathione S-transferase M1 is an important phase II enzyme involved in the detoxification of many environmental carcinogens. It has been postulated that individuals with GSTM1 deficiency have increased susceptibility to carcinogens and are more likely to develop cancer. GSTM1 status has been extensively studied as a colon cancer risk factor, although published studies have produced conflicting results. To re-examine this controversy, we have undertaken a meta-analysis investigating the relationship of GSTM1 status and colon cancer risk. Odds ratio was employed to evaluate the risk of colon cancer and GSTM1 status. To take into account the possibility of heterogeneity across the studies, a statistical test for heterogeneity across the studies was performed. The summary odds ratios were assessed by calculating a weighted average of odds ratios for all of the studies. The pooled odds ratio of colon cancer risk associated with the GSTM1 deficiency is 0.99 (95% CI: 0.91-1.07). If pooling studies were based on the genotyping method, the overall odds ratio of colon cancer risk associated with the GSTM1 deficiency showed no difference. Moreover, the relationship of GSTM1 deficiency and colon cancer risk was also conducted on the specific ethnic groups and tumour site. The results of our meta-analysis does not support the hypothesis that GSTM1 alone is an important risk factor for colon cancer, and suggests that GSTM1 status has no effect on the risk of developing colon cancer.


[Regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats].
To investigate the regulatory effects of ninjurin-1 on adhesion of myeloid cells in the retina at the early stage of diabetic rats. Experimental study. The rat diabetic model was induced by intraperitoneal injection of streptozotocin. After 2 months of diabetes induction, 27 diabetic rats were randomly chosen and assigned to 3 groups, including diabetes and phosphate buffered saline (PBS) injection group (group B), diabetes and anti-Ninj-1 injection group (group C) and diabetes and anti-IgG injection group (group D), with 9 rats in each group. Nine age matched health rats were chosen as control group (group A). Retinal leukostasis was quantified with acridine orange leukocyte fluorography. Retinal myeloid cell infiltration activity was measured by enzyme linked immunosorbent assay of myeloperoxidase (MPO). The differences of the mean values among the four groups were analyzed by one-factor analysis of variance. The multiple comparisons of the mean values among the four groups were analyzed by LSD-t analysis. According to the results of the acridine orange leukocyte fluorography, the numbers of leukocyte adhesion in the four groups were 49.66 ± 13.51, 153.66 ± 20.43, 85.33 ± 15.03 and 156.33 ± 11.53, respectively. The differences among them were significant (F = 143.34, P = 0.000). The numbers of leukocyte adhesion in the group C were significantly lower than that in group B (P = 0.000, 95%CI: -82.68 - -53.98). The levels of retinal MPO in the four groups were (15.66 ± 2.08), (27.66 ± 2.51), (18.02 ± 2.01) and (26.66 ± 3.21) µg/L, respectively. The differences among them were significant (F = 17.61, P = 0.010). The level of retinal MPO in the group C was significantly lower than that in group B (P = 0.010, 95%CI: -14.37 - -4.95). Ninj-1 may play a role in the mediation of the adhesion of myeloid cell to the rat retina of early-stage of diabetes in vivo.


Minute Virus of Canines NP1 Protein Governs the Expression of a Subset of Essential Nonstructural Proteins via Its Role in RNA Processing.
Parvoviruses use a variety of means to control the expression of their compact genomes. The bocaparvovirus minute virus of canines (MVC) encodes a small, genus-specific protein, NP1, which governs access to the viral capsid gene via its role in alternative polyadenylation and alternative splicing of the single MVC pre-mRNA. In addition to NP1, MVC encodes five additional nonstructural proteins (NS) that share an initiation codon at the left end of the genome and which are individually encoded by alternative multiply spliced mRNAs. We found that three of these proteins were encoded by mRNAs that excise the NP1-regulated MVC intron immediately upstream of the internal polyadenylation site, (pA)p, and that generation of these proteins was thus regulated by NP1. Splicing of their progenitor mRNAs joined the amino termini of these proteins to the NP1 open reading frame, and splice site mutations that prevented their expression inhibited virus replication in a host cell-dependent manner. Thus, in addition to controlling capsid gene access, NP1 also controls the expression of three of the five identified NS proteins via its role in governing MVC pre-mRNA splicing.IMPORTANCE The Parvovirinae are small nonenveloped icosahedral viruses that are important pathogens in many animal species, including humans. Minute virus of canine (MVC) is an autonomous parvovirus in the genus Bocaparvovirus It has a single promoter that generates a single pre-mRNA. NP1, a small genus-specific MVC protein, participates in the processing of this pre-mRNA and so controls capsid gene access via its role in alternative internal polyadenylation and splicing. We show that NP1 also controls the expression of three of the five identified NS proteins via its role in governing MVC pre-mRNA splicing. These NS proteins together are required for virus replication in a host cell-dependent manner.


[Diagnosis and treatment of primary bronchial low-grade malignant tumors].
From Jan. 1978 to July 1992, 24 cases with primary bronchial low-grade malignant tumors were be operated at our hospital. They were collected from 1016 cases with primary pulmonary malignant tumors in the same period treated in our hospital. The incidence was 2.36%. Eleven cases were of bronchial carcinoid, 10 were mucoepidermoid, and 3 were adenoid cystic carcinoma. The preoperative disease history was average 19.6 months. The resection rate was 95.8% (23/24). Postoperative 5-year survival was 70%. Even though the operation was palliative resection, the cases can life many years with tumor. In the group, the malignancy of mucoepidermoid carcinoma was the highest. The authors agree to discard the traditional term "bronchial adenoma". The clinical and pathological characteristics of every type of the tumors were discussed.


Hematological Parameters for Predicting Mortality in Acute Exacerbation of Chronic Obstructive Pulmonary Disease.
(1) Introduction: COPD is a common and serious condition affecting a significant proportion of the population globally. Patients often suffer from exacerbations which lead to the worsening of their health status and respiratory function, and can often lead to death. Quick and cheap investigations are required that are capable of predicting mortality in patients with acute exacerbations that can be applied in low resource settings. (2) Materials and methods: This was a retrospective study carried out using hospital records of patients admitted for AECOPD from 1 January 2017 to 30 November 2022. Chi-square test (for sex) and Student's t-test were used to look for significant associations. Receiver Operating Characteristics (ROC) curves were plotted and Area Under Curve (AUC) values were calculated for various hematological parameters. Youden's J was used to identify the ideal cut-off with optimal sensitivity and specificity. Multivariate Cox regression was used to identify independent hematological predictors of mortality. Kaplan-Meir survival plots for neutrophil lymphocyte ratio (NLR) with the optimal cut-off were plotted. (3) Results: Amongst the 500 patients, 42 died while 458 survived, giving a mortality rate of 8.4%. NLR had the strongest association with mortality. The cut-off for various parameters were: NLR 14.83 (AUC 0.73), total leukocyte count (TLC) 13,640 cells/mm3 (AUC 0.60), absolute neutrophil count (ANC) 12,556 cells/mm3 (AUC 0.62), derived NLR (dNLR) 9.989 (AUC 0.73), hemoglobin 11.8 mg/dL (AUC 0.59), packed cell volume (PCV) 36.6% (AUC 0.60), and platelet lymphocyte ratio (PLR) 451.32 (AUC 0.55). (4) Conclusions: In patients with acute exacerbation of COPD, NLR was strongly associated with mortality, followed by dNLR. Cox regression identified NLR as an independent predictor of mortality.


Multi-view integration of microbiome data for identifying disease-associated modules.
Machine learning (ML) has become a widespread strategy for studying complex microbiome signatures associated with disease. To this end, metagenomics data are often processed into a single "view" of the microbiome, such as its taxonomic (species) or functional (gene) composition, which in turn serves as input to such ML models. When further omics are available, such as metabolomics, these can be analyzed as additional complementary views. Following training and evaluation, the resulting model can be explored to identify informative features, generating hypotheses regarding underlying mechanisms. Importantly, however, using a single view generally offers relatively limited hypotheses, failing to capture simultaneous shifts or dependencies across multiple microbiome layers that likely play a role in microbiome-host interactions. In this work, inspired by the broad domain of multi-view learning , we aimed to investigate the impact of various integration approaches on the ability to predict disease state based on multiple microbiome views, and primarily to generate multifaceted biological hypotheses linking features across views. We first implemented an "early integration" ML pipeline to serve as a baseline for disease predictability and informative features' detection, and compared the resulting multi-view models to naïve single view models. Using a dataset collection of 25 case-control metagenomic studies, we found that multi-view models typically offer prediction accuracy that is comparable to that of the best-performing single view model, yet, further provide a mixed set of informative features from different views while accounting for between-views dependencies. Such early-integration multi-view models, however, are still limited in their ability to provide well-defined disease-associated multi-view modules that can be used to generate mechanistic hypotheses concerning the disease in question. To address this challenge, we developed a novel "intermediate integration" framework termed MintTea, based on sparse generalized canonical correlation analysis (CCA), to identify multi-view modules of features, highlighting shared disease-associated trends in the data expressed by the different views. We showed that this framework identified multiple modules that both are highly predictive of the disease, and exhibit strong within-module associations across features from different views. We further demonstrated that MintTea has significantly lower false discovery rates compared to other CCA-based approaches. We accordingly advocate for using multi-view models to capture multifaceted microbiome signatures that likely better reflect the complex mechanisms underlying microbiome-disease associations.


An objective measure of seat comfort.
Uncomfortable aircrew seating is more than just a nuisance, it has the potential to produce a cumulative trauma which can significantly affect attention, information processing, and task performance to the extent of interfering with mission completion or contributing to mishaps. Yet, for decades uncomfortable seating has endured as an aircrew complaint with little progress made toward resolving it. Aircraft design techniques have steadily progressed, but the method for ascertaining seating pressure issues has remained, unfortunately, the same: simply ask aircrew where it hurts and hope some cushion changes work. Currently, there exist sensor technologies which potentially can economically and effectively address this problem by reducing the comfort analysis to the examination of an objective, quantitative pressure map. This technical note discusses the brief history of seat pressure measurement research, enumerates some of the technologies that are available that can be applied to the problem, and finally, describes a seated pressure measurement demonstration which shows the power of the approach for maximizing comfort.


A new monoclonal antibody recognizing anthracyclinic molecule.
The immunosuppressive effect of Doxorubicin (DXR) has been circumvented so that monoclonal antibodies (MAbs) reacting with DXR and other anthracycline derivatives have been obtained. The MAb described here (MAD11) belongs to the IgG2 class and selectively recognizes epitopes located at or near the aromatic ring D of the anthracycline molecule. MAD11 differs from another MAb (MAD2) obtained from the same somatic hybridization and previously described which preferentially reacts with aliphatic ring A of anthracycline.


The human RVB complex is required for efficient transcription of type I interferon-stimulated genes.
Type I interferons (IFNs) stimulate transcription through a latent heterotrimeric transcription factor composed of tyrosine-phosphorylated STAT1 and STAT2 and the DNA binding partner IRF9, with STAT2 contributing a critical transactivation domain. Human RVB1 and RVB2, which are highly conserved AAA(+) ATP binding proteins contained in chromatin-remodeling complexes such as Ino80, SNF2-related CBP activator protein (SRCAP), and Tip60/NuA4, interacted with the transactivation domain of STAT2 in the nuclei of IFN-stimulated cells. RNA interference (RNAi) experiments demonstrated that RVB proteins were required for robust activation of IFN-α-stimulated genes (ISGs). The requirement for RVB proteins was specific to IFN-α/STAT2 signaling; transcription of tumor necrosis factor alpha (TNF-α)- and IFN-γ-driven genes was not affected by RVB1 depletion. Using RNAi-based depletion, we assessed the involvement of catalytic subunits of the RVB-containing Tip60, BRD8, Ino80, SRCAP, and URI complexes. No component other than RVB1/2 was uniquely required for ISG induction, suggesting that RVB1/2 functions as part of an as yet unidentified complex. Chromatin immunoprecipitation assays indicated that RVB1/2 was required for recruitment of RNA polymerase II (Pol II) to ISG promoters but was dispensable for STAT2 recruitment to chromatin. We hypothesize that an RVB1/2 chromatin-remodeling complex is required for efficient Pol II recruitment and initiation at ISG promoters and is recruited through interaction with the STAT2 transactivation domain.


Subcategory learning in normal and language learning-disabled adults: how much information do they need?
The purpose of this experiment was to determine if nonreferential morphophonological information was sufficient to facilitate the learning of gender subcategories (i.e., masculine vs. feminine) in individuals with normal language (NL) and those with a history of language-based learning disabilities (HLD). Thirty-two adults listened for 18 min to a familiarization set of Russian words that included either 1 (single-marked) or 2 (double-marked) morphophonological markers indicating gender. Participants were then tested on their knowledge of both trained and untrained members of each gender subcategory. Testing indicated that morphophonological information is sufficient for lexical subcategory learning in both NL and HLD groups, although the HLD group had lower overall accuracy. The HLD group benefited from double-marking relative to single-marking for subcategory learning. The results demonstrated that learning through implicit mechanisms occurred after a relatively brief exposure to the language stimuli. In addition, the weaker overall learning by the HLD group was facilitated when multiple cues to linguistic subcategory were available in the input group members received.


A Mercury Toxicity Case Complicated by Hyponatremia and Abnormal Endocrinological Test Results.
Mercury (Hg) poisoning is considered a rare disease by the National Institutes of Health and the diagnosis can present great challenges to clinicians. Children who are exposed to Hg can present with a wide variety of symptoms, including acrodynia, tremor, excessive salivation, and psychiatric symptoms, including insomnia. However, endocrinologic manifestations from Hg exposure are less well known. This is a case report of a 12-year-old boy who presented with body rash, irritability, insomnia, and profuse sweating after returning from a summer camp. The child was initially managed in the outpatient setting, and the investigation was mainly targeted toward infectious etiology, including Rocky Mountain spotted fever and Lyme disease. He was eventually admitted to the hospital with altered mental status and was noted to have hyponatremia with serum sodium of 121 mEq/L. Thyroid studies also revealed elevated free thyroxine levels in the presence of normal triiodothyronine and thyrotropin. The patient developed hypertension and tachycardia, and was found to have elevated 24-hour vanillylmandelic acid and metanephrines. Finally, heavy metal measurements revealed a blood Hg level that was greater than the reference values of 0 to 9 ng/mL. Chelation treatment with 2,3-dimercaptopropane-1-sulfonate was subsequently initiated and over a period of 8 months his symptoms resolved and his thyroid function test returned to normal. This case highlights some of the challenges commonly encountered in identifying Hg exposure. More importantly, it illustrates that exposure to Hg should be considered in children who present with the symptoms and abnormal endocrinologic test results described in this report.


Phenanthrene-Incorporated Isoamethyrin: A Near-Planar Macrocycle That Display Enhanced Aromaticity via Protonation-Triggered Conformation Changes.
Controlling the aromaticity in expanded porphyrins is a forefront research topic, and the strategy of using protonation-triggered conformational changes to fine-tune electronic properties and aromaticity has yet to be generalized in rigid and planar expanded porphyrins. Here, we synthesized phenanthrene-incorporated isoamethyrins that possess near-planar conformations and nonaromatic characters. However, when methanesulfonic acid (MSA) was added, geometric deformations occurred to minimize the unfavorable strain, resulting in macrocycles that were weakly aromatic as a whole.


Physical activity levels of economically disadvantaged women living in the Olympic city of Rio de Janeiro.
The objective of this study was to analyze the physical activity patterns of women living in a low-income community located in close proximity to the 2016 Rio de Janeiro Olympic Park. Data (N = 140) were collected in June and July 2012 using the International Physical Activity Questionnaire. Findings indicated that the majority (54.8%) of participants reported high levels of physical activity. The domains that contributed the most to this pattern were occupational and household physical activity. Significantly, 88.1% of participants reported low physical activity levels during their leisure-time. In the transport-related domain, participants were relatively more active, but more than half of them (57%) spent less than 600 MET-minutes/week in this domain. The results highlighted the discrepancies between different physical activity domains. In addition, the findings also suggested that low-income women in our study engaged little in physical activity during their leisure time. Therefore, the proposed commitments found in the Rio de Janeiro Candidature File to host the 2016 Olympic Games to increase sport/physical activity participation within low-income communities in Rio de Janeiro need to be implemented effectively if this physical activity behavior during self-directed time is to be changed.


Hemodynamic collapse due to the stenosis of four pulmonary veins in a patient with mediastinal tumor.
Cardiogenic shock can occur due to compression of the four pulmonary veins and the left atrium by a mediastinal tumor. Steroid infusion can be a temporary alternative therapy before obtaining a definite diagnosis and performing an intervention with stents to dilate the pulmonary veins.


[Diagnostic imaging and interventional radiology in abdominal abscess formations].
Abdominal abscesses as a complication of laparotomic surgery have a high mortality rate. The authors reviewed the diagnostic and therapeutic procedures of 36 patients who developed intra-abdominal abscesses after surgical treatment for abdominal neoplasias. The first-step diagnostic procedures (plain film of the abdomen and chest, CT and US) showed a sensibility of 78%. In 25/36 patients (69.5%) two interventional radiology procedures were performed: fine needle aspiration and catheter drainage of the abscess. In 16% of patients fine needle aspiration led to a complete evacuation of the abscess cavity and guaranteed the recovery. In 84% of cases a drainage catheter was positioned into the cavity and left indwelling. This case review is aimed at stressing how plain film of the abdomen is still a diagnostic procedure with high sensibility and specificity for this pathology, even though it is currently considered as a second-choice diagnostic step--US and CT being assessed as the methodologies of choice. The latter techniques can both provide a more accurate imaging when interventional radiology procedures are to be performed.


Toward patient-tailored summarization of lung cancer literature.
As the volume of biomedical literature increases, it can be challenging for clinicians to stay up-to-date. Graphical summarization systems help by condensing knowledge into networks of entities and relations. However, existing systems present relations out of context, ignoring key details such as study population. To better support precision medicine, summarization systems should include such information to contextualize and tailor results to individual patients. This paper introduces "contextualized semantic maps" for patient-tailored graphical summarization of published literature. These efforts are demonstrated in the domain of driver mutations in non-small cell lung cancer (NSCLC). A representation for relations and study population context in NSCLC was developed. An annotated gold standard for this representation was created from a set of 135 abstracts; F1-score annotator agreement was 0.78 for context and 0.68 for relations. Visualizing the contextualized relations demonstrated that context facilitates the discovery of key findings that are relevant to patient-oriented queries.


Luminography--an alternative assay for detection of von Willebrand factor multimers.
A luminescence assay was adapted for detection of von Willebrand factor multimers subsequent to SDS-agarose gel electrophoresis and electroblotting onto nitrocellulose. The method is as fast as chromogenic detection methods and appears to be as sensitive as autoradiography without the disadvantages of the latter.


An association study of SNP + 45 T > G of the AdipoQ gene with type 2 diabetes in Yi and Han people in China.
The Yi people are considered the most primitive society in China, and live in the remote mountainous areas of Southwestern China. There have been no previous publications on genetic research concerning type 2 diabetes (T2D) in the Yi people. This is the first report that presents the association between SNP + 45 T > G (rs2241766) of the AdipoQ gene and T2D in Yi people. Our previous study showed that the prevalence of T2D in Yi people was lower than the national level in 2008. Genetic differences between Yi and Han people might be one possible explanation for this observation. Studies on the single nucleotide polymorphism SNP + 45 T > G (rs2241766) of the AdipoQ gene in Chinese Han people showed inconsistent results. This study was designed to identify genetic variants of the AdipoQ gene that contribute to the development of T2D in Yi and Han people. A case-control study on the association between SNP + 45 T > G (rs2241766) of the AdipoQ gene and T2D was carried out based on a cross-sectional study in the Liangshan area, Sichuan province in Southwestern China. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to test for the presence of SNP + 45 T > G (rs2241766) in the AdipoQ gene. Distributions of genotypes variants (TT/GG/TG) were not significantly different between T2D cases and controls both in Yi and Han people in China (p > 0.05). The allele frequencies (T/G) demonstrated a non-significant association with T2D, displaying OR of 1.1 (95 % CI: 0.8, 1.6) in Yi people and OR of 1.0 (95 % CI: 0.7, 1.4) in Han people. The SNP + 45 (rs2241766) of the AdipoQ gene is not associated with T2D neither in Yi nor in Han people in southwestern China.


N1 latencies of the slow auditory evoked potential.
Several studies have been published concerning the relation between stimulus level and amplitude of the slow auditory evoked response. Little attention has, however, been given to the relation between level and latency of the N1 component (100-200 ms). A mathematical model of such a relation is proposed based on the assumption of an exponential relationship. The model has been tested on normally hearing subjects as well as on patients with sensorineural lesions, cochlear as well as retrocochlear. The results indicate that the proposed method of evaluating the slow evoked responses offers a way of threshold extrapolation with rather good accuracy. It also appears to be useful in determining the type of hearing loss.


Oxidation of Cathepsin D by Hydroxy Radical: Its Effect on Enzyme Structure and Activity against Myofibrillar Proteins Extracted from Coregonus peled.
In this study, cathepsin D was oxidized in vitro with different concentrations of H2O2, and the activity, structure, and extent of myofibrillar protein degradation by oxidized cathepsin D were evaluated. The sulfhydryl content of cathepsin D decreased to 9.20% after oxidation, while the carbonyl content increased to 100.06%. The β-sheet in the secondary structure altered due to oxidation as well. The changes in the intrinsic fluorescence and UV absorption spectra indicated that oxidation could cause swelling and aggregation of cathepsin D molecules. The structure of cathepsin D could change its activity, and the activity was highest under 1 mM H2O2. Cathepsin D could degrade myofibrillar proteins in different treatment groups, and the degree of degradation is various. Therefore, this study could provide a scientific basis for the mechanism of interaction among hydroxyl radical oxidation, cathepsin D, and MP degradation.


Delayed Metastatic Melanoma to the Pharyngeal Tonsil in an African American Female.
Background: Metastatic melanoma to the mucosa of the upper aerodigestive tract is extremely rare, accounting for <0.6% of known metastasis to the head and neck region. We present a case of delayed metastatic melanoma to the pharyngeal tonsil. Case Report: A 57-year-old African American female presented for evaluation of a rapidly enlarging unilateral tonsil mass. Three years prior to presentation, she had undergone primary resection of and systemic therapy for cutaneous melanoma on the sole of her right foot. Tonsillectomy confirmed the diagnosis of metastatic melanoma. Because of the poor prognosis of the disease, the patient was referred for palliative chemotherapy but died shortly after beginning treatment. Conclusion: Metastatic melanoma is a rare disease in African Americans, and the presence of metastatic lesions is a significant prognostic indicator for long-term patient survival. Meticulous head and neck examinations should be performed during the follow-up period, and any pigmented lesion should have a high suspicion for metastasis in any patient with a history of cutaneous melanoma.


Biological monitoring of occupational exposure to different chromium compounds at various valency states.
Chromium concentrations in the air were measured in seven different workroom environments, where exposure to water soluble hexavalent or trivalent compounds was expected. Urinary excretion of chromium was measured before and after the same arbitrarily chosen working day. End-of-shift urinary chromium and its increase above pre-exposure levels were closely related to the concentration of water soluble chromium (VI) in the air. The values corresponding to 50 micrograms m-3 in the air, which is the current threshold limit value in most countries, were 29.8 and 12.2 micrograms g-1 of creatinine, respectively. Urinary chromium in workers exposed to water insoluble chromates or to water soluble chromic (III) sulphate was definitely higher than that observed in subjects not occupationally exposed to chromium compounds, but it cannot be recommended as short-term exposure test for evaluation of the job-related hazard.


Nhp2 is a reader of H2AQ105me and part of a network integrating metabolism with rRNA synthesis.
Ribosome biogenesis is an essential cellular process that requires integration of extracellular cues, such as metabolic state, with intracellular signalling, transcriptional regulation and chromatin accessibility at the ribosomal DNA. Here, we demonstrate that the recently identified histone modification, methylation of H2AQ105 (H2AQ105me), is an integral part of a dynamic chromatin network at the rDNA locus. Its deposition depends on a functional mTor signalling pathway and acetylation of histone H3 at position K56, thus integrating metabolic and proliferative signals. Furthermore, we identify a first epigenetic reader of this modification, the ribonucleoprotein Nhp2, which specifically recognizes H2AQ105me. Based on functional and proteomic data, we suggest that Nhp2 functions as an adapter to bridge rDNA chromatin with components of the small subunit processome to efficiently coordinate transcription of rRNA with its post-transcriptional processing. We support this by showing that an H2AQ105A mutant has a mild defect in early processing of rRNA.


Assessment of geometrical characteristics of dental endodontic micro-instruments utilizing X-ray micro computed tomography.
The aim of this study was to quantify the surface area, volume and specific surface area of endodontic files employing quantitative X-ray micro computed tomography (mXCT). Three sets (six files each) of the Flex-Master Ni-Ti system (Nº 20, 25 and 30, taper .04) were utilized in this study. The files were scanned by mXCT. The surface area and volume of all files were determined from the cutting tip up to 16 mm. The data from the surface area, volume and specific area were statistically evaluated using the one-way ANOVA and SNK multiple comparison tests at α=0.05, employing the file size as a discriminating variable. The correlation between the surface area and volume with nominal ISO sizes were tested employing linear regression analysis. The surface area and volume of Nº 30 files showed the highest value followed by Nº 25 and Nº 20 and the differences were statistically significant. The Nº 20 files showed a significantly higher specific surface area compared to Nº 25 and Nº 30. The increase in surface and volume towards higher file sizes follows a linear relationship with the nominal ISO sizes (r²=0.930 for surface area and r²=0.974 for volume respectively). Results indicated that the surface area and volume demonstrated an almost linear increase while the specific surface area exhibited an abrupt decrease towards higher sizes. This study demonstrates that mXCT can be effectively applied to discriminate very small differences in the geometrical features of endodontic micro-instruments, while providing quantitative information for their geometrical properties.


The level of MAP kinase activity in the stomach stump in rats after subtotal gastrectomy.
MAPK (Mitogen-Activated Protein Kinase) is one of the elements of kinase cascades (MAPK, MEK-MAP kinase, kinase, Raf-1, Ras) regulating cellular proliferation and differentiation processes. It seems that the changes in its number and activity may be the factor having influence on carcinogenesis. In some human carcinomas a significant increase of its activity is observed, in others a decrease of its activity is described. Our research aimed at the evaluation of the dynamics of precancerous and cancerous changes in the stomach stump in rats after the experimental, partial stomach resection. Apart from histological and ultrastructural examination we also determined the activity of the sub-unit p42 MAP kinase. The material comprised segments of gastric mucosa of the stomach stump of 15 rats after subtotal gastrectomy. Part of the rats after the procedure were administered carcinogen orally (MNNG). On the histological and ultrastructural examination we used routine methods, the activity of MAP kinase was determined by western-blotting method with the use of IgG against MAPK p42, Santa Cruz #154). In 8 examined rats we observed the increase of MAP kinase activity. We established probable correlation (without statistical analysis, regarding miserly material) between the increase of MAPK activity and histological and ultrastructural changes. Among three cases diagnosed as adenoma tubulare in two we observed the increase of MAPK activity. A clear increase of this kinase was also present in the stomach stump of a rat, which was diagnosed as adenocarcinoma. On the basis of our research carried so far we think that the increase of the MAPK activity may be one of the causes of the neoplasm development. It seems important to obtain the confirmation of our results and to establish a possible usefulness of MAPK activity determination as a prognostic indicator in case of the neoplasm of stomach stump.


Michaelis-Menten kinetics under non-isothermal conditions.
We extend the celebrated Michaelis-Menten kinetics description of an enzymatic reaction taking into consideration the presence of a thermal driving force. A coupling of chemical and thermal driving forces is expected from the principle of non-equilibrium thermodynamics, and specifically we obtain an additional term to the classical Michaelis-Menten kinetic equation, which describes the coupling in terms of a single parameter. A companion equation for the heat flux is also derived, which actually can exist even in the absence of a temperature difference. Being thermodynamic in nature, this result is general and independent of the detailed mechanism of the coupling. Conditions for the experimental verification of the new equation are discussed.


Consideration of the production methods and safety evaluation of cytokines.
Cytokines are natural endogenous substances whose biological effects in humans are little known when given in therapeutic rather than physiologic doses. Yet, there is intense interest in seeking their possible clinical use. While E. coli are effective in making "simple proteins" with few disulfide bonds, mammalian cells are becoming more generally used for the production of "complex proteins" with multiple disulfide bonds and glycoproteins. There appears to be much less concern about the safety of possibly oncogenic residual DNA from transformed cell lines, but viral contamination of products continues to be an active concern. Both physicochemical and biological methods are necessary to establish the identity, purity and potency of biological drugs. For proteins to manifest their proper biological and therapeutic effects in humans, their correct conformation must be maintained throughout production, purification and formulation. Regulating novel biological drugs such as the cytokines might raise new scientific issues that are not currently apparent, but the basic principles involved will be consistent with those used to evaluate other biologics, e.g., sound scientific principles, flexibility, case-by-case approach, good common sense and risk vs benefit assessment.


An Isolable Diboron-Centered Diradical with a Triplet Ground State.
Two new diboranes, 2,6-bis(BMes2 )mesitylene (1) and 3,3'-bis(BMes2 )bimesitylene (3), were synthesized. Two-electron reduction of 1 with elemental potassium afforded the C-H activation product [(18-c-6)K(THF)2 ]2+ ⋅22- bearing a BC3 four-membered ring as colorless crystals, whereas the reduction of 3 with potassium led to the isolation of [(18-c-6)K(THF)2 ]2+ ⋅32-.. as dark blue crystals. Both reduction products were characterized by structural and spectroscopic methods. Electron paramagnetic resonance (EPR) spectroscopy and theoretical calculations revealed that the electron spin density of 32-.. mainly resides on the two boron nuclei and features a triplet ground state, which was confirmed by superconducting quantum interference device (SQUID) measurements as well as theoretical calculations. 32-.. represents the first structurally characterized boron-centered diradical with a triplet ground state. In addition, the reactivity of [(18-c-6)K(THF)2 ]2+ ⋅32-.. toward PhSeSePh and nBu3 SnH was investigated, which is consistent with its radical character.


Cue reactivity towards bodies in anorexia nervosa - common and differential effects in adolescents and adults.
Aberrant reward mechanisms with regard to slim body shapes are discussed in patients with anorexia nervosa (AN). The aim of the present study was to examine of cue reactivity toward body shapes in AN via the late positive potential (LPP), an event-related electroencephalography (EEG) component. By including adolescents and adults, aspects of development and chronification could be studied (2 × 2 design). Thirty-two female AN patients (19 adolescents and 13 adults) and 37 control participants (16 adolescents and 21 adults) were included. Standardized photographic stimuli showing women's bodies in underwear from five body mass index (BMI) categories (extremely underweight to extremely overweight) were presented. During picture evaluation, EEG activity was recorded (10-20 system). The LPP was measured in two time windows characterized by different topographies (450-700 ms: posterior; 1000-1300 ms: central). Regarding the posterior component, LPP amplitudes were clearly reduced in adult but not in adolescent patients; for both time windows the LPP showed differential patterns over BMI categories for patients and controls. Regarding the central component, a highly significant linear decrease from extremely underweight to extremely overweight body shapes was revealed in patients and no significant modulation in control participants. Adolescent and adult patients show increased sustained attention toward extremely underweight bodies. In chronically ill patients, this bias appears to be accompanied by generally reduced automatic attention. The LPP findings provide a differentiated picture of aberrant cue reactivity which could be interpreted as motivated attention toward body shapes in AN.


Glyphosate and adverse pregnancy outcomes, a systematic review of observational studies.
A study in frog and chicken embryos, and reports of a high incidence of birth defects in regions of intensive GM-soy planting have raised concerns on the teratogenic potential of glyphosate-based herbicides. These public concerns prompted us to conduct a systematic review of the epidemiological studies testing hypotheses of associations between glyphosate exposure and adverse pregnancy outcomes including birth defects. A systematic and comprehensive literature search was performed in MEDLINE, TOXLINE, Bireme-BVS and SCOPUS databases using different combinations of exposure and outcome terms. A case-control study on the association between pesticides and congenital malformations in areas of extensive GM soy crops in South America, and reports on the occurrence of birth defects in these regions were reviewed as well. The search found ten studies testing associations between glyphosate and birth defects, abortions, pre-term deliveries, small for gestational date births, childhood diseases or altered sex ratios. Two additional studies examined changes of time-to-pregnancy in glyphosate-exposed populations. Except for an excess of Attention Deficit Hyperactivity Disorder - ADHD (OR = 3.6, 1.3-9.6) among children born to glyphosate appliers, no significant associations between this herbicide and adverse pregnancy outcomes were described. Evidence that in South American regions of intensive GM-soy planting incidence of birth defects is high remains elusive. Current epidemiological evidence, albeit limited to a few studies using non-quantitative and indirect estimates and dichotomous analysis of exposures, does not lend support to public concerns that glyphosate-based pesticides might pose developmental risks to the unborn child. Nonetheless, owing to methodological limitations of existing analytical observational studies, and particularly to a lack of a direct measurement (urine and/or blood levels), or an indirect estimation of exposure that has proven valid, these negative findings cannot be taken as definitive evidence that GLY, at current levels of occupational and environmental exposures, brings no risk for human development and reproduction.