What macromolecular crowding can do to a protein.
The intracellular environment represents an extremely crowded milieu, with a limited amount of free water and an almost complete lack of unoccupied space. Obviously, slightly salted aqueous solutions containing low concentrations of a biomolecule of interest are too simplistic to mimic the "real life" situation, where the biomolecule of interest scrambles and wades through the tightly packed crowd. In laboratory practice, such macromolecular crowding is typically mimicked by concentrated solutions of various polymers that serve as model "crowding agents". Studies under these conditions revealed that macromolecular crowding might affect protein structure, folding, shape, conformational stability, binding of small molecules, enzymatic activity, protein-protein interactions, protein-nucleic acid interactions, and pathological aggregation. The goal of this review is to systematically analyze currently available experimental data on the variety of effects of macromolecular crowding on a protein molecule. The review covers more than 320 papers and therefore represents one of the most comprehensive compendia of the current knowledge in this exciting area.


Impact of placental mTOR deficiency on peripheral insulin signaling in adult mice offspring.
Suboptimal in utero environments such as poor maternal nutrition and gestational diabetes can impact fetal birth weight and the metabolic health trajectory of the adult offspring. Fetal growth is associated with alterations in placental mechanistic target of rapamycin (mTOR) signaling; it is reduced in fetal growth restriction and increased in fetal overgrowth. We previously reported that when metabolically challenged by a high-fat diet, placental mTORKO (mTORKOpl) adult female offspring develop obesity and insulin resistance, whereas placental TSC2KO (TSC2KOpl) female offspring are protected from diet-induced obesity and maintain proper glucose homeostasis. In the present study, we sought to investigate whether reducing or increasing placental mTOR signaling in utero alters the programming of adult offspring metabolic tissues preceding a metabolic challenge. Adult male and female mTORKOpl, TSC2KOpl, and respective controls on a normal chow diet were subjected to an acute intraperitoneal insulin injection. Upon insulin stimulation, insulin signaling via phosphorylation of Akt and nutrient sensing via phosphorylation of mTOR target ribosomal S6 were evaluated in the offspring liver, white adipose tissue, and skeletal muscle. Among tested tissues, we observed significant changes only in the liver signaling. In the male mTORKOpl adult offspring liver, insulin-stimulated phospho-Akt was enhanced compared to littermate controls. Basal phospho-S6 level was increased in the mTORKOpl female offspring liver compared to littermate controls and did not increase further in response to insulin. RNA sequencing of offspring liver identified placental mTORC1 programming-mediated differentially expressed genes. The expression of major urinary protein 1 (Mup1) was differentially altered in female mTORKOpl and TSC2KOpl offspring livers and we show that MUP1 level is dependent on overnutrition and fasting status. In summary, deletion of placental mTOR nutrient sensing in utero programs hepatic response to insulin action in a sexually dimorphic manner. Additionally, we highlight a possible role for hepatic and circulating MUP1 in glucose homeostasis that warrants further investigation.


Peer-led active tuberculosis case-finding among people living with HIV: lessons from Nepal.
People living with a human immunodeficiency virus (HIV) infection have a high risk of tuberculosis and should undergo regular screening. However, they can be difficult to reach because they are stigmatized and discriminated against. In Nepal, the nongovernmental organization Naya Goreto implemented a peer-led tuberculosis screening project in which people living with HIV volunteered to contact others in this high-risk population. Volunteers took part in a short training course, after which they attempted to contact people living with HIV through existing networks and self-help groups. Tuberculosis screening and testing were carried out in accordance with national guidelines. In Nepal, the prevalence of HIV infection is 0.3% in the general population but is much higher, at 6%, in people in Kathmandu who inject drugs. To date, the health system has not been able to implement systematic tuberculosis screening in people living with HIV. Between May 2014 and mid-September 2015, 30 volunteers screened 6642 people in 10 districts, 5430 (82%) of whom were living with HIV. Of the 6642, 6046 (91%) were tested for tuberculosis and 287 (4.3%) were diagnosed with the disease, 240 of whom were HIV-positive. Of those with tuberculosis, 270 (94%) initiated treatment. Using peers to contact people living with HIV for tuberculosis screening resulted in a high participation rate and the identification of a considerable number of HIV-positive tuberculosis patients. Follow-up during treatment was difficult in this highly mobile group and needs more attention in future interventions.


An Uncommon Cause of Longitudinally Extensive Transverse Myelitis.
Considering that currently Romania has the highest tuberculosis incidence in Europe, the recognition of the infection is an acknowledged health issue. Central nervous system tuberculosis accounts for approximately 1% of all cases of tuberculosis. Longitudinally extensive transverse myelitis is a contiguous infl ammatory lesion of the spinal cord which involves three or more spinal segments. In tuberculosis, spinal cord involvement is rare and is usually rather due to radiculomyelitis or spinal tuberculoma, and only very rare due to longitudinally extensive transverse myelitis. We present the case of a 52-year-old man referred to our department for progressive neurological deficits due to a longitudinally extensive transverse myelitis. After a thorough work-up we diagnosed the patient with longitudinally extensive transverse myelitis secondary to infection with Mycobacterium tuberculosis.


Synthesis of Complex Diarylamines through a Ring-Opening Difunctionalization Strategy.
The diarylation and skeletal diversification of unstrained cyclic amines was exploited to expand and modify the favorable properties of this important substrate class with pivotal roles in drug discovery. Cyclic amines were employed in the synthesis of a novel class of amino-substituted diaryliodonium salts, which were converted to highly functionalized diarylamines through an atom-efficient one-pot N-arylation/ring opening reaction with external nucleophiles. The reaction proceeds through in situ formation of a diarylammonium intermediate that undergoes a nucleophilic ring opening by cleavage of the strong C-N bond. A wide variety of diarylamines was obtained through introduction of two different aryl groups of varied electronics, and the retained iodo-substituent enables downfield diversifications of the products. More than 20 nucleophiles, including amines, phenols, carboxylic acids, thiols and halides, were alkylated with high functional group tolerance, and the strategy proved efficient also in in late-stage functionalization of natural products and pharmaceuticals.


Evaluation of slice sensitivity profiles for helical and axial 4D-CT acquisitions on the Philips Brilliance CT Big Bore.
4D-CT can be performed using two acquisition modes. One employs a cine axial scan and the other acquires the data using a very low pitch helical acquisition. This study evaluates the longitudinal resolutions of each of these methods by creating slice sensitivity profiles (SSP). An SSP phantom was scanned using both axial and helical scanning modes. The phantom was scanned at the center of the field of view (FOV) and at several points offset from the FOV center. For helical scans, the pitch was varied from 0.04 to 0.2. With the axial scans, the phantom position relative to the center of the detector ring was varied. All of these were performed using a 16 × 1.5 mm collimation. The SSP graphs were generated from these scanned datasets. The full width at half maximum (FWHM) of the graphs was used as the surrogate for longitudinal resolution. The results of these experiments demonstrated that axial scans have a slightly better resolution at CT isocenter (1.5 vs 1.8 mm). Helical mode scanning maintained this measurement for varying pitch factors and placement with the scan field. However, the resolution for axial scans degrades as the phantom is moved further from the center of the FOV and is positioned nearer to the edge of the detector rings. When it is imperative to maintain uniform longitudinal resolution throughout the FOV, it is suggested that helical acquisition be utilized or the axial mode data be reconstructed to account for beam divergence. For axial scans, this will require either limiting the longitudinal extent of each cine axial acquisition and/or using a smaller reconstructed FOV.


Boosting of Cross-Reactive and Protection-Associated T Cells in Children After Live Attenuated Influenza Vaccination.
Live attenuated influenza vaccines (LAIVs) stimulate a multifaceted immune response including cellular immunity, which may provide protection against newly emerging strains. This study shows proof of concept that LAIVs boost preexisting, cross-reactive T cells in children to genetically diverse influenza A virus (IAV) strains to which the children had not been exposed. We studied the long-term cross-reactive T-cell response in 14 trivalent LAIV-vaccinated children using the fluorescent immunospot assay (FluoroSpot) with heterologous H1N1 and H3N2 IAVs and CD8+ peptides from the internal proteins (matrix protein 1 [M1], nucleoprotein [NP], polymerase basic protein 1 [PB1]). Serum antibody responses were determined by means of hemagglutination inhibition assay. Blood samples were collected before vaccination and up to 1 year after vaccination. Preexisting cross-reactive T cells to genetically diverse IAV strains were found in the majority of the children, which were further boosted in 50% of them after receipt of LAIV. Further analyses of these T cells showed significant increases in CD8+ T cells, mainly dominated by NP-specific responses. After vaccination with LAIV, the youngest children showed the highest increase in T-cell responses. LAIV boosts durable, cross-reactive T-cell responses in children and may have a clinically protective effect at the population level. LAIV may be a first step toward the desired universal influenza vaccine.


Influence of atazanavir 200 mg on the intracellular and plasma pharmacokinetics of saquinavir and ritonavir 1600/100 mg administered once daily in HIV-infected patients.
To examine cellular and plasma concentrations of atazanavir when given in combination with saquinavir/ritonavir in HIV+ patients. Twelve HIV+ patients were receiving saquinavir/atazanavir/ritonavir 1600/200/100 mg once daily and venous blood samples were taken to determine cellular and plasma concentrations of each protease inhibitor at 2, 6, 12 and 24 h. Peripheral blood mononuclear cells were separated by density gradient centrifugation. The ratio of the cellular AUC0-24/plasma AUC0-24 was calculated to determine cellular drug accumulation. Lymphocyte P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) expression was determined by flow cytometry. Nine of the patients had previously received a regimen of saquinavir/ritonavir 1600/100 mg; therefore the effect of atazanavir on the cellular and plasma pharmacokinetics of saquinavir and ritonavir was examined. In vivo cellular and plasma determinations of saquinavir, atazanavir and ritonavir gave accumulation ratios of 4.9, 1.2 and 1.7, respectively. There was no relationship between saquinavir, atazanavir or ritonavir accumulation and P-gp, MRP1 or BCRP expression. When comparing pharmacokinetic values in the nine patients receiving saquinavir/ritonavir with and without atazanavir, the median cellular saquinavir AUC0-24 was significantly increased (34.9-117.2 mg.h/L) on addition of atazanavir (P=0.004). The C24 of saquinavir in plasma and cells was significantly higher with atazanavir (plasma C24 0.05 versus 0.14 mg/L with atazanavir; cellular C24 0.61 versus 2.03 mg/L with atazanavir, P=0.02). The mechanism of differential intracellular protease inhibitor accumulation is unclear. Co-administration of atazanavir caused an increase in both the plasma and cellular exposure (AUC0-24) and C24 of saquinavir but not ritonavir.


Efficacy of sequential treatment of HCT116 colon cancer monolayers and xenografts with docetaxel, flavopiridol, and 5-fluorouracil.
Clinical treatment of solid tumors with docetaxel, flavopiridol, or 5-fluorouracil (5-FU) often encounters undesirable side effects and drug resistance. This study aims to evaluate the potential role of combination therapy with docetaxel, flavopiridol, or 5-FU in modulating chemosensitivity and better understand how they might be used clinically. HCT116 colon cancer cells were treated with docetaxel, flavopiridol, and 5-FU in several different administrative schedules in vitro, either sequentially or simultaneously. Cell survival was measured by MTT assay. The activity of caspase-3 was determined by caspase-3 assays and the soft agar colony assay was used to test the colony formation of HCT116 cells in soft agar. We also established xenograft models to extend in vitro observations to an in vivo system. The maximum cytotoxicity was found when human colon cancer HCT116 cells were treated with docetaxel for 1 h followed by flavopiridol for 24 h and 5-FU for another 24 h. This sequential combination therapy not only inhibits tumor cell growth more strongly compared to other combination therapies but also significantly reduces colony formation in soft agar and augments apoptosis of HCT116 cells. Sequencing of docetaxel followed 1 h later by flavopiridol, followed 24 h later by 5-FU in xenograft models, also resulted in delayed tumor growth and higher survival rate. These results highlight the importance of an administrative schedule when combining docetaxel with flavopiridol and 5-FU, providing a rationale explanation for its development in clinical trials.


Renal cell carcinoma, unclassified with medullary phenotype: poorly differentiated adenocarcinomas overlapping with renal medullary carcinoma.
Renal medullary carcinoma (RMC) is a highly aggressive renal cell carcinoma arising in the collecting system and requiring careful correlation with status of sickle cell trait. A panel of international experts has recently proposed provisional diagnostic terminology, renal cell carcinoma, unclassified, with medullary phenotype, based on encountering an extraordinarily rare tumor with RMC morphology and immunophenotype in an individual proven not to have a hemoglobinopathy. Herein, we extend this observation to a cohort of 5 such tumors, morphologically similar to RMC, lacking SMARCB1 expression by immunohistochemistry, but each without evidence of a hemoglobinopathy. The tumors arose in 4 men and 1 woman with a mean age of 44 years, occurring in 3 left and 2 right kidneys. Clinically, aggression was apparent with involvement of perinephric adipose tissue in all 5 cases, nodal metastasis in 4 of 5 cases, and death of disease in 4 of 5 cases within 3-27 months. Histologic sections showed poorly differentiated adenocarcinoma, often with solid and nested growth patterns, as well as infiltrative glandular, tubulopapillary, cribriform, or reticular growth. Rhabdoid and sarcomatoid cytomorphology was seen in a subset. All tumors showed PAX8 nuclear positivity and SMARCB1 loss, with OCT3/4 expression in 4 of 5 cases. In summary, this first series of renal cell carcinoma, unclassified, with medullary phenotype documents tumors with morphologic, immunophenotypic, and prognostic features of RMC occurring in individuals without sickle cell trait. Although greater biologic and molecular understanding is needed, the available evidence points to these cases representing a sporadic counterpart to sickle cell trait-associated RMC.


Apparatus for testing gas-surface reactions for epicatalysis.
Recently, a new mode of gas-surface heterogeneous catalysis (epicatalysis) has been identified, having potential applications ranging from industrial and green chemistry to novel forms of power generation. This article describes an inexpensive, easily constructed, vacuum-compatible apparatus by which multiple candidate gas-surface combinations can be rapidly screened for epicatalytic activity. In exploratory experiments, candidate surfaces (teflon, kapton, glass, and gold) and gases (helium, argon, cyclohexane, water, methanol, formic acid, and acetic acid) were tested for epicatalytic activity. Kapton and teflon displayed small but reproducible differences in formic acid and methanol dimer desorption, thereby demonstrating the first examples of room-temperature epicatalysis. Other gas-surface combinations showed smaller or inconclusive evidence for epicatalysis.


Evidence for different polymorphisms with and without an external electric field in a series of bent-shaped molecules.
Five fluid tilted mesophases are observed in a series of achiral banana-shaped compounds. The terminal chain length is the pertinent molecular parameter which induces the polymorphism change. All the phases, refer to tilted lamellar structure without in-plane order in the layers. The observation of monolayer, bilayer, ribbon phase, and undulated structures recalls the richness of the polymorphism of the frustrated polar calamitic liquid crystals. Among the mesophases, we highlight two: a Sm-C G2 phase corresponding to a bilayer structure made of Sm-CG layers, and its two-dimensional variant, Sm- Ctilde; G2. The five mesophases observed at zero field are switchable under electric field. At least three ferroelectric phases are induced by an applied field. There is no direct correspondence between the zero field phases and the phases observed under electric field. These observations show that different polymorphisms exist in the series with and without an applied field. A unique ( E,T ) phase diagram is presented, corresponding to the superposition of the ( E,T ) diagrams obtained for each homolog of the series, where the influence of the chain length is equivalent to a shift on the temperature axis.


[Thrombin-stimulated release of serotonin from blood platelets].
The mechanism of platelet activation by thrombin was investigated using suspensions of human platelets. The assumption that the thrombin-platelet reaction shows characteristics of an agonist-receptor interaction was corroborated by an analysis of the relation between thrombin concentration and yield of 14C-serotonin secretion. However, silent thrombin binding sites that decrease the free thrombin concentration interfere with this interaction. When the influence of these binding sites is eliminated by a decrease in platelet concentration or by saturation with DIP-thrombin the concentration-response relationship can be interpreted by the adsorption isotherm of Langmuir. The binding sites interfering with the thrombin receptor interaction are identical with the high affinity binding sites of platelets. For the yield of secretion the velocity of thrombin addition is important. The platelet reaction decreases by slowing the rate of thrombin addition. In comparison with the reaction occurring at 37 degrees C, in that occurring at 0 degree C only the rate but not the yield of receptor stimulation is diminished. The results are in accordance with the assumption that the yield of platelet activation is determined by the equilibrium binding of thrombin. It is suggested that at 37 degrees C the processes of thrombin binding to the receptor, of receptor modification and of cellular response are immediately coupled with one another and that the rate-limiting step is the binding of thrombin to the receptor.


Multidisciplinary management of orthopedic patients with sickle cell disease.
With pharmacological treatment, the lifespan of the patient with sickle cell disease can be extended to the sixth decade. Currently the only curative therapy for sickle cell disease is hemopoietic cell transplantation, which is still undergoing technical refinement. Most patients can be expected to undergo at least one orthopedic surgical procedure in their lifetime. Multidisciplinary management of orthopedic patients with sickle cell disease will decrease the overall complication rates and improve clinical outcomes.


Mispair formation in DNA can involve rare tautomeric forms in the template.
The formation of pyridine-pyrimidine- and pyrimidine-pyrimidine base pairs after in vitro DNA replication with the large fragment of Escherichia coli DNA polymerase I indicates that Watson-Crick-like base pairing between pyrimidine bases can occur in the enzyme due to the presence of the rare tautomers of deoxycytidylate and thymidylate in the template strand. The implications to mispair formation in DNA, such as the difference between the structures of the mispairs during and after replication, are discussed and the possible action of mutagenic DNA protonating and deprotonating agents in vivo is considered.


Primary CNS lymphoma: update on molecular pathogenesis and therapy.
Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of extra-nodal non-Hodgkin lymphoma that as a brain tumor poses a unique set of challenges in diagnosis and management. With the advent of next-generation sequencing, we review updates in the understanding of its molecular and genomic pathogenesis. We also highlight key issues in management, with a focus on emerging technologies and new biological therapies including monoclonal antibodies, IMiDs, BTK inhibitors, PD-1 inhibitors, and CAR-T therapy. Integration of these approaches will likely enhance induction and consolidation strategies to suppress NF-κB activation and the anti-tumor immune response, while minimizing the often noxious effects of genotoxic approaches.


Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775).
Lysergic acid diethylamide (LSD) is perhaps one of the best-known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as 'research chemicals' or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM-775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM-775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM-775. A powdered sample of LSM-775 was characterized by X-ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC-MS), high mass accuracy electrospray MS/MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid-state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM-775 acts as a nonselective agonist at 5-HT1A and 5-HT2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM-775 activates 5-HT2A receptors and produces hallucinogen-like effects in vivo. LSM-775 did not induce the head twitch response unless 5-HT1A receptors were blocked by pretreatment with the antagonist WAY-100,635 (1 mg/kg, subcutaneous). These findings suggest that 5-HT1A activation by LSM-775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM-775 is only capable of producing weak LSD-like effects in humans.


Formation and Inhibition of Lipid Alkyl Radicals in Roasted Meat.
Free radicals are ubiquitous in roasted foods. In this work, lipid-derived carbon-centered alkyl radical formation was first studied in roasted meat by electron spin resonance (ESR). The influence of antioxidants on the inhibition of free radicals was investigated. The results showed that the high temperature, high heat transfer rate, and high polyunsaturated fatty acid (PUFA) content resulted in high radical content in roasted meat, while the high water content in meat retarded radical formation. The 0.03% addition of tea polyphenols (TPP) significantly reduced radical formation during roasting (p < 0.05), whereas the 0.03% rosemary extract (RE) had no significant inhibitory effect (p > 0.05). These results suggested that water retention and the addition of TPP would decrease radical generation during the roasting of meat.


Implications of acquired oxacillin resistance in the management and control of Staphylococcus aureus infections.
Refinements in testing for resistance to penicillinase-resistant penicillins (PRP) in Staphylococcus aureus have resulted in confusion in classifying isolates as PRP susceptible or resistant. Specifically, a group of organisms has been identified that produce large amounts of beta-lactamase and appear borderline resistant. These organisms have been called "occult resistant" or "acquired oxacillin-resistant" S. aureus (AORSA). A retrospective study was conducted to evaluate the implication of this in vitro phenomenon in managing patients with AORSA infections. Among 134 patients with S. aureus infections, 89 were infected with oxacillin-susceptible S. aureus (OSSA), 26 with AORSA, and 19 with oxacillin-resistant S. aureus (ORSA). There were no significant differences in outcomes when OSSA and AORSA infections were treated with PRP (chi 2MH = .990; P = .32). These results do not suppor the contention that AORSA infections should be managed differently from OSSA infections. Identifying AORSA may not be helpful in guiding antimicrobial therapy or predicting the outcome of infections with AORSA.


Anatomy, biochemistry, and physiology laboratory programs in the education of physicians.
The amount of laboratory time devoted to anatomy, biochemistry, and physiology has decreased substantially while lecture time has remained essentially unchanged. Most laboratories consist of student conduction of assigned exercises with a sprinkling of demonstrations, conferences, and seminars. Various objectives for laboratory programs are discussed. A great percentage of the student's final anatomy grade (approximately 40%) still depends on his laboratory performance, while in biochemistry and physiology, lab work contributes only 12% and 10%, respectively, toward his final grade. There is great reluctance to abandon the laboratory program, however, because of the significant role it is thought to play in medical education.


Potential Role of Cannabidiol on Sports Recovery: A Narrative Review.
The use of cannabidiol (CBD) among athletes is becoming extensive and frequent. This could be due to the elimination of CBD from the list of prohibited substances by federations and international institutions of sport. The legalization and resulting production, and commercialization of CBD, could increase its intake in sports professionals. This commercialization of cannabinoids has fueled a race to study their properties, benefits, and risks for health and performance in athletes. Although there is evidence that suggests some beneficial properties such as anxiolytics, antidepressants, anti-inflammatory, and antioxidants among others, the evidence presented so far is neither clear nor conclusive. There are significant gaps in knowledge of the physiological pathways that explain the role of CBD in sports performance. This mini-review examines evidence suggesting that CBD has the potential to be used as a part of the strategies to recover from fatigue and muscle damage related to physical and cognitive exertion in sports.


Reactions of substituted benzene anions with N and O atoms: Chemistry in Titan's upper atmosphere and the interstellar medium.
The likely existence of aromatic anions in many important extraterrestrial environments, from the atmosphere of Titan to the interstellar medium (ISM), is attracting increasing attention. Nitrogen and oxygen atoms are also widely observed in the ISM and in the ionospheres of planets and moons. In the current work, we extend previous studies to explore the reactivity of prototypical aromatic anions (deprotonated toluene, aniline, and phenol) with N and O atoms both experimentally and computationally. The benzyl and anilinide anions both exhibit slow associative electron detachment (AED) processes with N atom, and moderate reactivity with O atom in which AED dominates but ionic products are also formed. The reactivity of phenoxide is dramatically different; there is no measurable reaction with N atom, and the moderate reactivity with O atom produces almost exclusively ionic products. The reaction mechanisms are studied theoretically by employing density functional theory calculations, and spin conversion is found to be critical for understanding some product distributions. This work provides insight into the rich gas-phase chemistry of aromatic ion-atom reactions and their relevance to ionospheric and interstellar chemistry.


Thyroid function following radiation and surgical therapy in head and neck malignancy.
A retrospective 10-year review of thyroid function in 144 patients treated for cancer of the head and neck by radiation therapy, surgery, and combined surgery and radiation therapy was done. In five patients, hypothyroidism had been found in the posttreatment period. Two of them had developed a pharyngeal fistula resistant to intensive local care and surgical procedures, and a third patient had edema and necrosis of the skin flap. The five hypothyroid patients reported here have all been treated for laryngeal malignancy. In any other group of patients treated for head and neck malignancies studied within this article, we did not find clinical or chemical signs of thyroid hypofunction. Our report stresses the importance of periodic evaluation of thyroid function in patients who underwent irradiation of the neck or combined therapy for malignancy in the neck, even if they were clinically euthyroid. Hypofunction may be more frequent than generally recognized after multimodality treatment, and hormonal replacement therapy may be the keystone in curing rebellious pharyngeal fistula and shortening the disabled state of the patient.


Next-generation sequencing of BRCA1 and BRCA2 genes in Moroccan prostate cancer patients with positive family history.
Prostate cancer is the most common male cancer in Morocco. Although sporadic forms account for a large proportion of patients, familial forms of prostate cancer are observed in 20% of cases and about 5% are due to hereditary transmission. Indeed, germline mutations in BRCA1/2 genes have been associated with prostate cancer risk. However, the spectrum of these mutations was not investigated in Moroccan Prostate cancer patients. Thereby, the aim of this study was to characterize and to estimate the prevalence of germline BRCA1/2 mutations and large rearrangements in Moroccan patients with familial prostate cancer. The entire coding regions and intron/exon boundaries of BRCA1 and BRCA2 genes have been analyzed by next generation sequencing (NGS) in a total of 30 familial prostate cancer patients. Three pathogenic mutations were detected in four unrelated patients (13.3%). One BRCA1 mutation (c.1953_1956delGAAA) and two BRCA2 mutations (c.7234_7235insG and BRCA2ΔE12). In addition, sixty-three distinct polymorphisms and unclassified variants have been found. Early identification of germline BRCA1/2 mutations may be relevant for the management of Moroccan prostate cancer patients.


Chest wall shrapnel-induced beryllium-sensitization and associated pulmonary disease.
Chronic beryllium disease (CBD) is an exposure-related granulomatous disease mimicking sarcoidosis. Beryllium exposure-associated disease occurs mainly via inhalation, but skin may also be a source of sensitization. A 65-year-old male with a history of war-related shrapnel wounds was initially diagnosed with pulmonary sarcoidosis. Twenty years later, the possibility of a metal-related etiology for the lung disease was raised. A beryllium lymphocyte proliferation test, elemental analysis of removed shrapnel, and genetic studies were consistent with a diagnosis of CBD. This case demonstrates that retained beryllium-containing foreign bodies can be linked to a pathophysiologic response in the lung consistent with CBD.


Cord-blood 25-hydroxyvitamin D levels and risk of early-onset neonatal sepsis: a case-control study from a tertiary care center in Turkey.
Vitamin D has been linked with immunity, and the immunomodulatory role of this molecule in regulating key elements of the immune system has become an area of intense scientific investigation. We designed a case-control study to investigate whether neonates with early-onset neonatal sepsis (EONS) had lower levels of vitamin D. The primary exposure for the analysis in the study was the cord-blood level of 25-hydroxyvitamin D (25(OH)D). Of the 2571 live births occurring during the 18-month study period, 53 infants were admitted to the neonatal intensive care unit with suspected EONS. After clinical and laboratory confirmation, 40 newborns with EONS and 43 controls were analyzed. Cord-blood 25(OH)D levels of infants in the study group were significantly lower than that of the control group (median 12.6 ng/mL (3.1-78.9) vs. 21 (5-118); p = 0.038, respectively). In multivariate models, a low cord-blood 25(OH)D level (<30 ng/ml) was associated with an increased risk of EONS (OR = 5.6; 95% CI = 1.3-23.5). Cord-blood 25(OH)D levels of neonates with EONS were significantly lower than that of the healthy controls, and a low level of cord-blood vitamin D was found to be associated with an increased risk of EONS. Further studies are warranted to confirm this association.


Unified additional requirement in consideration of regional approval for multiregional clinical trials.
To speed up the process of bringing a new drug to the market, more and more clinical trials are being conducted simultaneously in multiple regions. After demonstrating the overall drug's efficacy across regions, the regulatory and drug sponsor may also want to assess the drug's effect in specific region(s). Most of the recent approaches imposed a uniform criterion to assess the consistency of treatment effects between the interested region(s) and the entire study population regardless of the number of regions in multiregional clinical trials (MRCT). As a result, the needed sample size to achieve the desired probability of satisfying the regional requirement could be huge and implausible for the trial sponsors to implement. In this paper, we propose a unified additional requirement for regional approval by differing the parameters in the additional requirement depending on the number of planned regions. In particular, the values of the parameters are determined by a reasonable sample size increase with the desired probability satisfying the additional requirement. Considering the practicality of the global trial or sample size increase, we recommend specific values of the parameters for a different number of planned regions. We also introduce the assurance probability curve to evaluate the performance of different regional requirements.


The therapeutic potential of immuno-cell therapy of cancer in combination with aminobisphosphonates.
Many university hospitals and cancer centers in Japan have actively investigated the use of autologous activated lymphocyte therapy (ALT). However its therapeutic efficacy was found to be quite limited. The efficacy of aminobisphosphonates (aBPs) has been shown for osteolytic bone disease. aBPs could activate and induce the proliferation of gamma/delta (gamma/delta) T-cells. The application of aBPs to ALT in vivo or ex vivo may be beneficial. A brief overview of aBPs and gamma/delta T-cells is provided, together with some preliminary results and discussion of the therapeutic potential of ALT in combination with aBPs.


A Novel Night Moisturizer Enhances Cutaneous Barrier Function in Dry Skin and Improves Dermatological Outcomes in Rosacea-prone Skin.
Objective: We assessed whether Cetaphil Redness Control Night Cream (CRCNC; Galderma Laboratories, Fort Worth, Texas) improves electrical capacitance (EC) and transepidermal water loss (TEWL) in healthy subjects with dry skin and determined efficacy and tolerability in subjects with rosacea. Study design: The present study included two independent, open-label investigations: in the first, EC and TEWL were measured at baseline and at two, four, eight, and 24 hours after one application of CRCNC to dry skin; in the second, an evaluation of once-daily CRCNC application for 22 days using a chromameter, image analysis, and trained rater was performed, with patient evaluations at baseline and Days 1, 8, and 22 collected. The first study enrolled 20 subjects (13 women; mean age: 45 years). The second study enrolled 33 women (mean age: 54 years), with 30 having sensitive skin. Results: EC increased significantly at two (by 67.0%), four (60.2%), eight (52.1%), and 24 (17.9%) hours after CRCNC application. TEWL was reduced significantly at two (18.0%), four (14.3%), and eight (18.2%) hours after application. Additionally, improvements in redness were seen at Days 8 (24.2%; p=0.008) and 22 (27.3%; p=0.004). Versus baseline, 21.2% (p=0.07), 39.4% (p<0.001), and 48.5% (p<0.001) of subjects reported improvements at 30 minutes after application and on Days 8 and 22, respectively. Conclusions: CRCNC is an effective and well-tolerated moisturizer that improves cutaneous barrier function in subjects with dry skin and in those subjects with sensitive skin and type 1 rosacea.


[Autophagy and neuronal diseases].
Autophagy is a dynamic process that allows recycling of long-lived proteins and damaged organelles into biosynthetic materials for maintaining the normal cellular homeostasis. Recently, accumulating evidence has indicated that autophagy played important roles in the pathogenesis of neuronal diseases. In this article, the research progress of autophagy in the pathogenesis and regulation mechanism of common nervous system diseases were reviewed to deepen the understanding of autophagy, and arouse researchers' attention on dynamic regulation of autophagy and alleviating autophagic flow injury.


Renal injury in a patient with lumbar scoliosis.
Kidney laceration following blunt trauma is responsible for up to 3% of trauma cases. The risk factors associated with renal injury are attributed to the risks of mechanical injury. However, anatomical variations that may accelerate the insult of injury are poorly documented. This case report describes a 25-year-old with degenerative lumbar scoliosis who presented with flank pain and visible haematuria following a low-impact injury. The patient had a grade IV renal injury. The curvature of the spine, shown on CT imaging, revealed a reduced retroperitoneal space around the left kidney. This case explores lumbar scoliosis as a risk factor for kidney laceration. We hypothesise that this increased risk is associated with asymmetry of the spine and reduced anatomical space in the retroperitoneum. Patients with lumbar scoliosis may be considered a high-risk category for renal injury, following low-impact trauma.


The prevalence of chronic obstructive pulmonary disease in hookah smokers.
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Hookah smoking is growing worldwide and particularly in Iran. The aim of this study was to determine the prevalence of obstructive pulmonary dysfunction in hookah smokers. We conducted a population-based study in Bushehr Province, Iran. A total of 245 subjects aged 35 years or older who were taking hookah for at least 15 years and 245 healthy controls were enrolled in the study and spirometry was done. Statistical analyses were performed using SPSS for windows software version 19. The prevalence of COPD among the exposed group of hookah smoke was 10.2%, with the rate being significantly higher in the patients with older age ( p < 0.001), duration of hookah smoking ( p < 0.001), men ( p = 0.026), ≥3 hookahs/day ( p = 0.006), history of cough for ≥2 years ( p = 0.002), in patients with a history of sputum for ≥2 years ( p = 0.031), and in patients with a history of dyspnea for ≥2 years ( p = 0.001). The results of the logistic regression analysis demonstrated that older age, male gender, smoking, and occupational exposure were independent predictive factors for COPD. The results of our study suggest that hookah smoking significantly increases the risk of COPD. Given the importance of COPD in the global burden of diseases, it is necessary to carry out further studies on the relationship between hookah use and COPD.


Borderline personality features and development of psychosis in an 'ultra high risk' (UHR) population: a case control study.
There is clinical uncertainty as to whether borderline personality disorder (BPD) traits in those with an 'at risk mental state' have an effect on the risk of 'transition' to psychosis. We aimed to investigate the relationship between baseline BPD features, risk of transition and type of psychotic disorder experienced. This is a case-control study of 'ultra high risk' (UHR) for psychosis patients treated at the clinic, between 2004 and 2007. 'Cases' were UHR individuals who made the 'transition' to full threshold psychotic disorder within 24 months; 'control' group was a matched UHR sample who had not developed a psychotic disorder at 24 months. Individuals were matched on time of entry to the clinic, age and gender. Diagnostic and statistical manual of mental disorders, fourth edition (DSM-IV) BPD features were assessed from clinical assessments using a structured instrument (Structured Clinical Interview for DSM-IV Axis II Disorder for BPD (SCID-II BPD)). Psychosis diagnosis following transition was rated from the clinical files using the operational criteria in studies of psychotic illness (OPCRIT) computer algorithm. The number of BPD traits and number with full threshold BPD were compared in those who developed psychosis and those who did not. We analysed data from 48 cases and 48 controls. There was no statistically significant difference in the rate of transition to psychosis for those with baseline full-threshold BPD, compared with those without BPD. The number of BPD traits or number with full threshold BPD did not differ by psychosis diagnosis grouping. Co-occurring BPD or BPD features does not appear to strongly influence the risk of short-term transition to psychosis or the risk of developing a non-affective psychotic disorder in this population.


Carcinogenic activity of condensate from coloquint seeds (Citrullus colocynthis) after chronic epicutaneous administration to mice.
In the Sahelian countries coloquint seed tar is used in traditional medicine. A condensate from the seed of Citrullus colocynthis was obtained in a camel nomad settlement. It contained a large number of polycyclic aromatic hydrocarbons, including known carcinogens [e.g., benzo(a)pyrene, benz(a)anthracene, benzo(b)fluoranthene, benzo(j)fluoranthene]. The dose-related carcinogenic activity of this condensate was established after chronic epicutaneous application to mouse skin. We conclude that the manufacture and use of coloquint tar and related compounds may involve a health hazard and could lead to the development of cancer.


Challenges associated with the identification of germline variants on myeloid malignancy genomic profiling-a Singaporean experience.
Genomic profiling to identify myeloid-malignancy-related gene mutations is routinely performed for patients with suspected or definite myeloid malignancies. The most common specimen types in our experience are peripheral blood and bone marrow aspirates. Although primarily intended to identify somatic mutations, not infrequently, potentially clinically significant germline variants are also identified. Confirmation of the germline status of these variants is typically performed by hair follicle or skin fibroblast testing. If the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene known to be associated with a disease relevant to the patient's phenotype (for example, the identification of a DDX41 pathogenic variant in an individual with acute myeloid leukemia), the management algorithm is typically quite straightforward. Challenging situations may occur such as when the germline variant is classified as a pathogenic or likely pathogenic variant and occurs in a gene not known to be associated with the patient's phenotype/presenting complaint. We have encountered several such challenging cases in which potentially clinically significant germline variants were identified on the initial genomic profiling of peripheral blood or bone marrow aspirate. In this article, we present these cases and discuss the genetic counseling and management approaches.


Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.
Recent data have indicated that the divalent cation Zn2+ can selectively block central neuronal excitation mediated by N-methyl-D-aspartate (NMDA) receptors. The present experiments were conducted to determine the action of Zn2+ at the single-channel level. Outside-out membrane patches were prepared from cultured murine cortical neurons. Glutamate, 3 microM, in the presence of 5 microM glycine activated channels with a main conductance state of about 50 pS which were blocked in a voltage-dependent manner by Mg2+. Zn2+ appeared to have 2 effects on these NMDA receptor-activated channels. First, at concentrations as low as 1-10 microM, Zn2+ produced a concentration-dependent reduction in channel open probability, insensitive to membrane voltage between -60 and +40 mV; about 50% reduction in open probability was produced by 3 microM Zn2+. This reduction was mostly due to a decrease in opening frequency and only weakly mimicked by Mg2+. Second, at higher concentrations (10-100 microM) and negative membrane voltages, Zn2+ additionally produced an apparent reduction in single-channel amplitude, associated with an increase in channel noise, suggestive of a fast channel block. The amplitude reduction was voltage-dependent, with a delta of 0.51; amplitude distribution analysis suggested that this voltage dependence was primarily contributed by the "on" blocking rate constant, with little contribution from the "off" rate constant. The channel block produced by Zn2+ was faster than that of Mg2+, which at 100 microM and negative membrane voltages induces flickering of the NMDA receptor-activated channel without changing apparent channel amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)


Reduced aboveground tree growth associated with higher arbuscular mycorrhizal fungal diversity in tropical forest restoration.
Establishing diverse mycorrhizal fungal communities is considered important for forest recovery, yet mycorrhizae may have complex effects on tree growth depending on the composition of fungal species present. In an effort to understand the role of mycorrhizal fungi community in forest restoration in southern Costa Rica, we sampled the arbuscular mycorrhizal fungal (AMF) community across eight sites that were planted with the same species (Inga edulis, Erythrina poeppigiana, Terminalia amazonia, and Vochysia guatemalensis) but varied twofold to fourfold in overall tree growth rates. The AMF community was measured in multiple ways: as percent colonization of host tree roots, by DNA isolation of the fungal species associated with the roots, and through spore density, volume, and identity in both the wet and dry seasons. Consistent with prior tropical restoration research, the majority of fungal species belonged to the genus Glomus and genus Acaulospora, accounting for more than half of the species and relative abundance found on trees roots and over 95% of spore density across all sites. Greater AMF diversity correlated with lower soil organic matter, carbon, and nitrogen concentrations and longer durations of prior pasture use across sites. Contrary to previous literature findings, AMF species diversity and spore densities were inversely related to tree growth, which may have arisen from trees facultatively increasing their associations with AMF in lower soil fertility sites. Changes to AMF community composition also may have led to variation in disturbance susceptibility, host tree nutrient acquisition, and tree growth. These results highlight the potential importance of fungal-tree-soil interactions in forest recovery and suggest that fungal community dynamics could have important implications for tree growth in disturbed soils.


Interaction of glutathione reductase with heavy metal: the binding of Hg(II) or Cd(II) to the reduced enzyme affects both the redox dithiol pair and the flavin.
To determine the inhibition mechanism of yeast glutathione reductase (GR) by heavy metal, we have compared the electronic absorption and resonance Raman (RR) spectra of the enzyme in its oxidized (Eox) and two-electron reduced (EH2) forms, in the absence and the presence of Hg(II) or Cd(II). The spectral data clearly show a redox dependence of the metal binding. The metal ions do not affect the absorption and RR spectra of Eox. On the contrary, the EH2 spectra, generated by addition of NADPH, are strongly modified by the presence of heavy metal. The absorption changes of EH2 are metal-dependent. On the one hand, the main flavin band observed at 450 nm for EH2 is red-shifted at 455 nm for the EH2-Hg(II) complex and at 451 nm for the EH2-Cd(II) complex. On the other hand, the characteristic charge-transfer (CT) band at 540 nm is quenched upon metal binding to EH2. In NADPH excess, a new CT band is observed at 610 nm for the EH2-Hg(II)-NADPH complex and at 590 nm for EH2-Cd(II)-NADPH. The RR spectra of the EH2-metal complexes are not sensitive to the NADPH concentration. With reference to the RR spectra of EH2 in which the frequencies of bands II and III were observed at 1582 and 1547 cm-1, respectively, those of the EH2-metal complexes are detected at 1577 and 1542 cm-1, indicating an increased flavin bending upon metal coordination to EH2. From the frequency shifts of band III, a concomitant weakening of the H-bonding state of the N5 atom is also deduced. Taking into account the different chemical properties of Hg(II) and Cd(II), the coordination number of the bound metal ion was deduced to be different in GR. A mechanism of the GR inhibition is proposed. It proceeds primarily by a specific binding of the metal to the redox thiol/thiolate pair and the catalytic histidine of EH2. The bound metal ion then acts on the bending of the isoalloxazine ring of FAD as well as on the hydrophobicity of its microenvironment.


Clinical application of the Fricke-glucomannan gel dosimeter for high-dose-rate (192)Ir brachytherapy.
This study investigates the efficacy of a new Fricke dosimeter formulation consisting of a standard Fricke gel dosimeter gelled with glucomannan (FrGDG). FrGDG was irradiated using a (192)Ir gamma-ray source with a remote afterloading system based on computed tomography images. (60)Co irradiation was performed for measuring the absorption of FrGDG and water. The distribution maps of T2 values from the irradiated containers were obtained by MR imaging and converted to the absorbed dose to visualize the dose distribution. We found that FrGDG was produced easily and quickly at room temperature. R2 (1/T2) values were reproducible and linearly correlated with the absorbed doses in the range from 0 to 30 Gy for irradiation with (192)Ir (the correlation coefficient was 0.99). The mean deviation between the doses obtained from the MR images of the FrGDG and those calculated by the treatment planning system for doses of 37.5, 40, 50, 62.5 and 75 Gy was 4.9%, 4.8%, 3.5%, 2.3% and 2.4%, respectively. In conclusion, MR imaging of FrGDG can visualize the dose distribution successfully, and thus serves as a useful quality assurance tool for complicated three-dimensional radiotherapy treatments.


The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-kappaB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-kappaB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-kappaB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin alpha2beta1 on collagen prevents flow-induced NF-kappaB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-kappaB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.


To Operate or not to Operate the Mid-Shaft Fractures of the Clavicle: A Comparative Study of Functional Outcomes of the Two Methods of Management.
Fractures of the clavicle are some of the most common fractures which are seen in the adult population. Mid-shaft fractures of the clavicle are considered the most common form of clavicle fractures and about half of them are displaced fractures. They have been managed non-operatively over the years. However, severe displacement and comminution of these fractures have warranted the requirement of operative intervention, due to increased incidence of mal-union, worsening of shoulder functions etc., after conservative management. The introduction of locking compression plates, have increased the incidence of operative intervention in the management of these injuries. To study and compare the functional outcome of the shoulder after open reduction and internal fixation versus non-operative management of mid-shaft clavicle fractures. A prospective study was conducted from June 2013-October 2015 in the Department of Orthopaedic Surgery, K.S. Hegde Medical Academy, Mangalore. A total of 30 skeletally mature patients between the age groups of 20-50 years with diagnosed fresh mid-shaft clavicle fractures, AO type A and B mild to moderate displacement, were enrolled into the study with. They were divided into two groups randomly. Group 1 consisted 16 patients who underwent open reduction and locking compression plate fixation and Group 2 consisted of 14 patients who were managed with application of a clavicle brace and arm pouch for three weeks. Reviews were done at three, six and 24 weeks postoperatively. The patients were assessed clinically and radiographs were taken during all the reviews. Scoring of shoulder function was done using the Disabilities of the Arm, Shoulder and Hand (DASH) score during all the reviews. The results were tabulated compared and analyzed statistically using the 'Independent t-test' and Chi-square test. The DASH scores at the end of 24 weeks were noted to be 8.57±6.073 points for the 14 patients in the conservative management group and 7.74±16.422 points for the 16 patients in the open reduction and internal fixation group. This indicated that there was no significant difference noted in terms of shoulder function between the two groups. Six of the 14 patients in the conservative management group were noted to have mal-union of the fracture. No non-unions were noted in the conservative or operative groups. No mal-union was noted in the open reduction and internal fixation group. Though open reduction and internal fixation of mid-shaft clavicle fractures reduced the incidence of mal-union, no significant difference was noted in the functional outcome of shoulder function as compared to when the fracture was managed conservatively.


Macroinvertebrates as indicators of pollution.
Various pollution indicators of stream Ban-Ganga have been identified on the basis of presence/absence/numerical abundance at various stations. They have been categorized as pollution tolerant, facultative and pollution intolerant groups in relation with the water quality at different stations of stream.


Teenage pregnancy among African-Americans: a qualitative examination of maternal education, teenage pregnancy, family dynamics, and conflict resolution.
This qualitative study is derived from interviews conducted during a larger quantitative study that examined facilitators and barrier to communication and negotiations in African American families whose teen daughters had one or more unwed teen pregnancies. Based on the larger study's findings that the education of the teens mother was a statistically significant factor in teen pregnancy, 17 robust interviews were analyzed in this study and sorted on variables of maternal education and teen pregnancies. From the analysis of the data, seven themes emerged. Findings indicated that almost all girls reported a lack of contact with a father and girls of higher educated mothers tended to have more supportive family structures than did girls of lower educated mothers. Most of the families rejected the teen pregnancy, although later some accepted the infant. In comparison to mothers with a higher level of education, mothers with a lower level of education leaned toward more absolutist and negative solutions without full discussions about ideas of sex with their teens. Discussion indicated the need for interventions based on negotiation principles and tactics.


Forbidden penta-peptides.
There are 3,200,000 amino acid sequences of length 5 (penta-peptides). Statistically, we expect to see a distribution of penta-peptides that is determined by the frequency of the participating amino acids. We show, however, that not only are there thousands of such penta-peptides that are absent from all known proteomes, but many of them are coded for multiple times in the non-coding genomic regions. This suggests a strong selection process that prevents these peptides from being expressed. We also show that the characteristics of these forbidden penta-peptides vary among different phylogenetic groups (e.g., eukaryotes, prokaryotes, and archaea). Our analysis provides the first steps toward understanding the "grammar" of the forbidden penta-peptides.


STOPPING DECEPTIVE HEALTH CLAIMS: THE NEED FOR A PRIVATE RIGHT OF ACTION UNDER FEDERAL LAW.
This Article offers a thorough analysis of an important public health issue, namely how to confront the growing problem of deceptive claims regarding foods and dietary supplements, including increasingly prevalent but unverifiable claims. The authors call for the creation of a limited private right of action under the Federal Trade Commission (FTC) Act for deceptive health-related claims for these products. The proposal responds to the growing market for these products and the inadequacy of current laws and enforcement actions to prevent such claims. In crafting the limited private right of action, the authors attempt to enhance consumer protection without undermining federal agency primacy in enforcement. The Article ends with an appendix setting forth proposed language for a statutory amendment to the FTC Act incorporating the authors' proposal.


The Progression of Neuropsychiatric Symptoms in Alzheimer's Disease During a Five-Year Follow-Up: Kuopio ALSOVA Study.
An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer's disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited. To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression. 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models. The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances. Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers.


[Could the BCG vaccine prevent bladder cancer?].
In developed countries, the incidence of tuberculous is major, and the incidence of bladder cancer is minor. Above the base of the utility of the BCG in the prevention of the tuberculous and the use in the treatment and prevention of the recurrences of cancer, it's investigated the relation between the 2 pathology's. We effected a study retrospective and prospective. It's revised the history's of 52 cases of bladder cancer, it's interview 100 persons, and interview medicals what to dedicate to treat patients whit tuberculous, above the existence before patient what had the 2 pathology's or before case vaccinate with BCG what to develop bladder cancer. It's a study effected in tree groups of patients, in a period of 14 year, between 1985-1999. First group: all the cases what development bladder of cancer none of them to vaccinate with BCG. Second group: all to vaccinate with BCG with prevention of lung tuberculous none of them development bladder of cancer in the course of mean of 32 year. Third group: none of the patients what to treat for tuberculous developed bladder of cancer. Never a medical interview observe case some what development the two pathology's, or patients what vaccinate with BCG what development bladder of cancer.


Structure and dynamics of L-selenomethionine in the solid state.
L-selenomethionine 1 crystallizes in P2(1) space group with two molecules in the asymmetric unit. Solid-state NMR spectroscopy is used for searching of structure and dynamics of 1 in the crystal lattice. The distinct molecular motion of side chains for A and B molecules of 1 is apparent from measurements of relaxation parameters (1H 1rho, 13C T1) and analysis of CSA data (2D-PASS experiment). The 13C delta(ii) and 77Se delta(ii) parameters are correlated with theoretical shielding parameters obtained by means DFT GIAO calculations. Attempt to explain the mechanism of phase transition of crystals of 1 at 313K is presented.


Size selective incorporation of gold nanoparticles in diblock copolymer vesicle wall.
A systematic study is conducted to reveal how far the polymeric vesicle wall can embed gold nanoparticles (AuNPs) with different sizes by combining experiments and self-consistent field simulations. Both the experimental and simulative results indicate that the location of AuNPs in vesicle wall or in spherical micelle is heavily size dependent. Whether the AuNPs enter the vesicle wall or not is determined by a ratio of the diameter of AuNPs (D0) to the thickness of the vesicle wall (d(w0)). The 1-dodecanethiol-coated AuNPs (Au(x)R) with D0/d(w0) < 0.3 will stably disperse in the vesicle walls. For polystyrene-coated AuNPs (Au(x)S), a criterion of D0/d(w0) is proposed based on the phase diagram; i.e., the Au(x)S with D0/d(w0) < 0.5 can be located in the vesicle wall. Otherwise, the Au(x)R and the Au(x)S prefer to locate in spherical micelles. Moreover, the contributions of enthalpy and entropy to the total free energy of the system are respectively calculated to reveal the mechanism of the size selective distribution of AuNPs. The results demonstrate that the escape of AuNPs from vesicle walls and their selective distribution in spherical micelles is an entropy-driven process. Our study provides an important guideline for fabricating nanoparticle/block copolymer hybrid vesicles in dilute solution.


Epidemiology and aetiology of impaired level of consciousness in prehospital nontrauma patients in an urban setting.
There is little information on the epidemiology and aetiology of nontraumatic loss of consciousness in patients in the Emergency Department, and this high-risk patient group has been poorly characterized in the prehospital setting as well. The aim of this study was to study the epidemiology and aetiology of nontraumatic impaired level of consciousness among the patients treated by an urban Emergency Medical Service (EMS) system in Finland. Data of all emergency calls not related to trauma in an urban EMS system in southern Finland during 2012 were analysed. The inclusion criterion in this study was impaired level of consciousness as identified from the EMS run sheets. Diagnoses made in the receiving facility were cross-checked with the data. During the study period, the EMS was alerted to 22 184 emergency calls. Of these, 306 calls met the inclusion criterion. The included patients could be categorized into four groups: seizures (32%), diabetes (24%), intoxication (17%) and impaired level of consciousness with no other obvious or specific cause (27%). The overall case fatality rate was 8%. Of all EMS calls, patients who presented with an impaired level of consciousness represented 1.4% of all patients, but the fatality rate in those who remained with an impaired level of consciousness during the prehospital phase was considerable. Impaired level of consciousness was associated with a multitude of aetiologies, of which seizures were the most common.


A Small Molecule Inhibitor Selectively Induces Apoptosis in Cells Transformed by High Risk Human Papilloma Viruses.
A phenotypic high-throughput cell culture screen was performed to identify compounds that prevented proliferation of the human Papilloma virus type 16 (HPV-16) transformed cell line Ca Ski. A series of quinoxaline compounds exemplified by Compound 1 was identified. Testing against a panel of cell lines demonstrated that Compound 1 selectively inhibited replication of all HPV-16, HPV-18, and HPV-31 transformed cell lines tested with 50% Inhibitory Concentration (IC50) values of 2 to 8 μM relative to IC50 values of 28 to 73 μM in HPV-negative cell lines. Treatment with Compound 1 resulted in a cascade of multiple apoptotic events, including selective activation of effector caspases 3 and 7, fragmentation of cellular DNA, and PARP (poly(ADP-ribose) polymerase) cleavage in HPV-positive cells relative to HPV-negative cells. Unregulated proliferation of HPV transformed cells is dependent on the viral oncogenes, E6 and E7. Treatment with Compound 1 resulted in a decrease in HPV E7 protein in Ca Ski cells. However, the timing of this reduction relative to other effects of compound treatment suggests that this was a consequence, rather than a cause, of the apoptotic cascade. Likewise, compound treatment resulted in no obvious effects on the E6- and E7- mediated down regulation of p53 and Rb, or their downstream effectors, p21 or PCNA. Further investigation of apoptotic signals induced by Compound 1 revealed cleavage of Caspase-8 in HPV-positive cells as early as 2 hours post-treatment, suggesting the compound initiates apoptosis through the extrinsic, death receptor-mediated, pathway of cell death. These studies provide proof of concept that cells transformed by oncogenic Papillomaviruses can be selectively induced to undergo apoptosis by compound treatment.


Genetic Sequencing of Attwater's Prairie Chicken Avian Poxvirus and Evaluation of Its Potential Role in Reticuloendotheliosis Virus Outbreaks.
Efforts to breed Attwater's prairie chickens (APC; Tympanuchus cupido attwateri) in captivity to supplement wild populations of this endangered bird have been negatively affected by infections with Avipoxvirus and reticuloendotheliosis virus (REV). Because REV can be integrated into the genome of fowlpox virus (FPV) and may be transmitted in that manner, identifying the source of avipox disease in APC is important to mitigate the impact of this virus. Tissue samples from APC were collected from breeding programs in Texas from 2016 to 2020. These samples consisted of 11 skin lesions and three internal organs from a total of 14 different birds that died of unknown causes or were euthanized. Avipoxvirus was detected by PCR and isolation in embryonating chicken eggs in all skin lesion samples but was not detected in internal organs. Using sequence analysis of FPV polymerase and 4b genes, we determined that 10 out of 11 Avipoxvirus detections resided within the fowlpox clade and a single sample resided within the canarypox clade. REV sequences were detected in all FPV positive samples and in all internal organ tissues but were not detected in the sample matching the canarypox clade. Analysis of REV sequences and PCR detection showed the REV infecting APC was consistent with REV-A and had little variability on analysis of the U3 region of the long terminal repeat. The results of this study indicate control of REV in APC breeding colonies may benefit by a vaccination program targeting FPV and REV. However, a commercially available vaccine for REV is not available at this time.


Considerations for the impact of personal genome information: a study of genomic profiling among genetics and genomics professionals.
With the expansion of genomic-based clinical applications, it is important to consider the potential impact of this information particularly in terms of how it may be interpreted and applied to personal perceptions of health. As an initial step to exploring this question, we conducted a study to gain insight into potential psychosocial and health motivations for, as well as impact associated with, undergoing testing and disclosure of individual "variomes" (catalogue of genetic variations). To enable the collection of fully informed opinions, 14 participants with advanced training in genetics underwent whole-genome profiling and received individual reports of estimated genomic ancestry, genotype data and reported disease associations. Emotional, cognitive and health behavioral impact was assessed through one-on-one interviews and questionnaires administered pre-testing and 1-week and 3-months post-testing. Notwithstanding the educational and professional bias of our study population, the results identify several areas of research for consideration within additional populations. With the development of new and less costly approaches to genome risk profiling, now available for purchase direct-to-consumers, it is essential that genome science research be conducted in parallel with studies assessing the societal and policy implications of genome information for personal use.


Fluc-EGFP reporter mice reveal differential alterations of neuronal proteostasis in aging and disease.
The cellular protein quality control machinery is important for preventing protein misfolding and aggregation. Declining protein homeostasis (proteostasis) is believed to play a crucial role in age-related neurodegenerative disorders. However, how neuronal proteostasis capacity changes in different diseases is not yet sufficiently understood, and progress in this area has been hampered by the lack of tools to monitor proteostasis in mammalian models. Here, we have developed reporter mice for in vivo analysis of neuronal proteostasis. The mice express EGFP-fused firefly luciferase (Fluc-EGFP), a conformationally unstable protein that requires chaperones for proper folding, and that reacts to proteotoxic stress by formation of intracellular Fluc-EGFP foci and by reduced luciferase activity. Using these mice, we provide evidence for proteostasis decline in the aging brain. Moreover, we find a marked reaction of the Fluc-EGFP sensor in a mouse model of tauopathy, but not in mouse models of Huntington's disease. Mechanistic investigations in primary neuronal cultures demonstrate that different types of protein aggregates have distinct effects on the cellular protein quality control. Thus, Fluc-EGFP reporter mice enable new insights into proteostasis alterations in different diseases.


Disability in systemic sclerosis -- a longitudinal observational study.
To assess disability in systemic sclerosis (SSc) longitudinally and to identify disease-specific determinants, after accounting for informative patient dropout. We performed a multicenter, longitudinal study of 745 patients with SSc followed in the Canadian Scleroderma Research Group registry. Disability was assessed using the Health Assessment Questionnaire (HAQ). Longitudinal changes in disability were modeled using statistical approaches accounting for various levels of patient dropout. In all the models, disability in SSc worsened over time. The magnitude of the worsening was small when patient dropout was assumed to be completely at random (increase in the HAQ of 0.022, 95% CI 0.002-0.042, per year). After accounting for different levels of informative patient dropout, the increase in the HAQ ranged from 0.039 (95% CI 0.018-0.061) per year to 0.071 (95% CI 0.048-0.094) per year. Thus, using the most conservative of these estimates, this was equivalent to an increase in the HAQ of 0.12 over 3 years. The disease correlates found to be most closely associated with disability were diffuse disease and breathing problems. Our study provides strong evidence that SSc causes increased disability over time, with breathing problems and disease type being the strongest predictors of disability. Statistical modeling accounting for informative patient dropout is necessary to properly assess the outcomes of patients followed longitudinally.


Inflammation Induces TDP-43 Mislocalization and Aggregation.
TAR DNA-binding protein 43 (TDP-43) is a major component in aggregates of ubiquitinated proteins in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we report that lipopolysaccharide (LPS)-induced inflammation can promote TDP-43 mislocalization and aggregation. In culture, microglia and astrocytes exhibited TDP-43 mislocalization after exposure to LPS. Likewise, treatment of the motoneuron-like NSC-34 cells with TNF-alpha (TNF-α) increased the cytoplasmic levels of TDP-43. In addition, the chronic intraperitoneal injection of LPS at a dose of 1mg/kg in TDP-43(A315T) transgenic mice exacerbated the pathological TDP-43 accumulation in the cytoplasm of spinal motor neurons and it enhanced the levels of TDP-43 aggregation. These results suggest that inflammation may contribute to development or exacerbation of TDP-43 proteinopathies in neurodegenerative disorders.


Detection of an immunoglobulin switch region-specific DNA-binding protein in mitogen-stimulated mouse splenic B cells.
We have detected a nuclear protein from lipopolysaccharide- and dextran sulfate-stimulated mouse splenic B cells which binds specifically to the immunoglobulin switch mu (S mu) sequence. We have termed the binding protein NF-S mu. DNA containing the S mu repeated sequence, GAGCTGGGGTGAGCTGAGCTGAGCT, was used as a probe in electrophoretic mobility shift assays. Methylation interference analysis indicated that binding centers on the run of four guanine residues. Competitions with mutated S mu sequences confirmed the importance of the run of G residues and revealed that optimal binding occurs when they are flanked by GAGCT. The kinetics of the expression of NF-S mu in splenic B cells treated with lipopolysaccharide and dextran sulfate parallels the induction of recombinational activity at S mu in these cells. On the basis of these data, we suggest that NF-S mu may be an effector of switch recombination.


[Brown tumor in hyperparathyroidism secondary to chronic renal failure].
Brown tumor (BT) is an uncommon condition that represents the terminal stage of the cystic osteitis fibrosa and have been increasingly reported in hyperparathyroidism secondary to renal failure, due to the increase of survival in patient with hemodialysis. The fine needle aspiration diagnosis is of great importance in the recognition of the BT, although it can be difficult to distinguish it of lesions as the aneurysmal bone cyst and giant-cell tumor. We describe the case of 20-year-old female with chronic renal failure undergoing hemodialysis during six years. Both x-rays and computer tomography revealed a tumor in head of right humerus and lytic images in scapula of the same side, clavicles and ribs. The patient was subjected to a fine needle aspiration biopsy of the tumor of humerus head and the sample was processed with the habitual technique of inclusion in paraffin and stained with hematoxilina and eosina. Histological preparations showed several multinucleate giant cells and spindly or fibrillary cells, feature that was pointed out as compatible, in a context of secondary hyperparathyroidism to chronic renal failure, with a BT. We consider that the radiological and tomographyc finds, besides the history of chronic renal failure with a long history of hemodialysis, were enough to link, with great approach, the histopathology with the diagnosis of BT.


Advancing a distributed multi-scale computing framework for large-scale high-throughput discovery in materials science.
We describe the development of a large-scale high-throughput application for discovery in materials science. Our point of departure is a computational framework for distributed multi-scale computation. We augment the original framework with a specialized module whose role is to route evaluation requests needed by the high-throughput application to a collection of available computational resources. We evaluate the feasibility and performance of the resulting high-throughput computational framework by carrying out a high-throughput study of battery solvents. Our results indicate that distributed multi-scale computing, by virtue of its adaptive nature, is particularly well-suited for building high-throughput applications.


Disintegration of microorganisms.
The most common methods for the large-scale disintegration of microorganisms are high-pressure homogenization and wet milling. The most-used homogenizer is produced by Manton Gaulin and the common ball mill is the Dyno-Mill. Other manufacturers are now producing similar equipment (e.g., Rannie homogenizers and Netzsch ball mills). However, only relatively limited information on these systems has been published so far. An additional system that might become available for large-scale disintegration is microfluidization. When coming to choose optimal equipment and conditions for cell disintegration, it might be useful to consider some relevant topics that were compiled by the Retsch company for particle disruption and are presented, with modification, in Table XIII. Obviously, the importance of the above points will vary in different processes, but all of them should be considered in any biotechnological large-scale application. It is important to realize that although the mechanical disintegration methods are of general use, it is essential to define the optimal disintegration conditions for each microorganism and/or product. As a starting point, the published data for a similar product should be consulted. This should be followed by laboratory-scale experiments carried out with equipment and conditions that can be easily scaled up.


A new genus, four new species and taxonomic and geographic notes in Mexican Cerambycidae.
Four new Mexican species are described: Ironeus curoei from Guerrero state, Psyrassa garciai from Tamaulipas state, Psyrassa belangeri from Guerrero state (Elaphidiini, Cerambycinae); and Cirrhicera bankoi from Chiapas state (Hemilophini, Lamiinae). A new Hesperophanini genus, Makromastax, and a new combination, Makromastax mandibularis are proposed. The current key to the Mexican genera of Hesperophanini is updated to include the new genus. Haplidus nitidus Chemsak and Linsley, 1963 is proposed as synonyms of Haplidus mandibularis Chemsak and Linsley, 1963. The male of Eburia (E.) girouxae is illustrated by the first time and Anelaphus hirtus is redescribed and figured. The geographical distribution of 9 species is expanded, the type locality of Osmidus guttatus is corrected, and Neocompsa intrincata is excluded from the fauna of the United States of America.


Diverse structures and dimensionalities in hybrid frameworks of strontium and lanthanum with isomeric dihydroxybenzoates.
Investigations of Sr and La derivatives of 2,3-, 2,4-, 3,5-, and 2,6-dihydroxybenzoic acids have revealed that it is possible to obtain chain and layered structures of these materials. [Sr2(2,3-DHB)4(H2O)4].3H2O, I, and [Sr(2,4-DHB)2(H2O)4].H2O, II, are both one-dimensional coordination polymers based on dimers; both the carboxylate and phenolic oxygens bond to the metal in I and only the carboxylate oxygens bond to the metal in II. [Sr(3,5-DHB)2(H2O)2].4H2O, III, has a one-dimensional chain structure with large channels and involves extended Sr-O-Sr connectivity. [Sr(CH3CO2)(2,4-DHB)(H2O)3].H2O, IV, also has a chain structure with extended Sr-O-Sr connectivity, but the chain structure is formed by bridging acetate units, unlike in III where the Dihydroxybenzoate (DHB) is the bridging unit. [Sr(2,6-DHB)2(H2O)2].0.5H2O, V, is a two-dimensional coordination polymer where both carboxylate and phenolic oxygens coordinate to the metal. A lanthanum compound with the composition [La(CH3CO2)2(2,4-DHB)H2O].0.18H2O, VI, with a one-dimensional chain structure with extended La-O-La connectivity, has been prepared. Besides these chain and layered structures, zero-dimensional dimers of rare-earth DHBs with the general formula [La(CH3CO2)2(DHB)(H2O)2], with 3,5- (VII), 2,6- (VIII), and 2,3-dihydroxybenzoic acids (IX) have been synthesized. The diverse structures of the strontium and lanthanum DHBs are described. The study demonstrates that it is possible to obtain interesting structures of metal DHBs with different dimensionalities. The structures appear to be controlled largely by geometrical rather than electronic factors.


Micronucleus, cell-free DNA, and plasma glycan composition in the newborns of healthy and diabetic mothers.
Diabetes is associated with certain environmental exposures, heritable factors, and metabolic conditions of intrauterine development due to diabetes in the mother. We evaluated genomic damage, cell-free DNA, N-glycosylation of umbilical cord plasma proteins (PG), and nuclear division index (NDI) as possible prognostic biomarkers of health risk in the newborns of mothers with treated pregestational diabetes (NBDM; 22 mothers), compared these parameters with those from newborns of healthy mothers (NBHM; 89 mothers), and associated the results with the mothers' lifestyle in both groups, based on a detailed questionnaire. Genomic damage was estimated by the in vitro micronucleus (MN) assay. NDI was detected on MN slides. Glycans were analyzed by ultra-performance liquid chromatography that separates the plasma N-glycome into 46 glycan peaks. Cell-free DNA was analyzed by real-time PCR. For the association between biomarkers and individual characteristics, generalized linear/nonlinear analysis was performed. No significant difference was found between NBHM and NBDM for cell-free DNA levels. There was no association between cell-free DNA levels and lifestyle. MN frequency was significantly higher in NBDM than in NBHM (median, 0.6 vs. 0.3%, p<0.001). MN frequency and NDI were significantly associated with residence (urban vs. rural). PG differed significantly between NBHM and NBDM (p<0.001). A significant association was found between PG and increase of MN frequency (p<0.001). As both MN frequency and altered N-glycosylation are associated with cancer risk, our study indicates need for further investigations.


Localization of amiloride-sensitive sodium channels in A6 cells by atomic force microscopy.
Atomic force microscopy (AFM) was used for high-resolution imaging of the apical distribution of epithelial Na+ channels in A6 renal epithelial cells. A6 cells grown on coverslips were labeled with antibodies generated against an amiloride-sensitive epithelial Na+ channel complex purified from bovine renal medulla that had been conjugated to 8-nm colloidal gold particles before preparation for AFM. AFM revealed that there was a marked increase in the height of the microvilli in cells labeled with the anti-epithelial Na+ channel antibodies compared with unlabeled cells or cells labeled with rabbit nonimmune immunoglobulin G conjugated to colloidal gold particles. We interpret this apparent increase in microvillar height to be due to anti-epithelial Na+ channel antibody binding to the apical microvilli. These data demonstrate that epithelial Na+ channels are restricted to the apical microvilli in Na+-transporting renal epithelial cells. Furthermore, they demonstrate the applicability of using AFM for high-resolution imaging of the cell surface distribution of epithelial ion channels.


Meibomian gland dropout rate as a method to assess meibomian gland morphologic changes during use of preservative-containing or preservative-free topical prostaglandin analogues.
To investigate the usefulness of meibomian gland (MG) dropout rate in the evaluation of MG morphological change associated with the use of prostaglandin for glaucoma treatment through the association between MG and the ocular surface parameters and medication duration and presence of preservative. This cross-sectional study was conducted on 88 eyes of 88 patients who were diagnosed with glaucoma and used only Tafluprost as treatment. The patients were divided into four "user" groups: 1) 23 patients used preservative-free (PF) Tafluprost for 6 months; 2) 21 patients used preservative-containing (PC) Tafluprost for 6 months; 3) 23 patients used PF-Tafluprost for 24 months; 4) 21 patients used PC-Tafluprost for 24 months. Ocular surface parameters and the MG condition, including MG dropout rate and meiboscale, were evaluated. Multiple regression was used to identify associations. There were significant differences in age (p = 0.003), tear breakup time (p = 0.016), lid margin abnormality (p = 0.016), expressibility (p = 0.039), meiboscale (p<0.001), and MG dropout rate (p<0.001) among the 4 groups. MG dropout rate and meiboscale showed significant differences in all post hoc analyses, except for the comparison between the PF-Tafluprost and PC-Tafluprost 6-month user groups. Medication duration, preservative status, and meiboscale were significantly correlated with MG dropout rate (p<0.001, p = 0.024, p<0.001, respectively). In the 6-month user group, preservative status significantly correlated with MG dropout rate (p = 0.015). However, in the 24-month user group, meiboscale was the only parameter significantly associated with MG dropout rate (p<0.001). MG dropout rate in patients using Tafluprost showed a significant correlation with medication duration and preservative status. This result indicates MG dropout rate reflects MG morphologic change associated with prostaglandin.


Babesiosis: Current status and future perspectives in Pakistan and chemotherapy used in livestock and pet animals.
Babesiosis is a protozoal disease affect livestock and pet animals such as cattle, buffaloes, sheep, goats, horses, donkeys, mules, dogs, and cats. It causes severe economic losses in livestock as well as in pet animals. A large number of dairy animals are imported in order to fulfill the demands of milk, milk, meat and its products. In addition, different pet animals are transported from Pakistan to various parts of the world, therefore, it is important to identify the current status and distribution of babesiosis throughout Pakistan in order to control the disease and draw attention for future research, diagnosis, treatment and control of this diseases. No work has been done on a complete review on up-to-date on blood protozoal disease burden in Pakistan. This article will provide about the complete background of babesiosis in ruminants, equines and pet animals, its current status, distribution, vectors in Pakistan and allopathic and ethnoveterinary treatments used against babesiosis. Babesiosis may be subclinical (apparently normal) and may be clinical with acute to chronic disease and sometimes fatal. Babesia is found and develops inside the erythrocytes (red blood cells). Clinically, it causes fever, fatigue, lethargy, pallor mucus membranes, malaise, cachexia, respiratory distress, jaundice, icterus, hemolytic anemia, hemoglobinuria, lymphadenopathy, chollangocytitis, hepatomegaly, and splenomegaly. Chemotherapy for babesiosis includes Imidocarb dipropionate, Diaminazine aceturate Atovaquone and Bupravaquone, Azithromycin, Quinuronium sulfate and Amicarbalidesio-thionate are most widely used. Supportive therapy includes multivitamins, fluid therapy, antipyretics intravenous fluids, and blood transfusions are used if necessary. In addition, there are certain ethnoveterinary (homeopathic) ingredients which having anti-babesial activity. As the resistance against these drugs is developing every day. New more specific long-lasting drugs should be developed for the treatment of Babesiosis. Further studies should be done on disease genome of different species of Babesia for vaccine development like malarial parasites.


[Carotenoids and their antioxidant function: a review].
Natural antioxidant in vegetables, and in some animals have been studied by their action in the protection of a considerable number of diseases, such as, certain types of cancer, cardiovascular diseases, and age-related macular degeneration. Experimental evidences suggest that these compounds are important for protecting biological macro-molecules against oxidative damage. The search of new and more efficient antioxidants appears to be directed with carotenoids which have demonstrated that their consumption may reduce the incidence of certain diseases. In addition they represent a provitamin A source, and their actual antioxidant activity in the cell by participating in the neutralization of reactive oxygen species, and nitrogen produced, as a part of the cellular metabolism. This paper is focused to review basic and clinical aspects of investigations which have been associated with the intake of carotenoids with cancer, heart diseases, and age-related macular degeneration; the above all, we have tried to identify basic concepts of the role of the carotenoids and their metabolism; after that, we have reviewed clinical evidence that show how the intake of carotenoids reduces certain diseases. Finally, we discuss some of the results of investigation.


Micromorphological analysis of dentinal structure after irradiation with Nd:YAG laser and immersion in acidic beverages.
The purpose of this study was to analyze dentinal surfaces that were exposed to acidic beverages, then treated with Nd:YAG laser and afterwards exposed to acidic beverages again. Dentin hypersensitivity can result from surface erosion caused by acidic beverages, which exposes and enlarges the dentinal tubules. Nd:YAG laser has been used as a treatment option. Sixty-eight dentin samples were prepared and assigned to five groups: G1, control (n = 4); G2, 3-h immersion (n = 16); G3, 3-h immersion + Nd:YAG; G4, 3-h immersion + Nd:YAG + 3-h immersion; and G5, 3-h immersion + Nd:YAG + 6-h immersion. Each group was divided into four subgroups, with different acid beverages: lemon (n = 4); passion fruit (n = 4); cola (n = 4); and wine (n = 4). Irradiation with the Nd:YAG was in contact mode, focused and perpendicular through a quartz fiber of 300 microm of diameter in scanning movements for 60 sec with a 10-sec interval and the paramenters 0.6 W, 10 Hz, 60 mJ, and 85 mJ/cm(2). Each subgroup was examined by scanning electron microscope. All the acidic beverages contributed to exposure and increased diameter of the dentinal tubules. Irradiation with Nd:YAG laser produced obliteration of and reduction in the number of dentinal tubules, thus modifying the original structure.


Role of integrin switch and transforming growth factor Beta 3 in hypoxia-induced invasion inhibition of human extravillous trophoblast cells.
The physiological hypoxic condition favors the angiogenesis in the placenta. However, it remains unclear how hypoxia regulates the invasion of human extravillous trophoblast cells. In the present study, we first showed that alpha5 integrin expression increased and alpha1 integrin expression decreased in human extravillous trophoblast cells cultured in 1% oxygen as compared with control cells cultured in 8% oxygen. Further data showed that the neutralizing antibody against alpha5 integrin increased the invasion of human extravillous trophoblast cells and the neutralizing antibody against alpha1 integrin inhibited the invasion of human extravillous trophoblast cells. Human extravillous trophoblast cells cultured in 1% oxygen showed reduced invasive capacity, which can be effectively blocked by alpha5 integrin neutralizing antibody. Moreover, human extravillous trophoblast cells exposed to 1% oxygen demonstrated increased expression of transforming growth factor-beta3 (TGFB3), and recombinant human TGFB3 inhibited the invasion of human extravillous trophoblast cells in a dose-dependent manner. The neutralizing antibodies against alpha5 integrin and TGFB3 markedly abrogated hypoxia-induced invasion inhibition in human extravillous trophoblast cells. These data indicate that hypoxia may inhibit the invasion of human extravillous trophoblast cells through inducing the integrin switch from alpha1 integrin to alpha5 integrin and promoting TGFB3 expression.


Esophageal cyst as a cause of chronic cough.
The previously unreported association of chronic persistent cough due to a duplication esophageal cyst is presented. The presence of a long history of atopy, bronchitis, and asthma resulted in a delay in diagnosis. When vigorous bronchodilator therapy was unsuccessful, close observation of the patient and review of her radiographs suggested the esophageal etiology of her cough. This case reinforces the observation that chronic persistent cough, although common, may present a very perplexing problem. A systematic approach considering the anatomy of the cough reflex, and an awareness of the esophageal and other nonpulmonary causes of cough, can aid in diagnosis and management of these patients.


Biomarkers in Transplantation--Proteomics and Metabolomics.
Modern multianalyte "omics" technologies allow for the identification of molecular signatures that confer significantly more information than measurement of a single parameter as typically used in current medical diagnostics. Proteomics and metabolomics bioanalytical assays capture a large set of proteins and metabolites in body fluids, cells, or tissues and, complementing genomics, assess the phenome. Proteomics and metabolomics contribute to the development of novel predictive clinical biomarkers in transplantation in 2 ways: they can be used to generate a diagnostic fingerprint or they can be used to discover individual proteins and metabolites of diagnostic potential. Much fewer metabolomics than proteomics biomarker studies in transplant patients have been reported, and, in contrast to proteomics discovery studies, new lead metabolite markers have yet to emerge. Most clinical proteomics studies have been discovery studies. Several of these studies have assessed diagnostic sensitivity and specificity. Nevertheless, none of these newly discovered protein biomarkers have yet been implemented in clinical decision making in transplantation. The currently most advanced markers discovered in proteomics studies in transplant patients are the chemokines CXCL-9 and CXCL-10, which have successfully been validated in larger multicenter trials in kidney transplant patients. These chemokines can be measured using standard immunoassay platforms, which should facilitate clinical implementation. Based on the published evidence, it is reasonable to expect that these chemokine markers can help guiding and individualizing immunosuppressive regimens, may be able to predict acute and chronic T-cell-mediated and antibody-mediated rejection, and may be useful tools for risk stratification of kidney transplant patients.


Handling Imbalanced Data: Uncertainty-Guided Virtual Adversarial Training With Batch Nuclear-Norm Optimization for Semi-Supervised Medical Image Classification.
In manyclinical settings, a lot of medical image datasets suffer from imbalance problems, which makes predictions of trained models to be biased toward majority classes. Semi-supervised Learning (SSL) algorithms trained with such imbalanced datasets become more problematic since pseudo-supervision of unlabeled data are generated from the model's biased predictions. To address these issues, in this work, we propose a novel semi-supervised deep learning method, i.e., uncertainty-guided virtual adversarial training (VAT) with batch nuclear-norm (BNN) optimization, for large-scale medical image classification. To effectively exploit useful information from both labeled and unlabeled data, we leverage VAT and BNN optimization to harness the underlying knowledge, which helps to improve discriminability, diversity and generalization of the trained models. More concretely, our network is trained by minimizing a combination of four types of losses, including a supervised cross-entropy loss, a BNN loss defined on the output matrix of labeled data batch (lBNN loss), a negative BNN loss defined on the output matrix of unlabeled data batch (uBNN loss), and a VAT loss on both labeled and unlabeled data. We additionally propose to use uncertainty estimation to filter out unlabeled samples near the decision boundary when computing the VAT loss. We conduct comprehensive experiments to evaluate the performance of our method on two publicly available datasets and one in-house collected dataset. The experimental results demonstrated that our method achieved better results than state-of-the-art SSL methods.