Real-world patterns on tumor mutation burden testing in a pan-tumor population.
Background: There is limited real-world information on use of tumor mutational burden (TMB) testing and characteristics of patients receiving it. Materials & methods: Patients ≥18 years old and diagnosed with advanced solid tumors between 1 January 2015 and 31 January 2019 with TMB testing (TMB cohort) and without it (non-TMB) were included in this retrospective, observational study. Results: The TMB cohort (n = 202) was younger than non-TMB (n = 212) (mean age: 62.1 vs 65.6 at diagnosis; p = 0.005). There were more Black patients in the TMB cohort (21.3 vs 11.8% in non-TMB; p = 0.004). Clinical characteristics were comparable between the two cohorts; however, systemic anticancer treatment was higher among TMB cohort (91.6 vs 77.8% in non-TMB). Conclusion: Notable differences were observed between patients receiving TMB test and those not receiving it.


Management of Status Epilepticus in Children.
Status epilepticus is a common pediatric neurological emergency. Management includes prompt administration of appropriately selected anti-seizure medications, identification and treatment of seizure precipitant(s), as well as identification and management of associated systemic complications. This review discusses the definitions, classification, epidemiology and management of status epilepticus and refractory status epilepticus in children.


Multiple Power Allocation Game Schemes for Spectrum Coexistence Model Between Multistatic MIMO Radar Sensors and MU Communication.
The normal operations of radar systems and communication systems under the condition of spectrum coexistence are facing a huge challenge. This paper uses game theory to study power allocation problems between multistatic multiple-input multiple-output (MIMO) radars and downlink communication. In the case of spectrum coexistence, radars, base station (BS) and multi-user (MU) have the working state of receiving and transmitting signals, which can cause unnecessary interferences to different systems. Therefore, when they work together, they should try to suppress mutual interferences. Firstly, the signal from BS is considered as interference when radar detects and tracks targets. A supermodular power allocation game (PAG) model is established and the existence and uniqueness of the Nash equilibrium (NE) in this game are proved. In addition, the power allocation problem from BS to MU is also analyzed, and two Stackelberg PAG models are constructed. It is proved that the NE of each game exists and is unique. Simultaneously, two Stackelberg power allocation iterative algorithms converge to the NEs. Finally, numerical results verify the convergence of the proposed PAG algorithms.


Interaction Mechanism of Anionic Lignin and Cationic Soft Surface in Saline Systems.
Lignin has a complicated three-dimensional structure that is different from other synthetic and bio-based materials. In this work, we first examined the physicochemical behavior, i.e., apparent hydrodynamic radius (Rh) and ζ-potential, of carboxymethylated lignin (CM) in a saline system. Then, the detailed interaction and adsorption behavior of CM on a cationic poly(diallyldimethylammonium chloride) (PDADMAC)-coated surface were investigated in a saline system by a quartz crystal microbalance with dissipation. The theoretical and experimental adsorption data revealed that CM made limited surface coverage at a low salt concentration via charge neutralization following an intrinsic compensation mechanism. At a higher salt concentration, the adsorption of CM was improved significantly following the extrinsic compensation mechanism and nonionic interaction (e.g., hydrophobic interaction). The adsorption affinity of CM in the urea environment revealed the contribution (10-30%) of hydrogen bonding in the adsorption of CM on the PDADMAC surface. Contrary to what was found for the CM, the adsorption of a linear poly(acrylic acid-acrylamide) (PAM) on the PDADMAC surface exhibited a dramatic decrease at higher salinity, possibly due to the absence of nonionic and hydrophobic interactions between PAM and the surface. The findings of this study showed the superior adsorption performance of the lignin-based polyelectrolytes to the synthetic ones in salt-containing systems.


[Cutaneous plasmacytoma: review of the literature apropos of a case].
Extramedullary plasmocytomas are ubiquitous plasmocytic tumours which are principally located in bones and mucosae but rarely found on the skin. Clinically, they present as purplish-blue cutaneous nodules or, less frequently, as papular or urticarial eruptions. The diagnosis rests on histology and immunostaining. Cutaneous plasmocytomas are usually divided into two types: (1) primary plamocytomas which occur in the absence of myeloma, present as solitary or multiple skin tumours, accompanied or not by monoclonal gammopathy, and have an imperfectly known course and prognosis; (2) secondary plasmocytomas--a case of which is reported here--which appear in the course of a large tumoral mass myeloma and have a very poor prognosis.


Importance of blood pressure variability in organ protection in spontaneously hypertensive rats treated with combination of nitrendipine and atenolol.
To study the importance of reduction of blood pressure variability (BPV) in the organ protection of long-term treatment with combination of nitrendipine and atenolol, which was abbreviated as Nile, in spontaneously hypertensive rats (SHR). Combination of nitrendipine (10 mg/kg/d) and atenolol (20 mg/kg/d) was given in SHR chow for 12 weeks. Blood pressure (BP) was then recorded during 24 h in conscious state. After the determination of baroreflex sensitivity (BRS), rats were killed for organ-damage evaluation. Long-term treatment with Nile significantly decreased BP and BPV, ameliorated impaired BRS, and obviously diminished end-organ damage in SHR. The indices of left ventricular and aortic hypertrophy, and glomerulosclerosis score were all positively related to BP and BPV, and negatively related to BRS in untreated and Nile-treated SHR. Multiple-regression analysis showed that decrease in left ventricular and aortic hypertrophy was mainly related to the decrease in systolic BPV, and amelioration in renal lesion was mainly determined by increase in BRS. Long-term treatment with Nile possessed obvious organ protection in SHR. Besides the BP reduction, the decrease in BPV and the restoration of BRS may importantly contribute to this organ protection.


Regulation of lymphocyte clustering by CD30-mediated ICAM-1 up-regulation.
CD30 is expressed transiently on activated B and T lymphocytes and constitutively on several B- and T cell lymphomas. CD30 functions include participation in negative selection of thymocytes, costimulation of activated T cells, isotype switching of B cells, and regulation of the effector activity of cytotoxic lymphocytes. Although CD30 is not a marker for T helper 2 (TH2) cells, it may participate in the polarization of TH1 and TH2 cells. The pleiotropic functions of CD30 are initiated by interaction of CD30-expressing cells with other immune competent cells expressing CD30-L and providing the signals for modulation of effector cell activity. Here, we report that CD30 signals generated by anti-CD30 on activated, normal murine T cells strongly up-regulate the expression of intercellular adhesion molecule 1 (ICAM-1, CD54), and to a lesser extent, ICAM-2 (CD102). CD30 signals moreover delay the subsequent decline of ICAM expression. CD30 cross-linking did not alter the expression of CD11a/CD18 (LFA-1), the counter receptor for ICAM abundant on T cells. CD30-mediated ICAM-1 up-regulation is independent of cytokine secretion and appears to be transmitted directly through NF-kappaB activation. CD30-mediated up-regulation of ICAM-1 expression led to a significant increase in cluster formation of lymph node cells. Increased lymphocyte self-aggregation mediated by CD30 may set the stage for fraternal signaling to modulate lymphocyte function.


3D Biofabrication of Thermoplastic Polyurethane (TPU)/Poly-l-lactic Acid (PLLA) Electrospun Nanofibers Containing Maghemite (γ-Fe₂O₃) for Tissue Engineering Aortic Heart Valve.
Valvular dysfunction as the prominent reason of heart failure may causes morbidity and mortality around the world. The inability of human body to regenerate the defected heart valves necessitates the development of the artificial prosthesis to be replaced. Besides, the lack of capacity to grow, repair or remodel of an artificial valves and biological difficulty such as infection or inflammation make the development of tissue engineering heart valve (TEHV) concept. This research presented the use of compound of poly-l-lactic acid (PLLA), thermoplastic polyurethane (TPU) and maghemite nanoparticle (γ-Fe₂O₃) as the potential biomaterials to develop three-dimensional (3D) aortic heart valve scaffold. Electrospinning was used for fabricating the 3D scaffold. The steepest ascent followed by the response surface methodology was used to optimize the electrospinning parameters involved in terms of elastic modulus. The structural and porosity properties of fabricated scaffold were characterized using FE-SEM and liquid displacement technique, respectively. The 3D scaffold was then seeded with aortic smooth muscle cells (AOSMCs) and biological behavior in terms of cell attachment and proliferation during 34 days of incubation was characterized using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and confocal laser microscopy. Furthermore, the mechanical properties in terms of elastic modulus and stiffness were investigated after cell seeding through macro-indentation test. The analysis indicated the formation of ultrafine quality of nanofibers with diameter distribution of 178 ± 45 nm and 90.72% porosity. In terms of cell proliferation, the results exhibited desirable proliferation (109.32 ± 3.22% compared to the control) of cells over the 3D scaffold in 34 days of incubation. The elastic modulus and stiffness index after cell seeding were founded to be 22.78 ± 2.12 MPa and 1490.9 ± 12 Nmm², respectively. Overall, the fabricated 3D scaffold exhibits desirable structural, biological and mechanical properties and has the potential to be used in vivo.


Imine-assisted C-F bond activation using low-valent cobalt compounds supported by trimethylphosphine ligands and formation of novel organic fluorides.
A cyclometalation reaction involving C-F bond activation at a cobalt(i) center with an aldazine-N atom as anchoring group affords ortho-chelated cobalt(iii) complexes containing a [C-Co-F] fragment [CoFMe(PMe(3))(2){(C(6)H(3)F-ortho)CH[double bond, length as m-dash]N-R}] 5-8. Under similar reaction conditions π-coordinated cobalt(0) complexes [Co(PMe(3))(3)((C(6)H(3)F-ortho)CH[double bond, length as m-dash]N-R)] 12-14 were formed when [Co(PMe(3))(4)], instead of [CoMe(PMe(3))(4)], was applied. C-F bond activation did not occur. Carbonylation of complexes 6-8 delivered novel organic fluorides 15-17. A proposed formation mechanism of the novel organic fluorides with demetallation and carbonylation of complexes 6-8 by CO is discussed with experimental support. As important intermediates, an acetyl cobalt complex, [CoFMeC[double bond, length as m-dash]O(PMe(3))(2){(C(6)H(3)F-ortho)CH[double bond, length as m-dash]N-R}] 20, and a 19-electron cobalt(0) complex, Co(CO)(3)(PMe(3))(2)21, were structurally characterized. The crystal and molecular structures of complexes 5, 6, 8, 12, 20 and 21 were determined by X-ray diffraction.


Spermine modulation of the glutamate(NMDA) receptor is differentially responsive to conantokins in normal and Alzheimer's disease human cerebral cortex.
The pharmacology of the N -methyl-d-aspartate (NMDA) receptor site was examined in pathologically affected and relatively spared regions of cerebral cortex tissue obtained at autopsy from Alzheimer's disease cases and matched controls. The affinity and density of the [(3)H]MK-801 binding site were delineated along with the enhancement of [(3)H]MK-801 binding by glutamate and spermine. Maximal enhancement induced by either ligand was regionally variable; glutamate-mediated maximal enhancement was higher in controls than in Alzheimer's cases in pathologically spared regions, whereas spermine-mediated maximal enhancement was higher in controls in areas susceptible to pathological damage. These and other data suggest that the subunit composition of NMDA receptors may be locally variable. Studies with modified conantokin-G (con-G) peptides showed that Ala(7)-con-G had higher affinity than Lys(7)-con-G, and also defined two distinct binding sites in controls. Nevertheless, the affinity for Lys(7)-con-G was higher overall in Alzheimer's brain than in control brain, whereas the reverse was true for Ala(7)-con-G. Over-excitation mediated by specific NMDA receptors might contribute to localized brain damage in Alzheimer's disease. Modified conantokins are useful for identifying the NMDA receptors involved, and may have potential as protective agents.


Consequences of the nuclear power plant accident at Chernobyl.
The Chernobyl Nuclear Power Plant accident, in the Ukrainian Soviet Socialist Republic (SSR), on April 26, 1986, was the first major nuclear power plant accident that resulted in a large-scale fire and subsequent explosions, immediate and delayed deaths of plant operators and emergency service workers, and the radioactive contamination of a significant land area. The release of radioactive material, over a 10-day period, resulted in millions of Soviets, and other Europeans, being exposed to measurable levels of radioactive fallout. Because of the effects of wind and rain, the radioactive nuclide fallout distribution patterns are not well defined, though they appear to be focused in three contiguous Soviet Republics: the Ukrainian SSR, the Byelorussian SSR, and the Russian Soviet Federated Socialist Republic. Further, because of the many radioactive nuclides (krypton, xenon, cesium, iodine, strontium, plutonium) released by the prolonged fires at Chernobyl, the long-term medical, psychological, social, and economic effects will require careful and prolonged study. Specifically, studies on the medical (leukemia, cancers, thyroid disease) and psychological (reactive depressions, post-traumatic stress disorders, family disorganization) consequences of continued low dose radiation exposure in the affected villages and towns need to be conducted so that a coherent, comprehensive, community-oriented plan may evolve that will not cause those already affected any additional harm and confusion.


Promoting safe motherhood in the community: the case for strategies that include men.
Although a decade has now passed since the launching of the Safe Motherhood Initiative, maternal mortality continues to be the health indicator showing the greatest disparity between developed and developing countries. Recently revised WHO and UNICEF figures indicate that an estimated 90% of the 585,000 worldwide maternal deaths that occur each year take place in sub-Saharan Africa and Asia. In terms of the lifetime risk of maternal death, this disparity remains striking: 1 in 12 women in parts of sub-Saharan Africa, compared with 1 in 4,000 women in Northern Europe. In addition, for every woman who dies, an estimated 16-17 will suffer from pregnancy-related complications. Research suggests that, in addition to biomedical interventions and the strengthening of health care services, improving awareness of obstetric complications among members of a pregnant woman's immediate and wider social network is an important step in improving her chances of survival when such complications occur. Many of the interventions implemented so far have focused exclusively on improving women's knowledge and practices as they relate to maternal health issues. Nevertheless, it is now increasingly being recognised that the actions required to achieve improvements in reproductive health outcomes in general, and maternal health in particular, should involve communities in the process and encourage men's active participation. Despite this, very few studies on risk perceptions or interventions to raise community awareness of obstetric risk factors, their complications and their consequences have targeted men. The present article argues for the development and testing of risk awareness interventions, which, in addition to women, target men in their familial and social roles within communities and as workers within health care services as a means of improving maternal health outcomes.


Effect of ultrasonic irradiation on the properties and performance of biodiesel produced from date seed oil used in the diesel engine.
In the present study, the effect of ultrasound irradiation on the transesterification parameters, biodiesel properties, and its combustion profiles in the diesel engine was investigated. Moreover, date seed oil (DSO) was firstly utilized in the ultrasound-assisted transesterification reaction. DSO was extracted from Zahidi type date (Phoenix dactylifera) and was esterified to reduce its Free Fatty Acid (FFA) content. Biodiesel yield was optimized in both heating methods, so that the yield of 96.4% (containing 93.5% ester) at 60 °C, with 6 M ratio of methanol/oil, 1 wt% of catalyst (NaOH) and at 90 min of reaction time was reported. The ultrasound irradiation did not influence the reaction conditions except reaction time, reduced to 5 min (96.9% yield and 91.9% ester). The ultrasonic irradiation also influenced on the physicochemical properties of DSO biodiesel and improved its combustion in the diesel engine. The analysis results related to the engine and gas emission confirmed that the ultrasound-assisted produced biodiesel has lower density and viscosity, and higher oxygen content facilitating injection of fuel in the engine chamber and its combustion, respectively. Although, B40 (biodiesel blend consisting of 40% biodiesel and 60% net diesel fuel) as a blend of both fuels presented higher CO2 and lower CO and HC in the emissions, the DSO biodiesel produced by ultrasound irradiation presented better specifications (caused about 2-fold improvement in emissions than that of conventional method). The findings of the study confirmed the positive effect of the ultrasound irradiation on the properties of the produced biodiesel along with its combustion properties in the diesel engine, consequently reducing air pollution problems.


Does dosing antihypertensive drugs at night alter renal or cardiovascular outcome: do we have the evidence?
Recent evidence suggests that blood pressure during nighttime and the early morning hours is associated with increased cardiovascular risk independently of the average 24 h blood pressure. The review aims to investigate whether nighttime administration of antihypertensive drugs alters the circadian blood pressure variation and prevents hypertension-induced target organ damage and cardiovascular or renal disease. Several studies showed that nighttime administration of antihypertensive drugs has a larger blood pressure lowering effect during nighttime and the early morning hours. Some studies of intermediate endpoints, such as albuminuria, ventricular hypertrophy and carotid thickness suggested beneficial effects of nighttime administration of drugs. Few long-term outcome studies showed impressive cardiovascular protection using nighttime administration of antihypertensive drugs. Owing to methodological issues, however, these studies cannot prove whether, for the same 24 h blood pressure reduction, nighttime dosing provides greater cardiovascular and renal protection than the conventional morning dosing. Whether nighttime dosing is superior to the conventional morning dosing in improving cardiovascular or renal outcome remains unclear. Randomized outcome studies comparing the same treatment administered in the morning versus at nighttime are needed. Until these data become available nighttime dosing of antihypertensive drugs cannot be recommended.


Effect of flutamide on 5 alpha-reductases, 5 beta-reductases, and 3-hydroxysteroid dehydrogenases in rat liver.
Flutamide (0.5 mM) decreased in vitro the activity of NADH-5 alpha-reductase (substrate testosterone) in liver homogenate of male and female rats, whereas no change of activity of NADPH-5 alpha-reductase was observed. NADH- and NADPH-5 beta-reductase activity increased only in liver of female, but not of male rats. NAD+-3 beta-hydroxysteroid dehydrogenase and NAD+-3 alpha-hydroxysteroid dehydrogenase (substrate 5 alpha-dihydro-testosterone) in liver homogenate from female rats were inhibited by flutamide (0.5 mM), whereas the activity of NADP+-3 alpha-hydroxysteroid dehydrogenase (substrate 5 alpha-dihydrotestosterone) and of NAD+-3 alpha-hydroxysteroid dehydrogenase (substrate 5 beta-dihydrotestosterone) increased in presence of flutamide. The activity of NADH- and NADPH-5 alpha-reductase decreased after flutamide administration to female rats at a dose of 5 mg per day for 7 days.


Reliability of the Nidek NT-1000 non contact tonometer.
In this prospective study, we compared the intraocular pressure (IOP) readings of 100 patients measured with the Goldmann applanation tonometer and the Nidek NT-1000 pneumotonometer. The correlation coefficient between the Goldmann and Nidek readings was 0.86. On the average the pneumotonometer overestimated the intraocular pressure with 0.43 mm Hg. The Nidek NT-1000 non contact tonometer can be used for screening purposes provided an appropriately low IOP value is used to indicate the need for further assessment with the Goldman applanation tonometer.


Radiation-chemical properties of the hypoxic cell radiosensitizer doranidazole (PR-350).
This study was performed to confirm the radiation-chemical properties of the 2-nitroimidazole derivative doranidazole, (+/-)-(2RS,3SR)-3-[(2-nitroimdazol-1-yl)-methoxy]butane-1,2,4-triol [CAS 137339-64-1], PR-350, which was synthesized as a hypoxic cell radiosensitizer with low toxicity. Radiation-chemical experiments using doranidazole showed that (1) unlike O2, it had high reactivity toward not only hydrated electrons (eaq-), but also hydroxyl radicals (.OH), (2) the reduced intermediates of doranidasole had no ability to induce immediate strand breaks of colE1 plasmid DNA, (3) doranidazole enhanced radiation-induced DNA strand breaks of colE1 plasmid DNA in the aqueous state, whereas it did not enhance the base alteration, such as 8-oxo-deoxyguanosine, (4) it enhanced the radiation-induced formation of strand breaks with 3'-phosophate and 3'-phosphoglycolate termini, and (5) it was bound to DNA after irradiation. These facts revealed that the majority of radiation-chemical properties of doranidazole, except for the high reactivity toward OH, were similar to those of oxygen.


Phytoconstituents as photoprotective novel cosmetic formulations.
Phytoconstituents are gaining popularity as ingredients in cosmetic formulations as they can protect the skin against exogenous and endogenous harmful agents and can help remedy many skin conditions. Exposure of skin to sunlight and other atmospheric conditions causes the production of reactive oxygen species, which can react with DNA, proteins, and fatty acids, causing oxidative damage and impairment of antioxidant system. Such injuries damage regulation pathways of skin and lead to photoaging and skin cancer development. The effects of aging include wrinkles, roughness, appearance of fine lines, lack of elasticity, and de- or hyperpigmentation marks. Herbal extracts act on these areas and produce healing, softening, rejuvenating, and sunscreen effects. We have selected a few photoprotective phytoconstituents, such as curcumin, resveratrol, tea polyphenols, silymarin, quercetin and ascorbic acid, and have discussed the considerations to be undertaken for the development of herbal cosmetic formulations that could reduce the occurrence of skin cancer and delay the process of photoaging. This article is aimed at providing specific and compiled knowledge for the successful preparation of photoprotective herbal cosmetic formulations.


Biocompatible surface preparation using amino-functionalized amylose.
Aminopropyl amyloses with various degrees of substitution (DS) were prepared and investigated with respect to their surface modification properties. Poly(acrylic acid) was grafted to plasma-activated PVDF films, and the functional amylose was bound via amide linkage formation. Layer formation was confirmed by X-ray photoelectron spectroscopy. Contact angle measurements and surface MALDI-TOF mass spectrometry indicated a hydrophilic surface and minimization of protein adsorption.


Localization of a human homolog of the mouse pericentrin gene (PCNT) to chromosome 21qter.
Exon trapping was used to identify portions of genes from cosmid DNA of a human chromosome 21-specific library LL21NC02-Q. More than 650 potential exons have been cloned and characterized to date. Among these, 3 trapped "exons" showed strong homology to different regions of the cDNA for the mouse pericentrin (Pcnt) gene (Doxsey et al., Cell 76: 639-650, 1994), indicating that these 3 exons are portions of a human homolog of the mouse pericentrin gene. With PCR amplification, Southern blot analysis, and FISH, we have mapped this presumed human pericentrin gene (PCNT) to the long arm of chromosome 21 between marker PFKL and 21qter. Pericentrin is a conserved protein component of the filamentous matrix of the centrosome involved in the initial establishment of the organized microtubule array. No candidate hereditary disorder for pericentrin deficiency/abnormality has yet been mapped in the most distal region of 21q; in addition the role of triplication of the pericentrin gene in the pathophysiology or etiology of trisomy 21 is currently unknown.


Embryonal carcinoma of the pineal gland with yolk sac tumor differentiation. A case report.
Twenty three old male patient was diagnosed as a pineal gland tumor and was operated in neurosurgical ward. He died four weeks later due to pneumonia and respiratory failure. Clinical diagnosis was based on computer tomography (CT) and magnetic resonance image (MRI) examination. Histological study of a biopsy and autopsy specimens showed embryonal carcinoma with yolk sac tumor differentiation. The diagnosis was supported by positive cytokeratin, placental alkaline phosphate and alpha-fetoprotein immunostainings.


Heterologous Production of Glycine Betaine Using Synechocystis sp. PCC 6803-Based Chassis Lacking Native Compatible Solutes.
Among compatible solutes, glycine betaine has various applications in the fields of nutrition, pharmaceuticals, and cosmetics. Currently, this compound can be extracted from sugar beet plants or obtained by chemical synthesis, resulting in low yields or high carbon footprint, respectively. Hence, in this work we aimed at exploring the production of glycine betaine using the unicellular cyanobacterium Synechocystis sp. PCC 6803 as a photoautotrophic chassis. Synechocystis mutants lacking the native compatible solutes sucrose or/and glucosylglycerol-∆sps, ∆ggpS, and ∆sps∆ggpS-were generated and characterized. Under salt stress conditions, the growth was impaired and accumulation of glycogen decreased by ∼50% whereas the production of compatible solutes and extracellular polymeric substances (capsular and released ones) increased with salinity. These mutants were used as chassis for the implementation of a synthetic device based on the metabolic pathway described for the halophilic cyanobacterium Aphanothece halophytica for the production of the compatible solute glycine betaine. Transcription of ORFs comprising the device was shown to be stable and insulated from Synechocystis' native regulatory network. Production of glycine betaine was achieved in all chassis tested, and was shown to increase with salinity. The introduction of the glycine betaine synthetic device into the ∆ggpS background improved its growth and enabled survival under 5% NaCl, which was not observed in the absence of the device. The maximum glycine betaine production [64.29 µmol/gDW (1.89 µmol/mg protein)] was reached in the ∆ggpS chassis grown under 3% NaCl. Taking into consideration this production under seawater-like salinity, and the identification of main key players involved in the carbon fluxes, this work paves the way for a feasible production of this, or other compatible solutes, using optimized Synechocystis chassis in a pilot-scale.


Antigen structural requirements for recognition by a cyclobutane thymine dimer-specific monoclonal antibody.
A monoclonal antibody (TDM-2) specific to a UV-induced cyclobutane pyrimidine dimer (T[cis-syn]T) has previously been established; however,the immunization had used UV-irradiated calf-thymus DNA containing a heterogeneous mixture of photoproduct sites. We investigated here the structural requirements of antigen recognition by the antibody using chemically synthesized antigen analogs. TDM-2 bound with cis-syn,but not trans-syn thymine dimer,and could bind strongly with four nucleotide analogs in which the cis-syn pyrimidine dimer was located in the center. Antigen analogs containing abasic linkers at the 5'- or 3'-side of the cis-syn cyclobutane pyrimidine dimer were synthesized and tested for binding to TDM-2. The results indicated that TDM-2 recognizes not only the cyclobutane ring but also both the 5'- and 3'-side nucleosides of the cyclobutane dimer. Furthermore,it was proved that either the 5'- or 3'-side phosphate group at a cyclobutane dimer site was absolutely required for the affinity to TDM-2. The antibody showed a strong binding to single stranded DNA but indicated little binding to double stranded DNA.


The Sense of Stigmatization in Patients with Plaque Psoriasis.
Psoriasis is a systemic inflammatory disease capable of creating stigmatization in the form of social exclusion and decrement of psychological conditions. The aim of the study was to determine the level of stigmatization in patients with plaque psoriasis. The study included 166 patients with plaque psoriasis (55.6% women and 44.3% men) with Psoriasis Area and Severity Index scores ≤10. The age of the study patients ranged between 18 and 72 years (arithmetic mean = 37.4; median = 38; standard deviation [SD] = 11.0). The mean age at the diagnosis of psoriasis was 21.5 years (median = 20; SD = 9.1) and disease duration varied from 2 to 59 years (arithmetic mean = 15.8; median = 15; SD = 11.3). The study patients completed the Polish version of the 6-item Stigmatization Scale and the 33-item Feelings of Stigmatization Questionnaire and a survey developed by the authors of this study, containing questions about the participants' sociodemographic characteristics (sex, age, place of residence, marital status, education, employment status) and information about their disease (location of psoriatic lesions, time elapsed since the diagnosis of psoriasis). The mean score for the 6-item Stigmatization Scale for the whole study group was 7.6 out of 18 points (median = 7; SD = 3.8; minimum = 0; maximum = 17). The average score for the 33-item Stigma Feelings Questionnaire in our series was 84.5 out of 165 points (median = 88; SD = 20.9; minimum = 30; maximum = 136). A statistically significant sex-related difference was observed in the 6-item Stigmatization Scale scores, with higher stigmatization levels found in men than in women (p = 0.0082). Moreover, significantly higher levels of stigmatization were observed in countryside dwellers (p = 0.0311) and unmarried persons (p = 0.0321). Patients with a longer history of the disease (≥15 years) scored significantly higher on the 6-item Stigmatization Scale (p = 0.0217) than those in whom psoriasis lasted less long, and presented with higher, at the threshold of statistical significance, scores for the 33-item Feelings of Stigmatization Questionnaire. Stigmatization awareness should be promoted among physicians and psoriatic patients to improve psoriasis management.


Congenital insensitivity to pain and anhydrosis: a report of two cases.
We report on 2 patients with congenital insensitivity to pain and anhydrosis. The first one was a 7-month-old boy who presented with non-traumatic, haematogenous septic dislocation of the right elbow with physeal separation of the distal humerus. The second one was a 3-year-old girl suspected to have Job syndrome with an altered immunological profile.


Evidence that periodontal treatment improves diabetes outcomes: a systematic review and meta-analysis.
The effect of periodontal therapy on diabetes outcomes has not been established. This update examines the effect of periodontal treatment on diabetes outcomes. Literature since October 2009 using MEDLINE. Published RCTs including periodontal therapy for diabetic subjects, a metabolic outcome, an untreated control group, and follow-up of 3 months. Pre-defined data fields, including study quality indicators were used. A search revealed 56 publications of which 9 met inclusion criteria. Mean change of HbA1c from baseline was compared across treatment groups. Pooled analysis was based on random effects models. A meta-analysis indicated a mean treatment effect of -0.36% HbA1c (CI -0.54, -0.19) compared to no treatment after periodontal therapy (p < 0.0001). Heterogeneity tests revealed only minimal evidence of publication bias (I(2 ) = 9%). Small sample size and high risk of bias remain problematic for studies of this type. Periodontal therapy varied considerably. The modest reduction in HbA1c observed as a result of periodontal therapy in subjects with type 2 diabetes is consistent with previous systematic reviews. Despite this finding, there is limited confidence in the conclusion due to a lack of multi-centre trials of sufficient sample size are lacking.


Advances in HER2-Positive Breast Cancer: Novel Therapies and Adverse Event Management.
Although breast cancer is a heterogeneous disease, approximately 20% to 25% of patients diagnosed with breast cancer have amplification of the HER2 gene. The FDA approval of trastuzumab for the treatment of HER2-positive (HER2+) metastatic breast cancer in 1998 represented a major breakthrough for patients with HER2+ disease. In 2006, the FDA extended its approval for use in the adjuvant setting. In recent years, trials have been conducted to identify the appropriate duration of therapy in combination with chemotherapy. More recently, trials incorporating newer HER2-targeted therapies have been conducted. Some trials have demonstrated the importance of considering neoadjuvant HER2-directed therapies for selected patients with HER2+ disease, highlighting the fact that achieving pathologic complete response has important prognostic implications. In order to continue treatment and optimize patient safety, the effective and timely management of treatment-related adverse events (AEs) is crucial. As they are on the front lines of patient care, advanced practitioners need to be able to assess the clinical implications of recent advances and integrate them into practice. One area of unmet need in the management of metastatic HER2-positive disease is the treatment of brain metastases, with several promising therapies under investigation. Using several case studies as a foundation, this article highlights current and emerging data on HER2-directed therapies, outlines strategies for managing AEs, and reviews the key issues surrounding brain metastases and associated novel therapies under investigation.


6-Cyclohexylmethyl-3-hydroxypyrimidine-2,4-dione as an inhibitor scaffold of HIV reverase transcriptase: Impacts of the 3-OH on inhibiting RNase H and polymerase.
3-Hydroxypyrimidine-2,4-dione (HPD) represents a versatile chemical core in the design of inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H and integrase strand transfer (INST). We report herein the design, synthesis and biological evaluation of an HPD subtype (4) featuring a cyclohexylmethyl group at the C-6 position. Antiviral testing showed that most analogues of 4 inhibited HIV-1 in the low nanomolar to submicromolar range, without cytotoxicity at concentrations up to 100 μM. Biochemically, these analogues dually inhibited both the polymerase (pol) and the RNase H functions of RT, but not INST. Co-crystal structure of 4a with RT revealed a nonnucleoside RT inhibitor (NNRTI) binding mode. Interestingly, chemotype 11, the synthetic precursor of 4 lacking the 3-OH group, did not inhibit RNase H while potently inhibiting pol. By virtue of the potent antiviral activity and biochemical RNase H inhibition, HPD subtype 4 could provide a viable platform for eventually achieving potent and selective RNase H inhibition through further medicinal chemistry.


Trends in Medicare reimbursement for end-stage renal disease: 1974-1979.
This article presents detailed analyses of the trends in Medicare expenditures for persons with end-stage renal disease. Program expenditures increased at an annual rate of 30.5 percent from 1974 to 1981. Three-fourths of this increase was a result of increases in enrollment. Per capita reimbursements for dialysis patients increased at a 5.2-percent annual rate and per capita reimbursements for transplant patients increased at a 10.5-percent annual rate. In 1979, per capital reimbursements for home dialysis patients were $5,000 less than for in-unit dialysis patients. Patient characteristics such as age, sex, race, and cause of renal failure were, for the most part, unrelated to the costs of dialysis and transplantation.


Neural Substrates of Brand Love: An Activation Likelihood Estimation Meta-Analysis of Functional Neuroimaging Studies.
Brand love is a critical concept for building a relationship between brands and consumers because falling in love with a brand can lead to strong brand loyalty. Despite the importance of marketing strategies, however, the underlying neural mechanisms of brand love remain unclear. The present study used an activation likelihood estimation meta-analysis method to investigate the neural correlates of brand love and compared it with those of maternal and romantic love. In total, 47 experiments investigating brand, maternal, and romantic love were examined, and the neural systems involved for the three loves were compared and contrasted. Results revealed that the putamen and insula were commonly activated in the three loves. Moreover, activated brain regions in brand love were detected in the dorsal striatum. Activated regions for maternal love were detected in the cortical area and globus pallidus and were associated with pair bonds, empathy, and altruism. Finally, those for romantic love were detected in the hedonic, strong passionate, and intimate-related regions, such as the nucleus accumbens and ventral tegmental area. Thus, the common regions of brain activation between brand and romantic love were in the dorsal striatum. Meanwhile, no common activated regions were observed between brand and maternal love except for the regions shared among the three love types. Although brand love shared little with the two interpersonal (maternal and romantic) loves and relatively resembled aspects of romantic rather than maternal love, our results demonstrated that brand love may have intrinsically different dispositions from the two interpersonal loves.


Perospirone (Sumitomo Pharmaceuticals).
Perospirone is a serotonin 5-HT2 antagonist and dopamine D2 antagonist developed by Sumitomo Pharmaceuticals for the potential treatment of schizophrenia and other psychoses [381769]. Its receptor binding profile and animal pharmacology resemble those of other atypical antipsychotic agents, in particular risperidone. In November 2000, CPAC's First Committee on Drugs recommended the approval of this product in Japan, [394007]; approval was granted in December 2000 [396121]. In January 2001, the NHI price was agreed by the Chuikyo [398222] and the drug was added to the NHI price list in February 2001 13982261. It was finally launched in Japan on February 8 2001 [399401]. In November 2000, Sumitomo and Welfide signed an agreement whereby Welfide's subsidiary Yoshitomi Yakuhin will copromote perospirone [394007]. Based on data from the Chuikyo, peak sales of perospirone are forecast to be yen9 billion in the sixth year following launch [398222], [398226]. In February 2001, Sumitomo predicted that perospirone would reach sales of yen10 billion within five to six years [399401].


Transferrin-liposome-mediated systemic p53 gene therapy in combination with radiation results in regression of human head and neck cancer xenografts.
The use of cationic liposomes as nonviral vehicles for the delivery of therapeutic molecules is becoming increasingly prevalent in the field of gene therapy. We have previously demonstrated that the use of the transferrin ligand (Tf) to target a cationic liposome delivery system resulted in a significant increase in the transfection efficiency of the complex [Xu, L., Pirollo, K.F., and Chang, E.H. (1997). Hum. Gene Ther. 8, 467-475]. Delivery of wild-type (wt) p53 to a radiation-resistant squamous cell carcinoma of the head and neck (SCCHN) cell line via this ligand-targeted, liposome complex was also able to revert the radiation resistant phenotype of these cells in vitro. Here we optimized the Tf/liposome/DNA ratio of the complex (LipT) for maximum tumor cell targeting, even in the presence of serum. The efficient reestablishment of wtp53 function in these SCCHN tumor cells in vitro, via the LipT complex, restored the apoptotic pathway, resulting in a significant increase in radiation-induced apoptosis that was directly proportional to the level of exogenous wtp53 in the tumor cells. More significantly, intravenous administration of LipT-p53 markedly sensitized established SCCHN nude mouse xenograft tumors to radiotherapy. The combination of systemic LipT-p53 gene therapy and radiation resulted in complete tumor regression and inhibition of their recurrence even 6 months after the end of all treatment. These results indicate that this tumor-specific, ligand-liposome delivery system for p53 gene therapy, when used in concert with conventional radiotherapy, can provide a new and more effective means of cancer treatment.


HIV and STI prevalence and testing history among men who have sex with men in Hanoi, Vietnam.
HIV and other sexually transmitted infections (STIs) have disproportionately affected communities of men who have sex with men (MSM). We describe HIV and STI prevalence and testing patterns among urban Vietnamese MSM. We conducted a cross-sectional community-based study of MSM in Hanoi, Vietnam in 2016. Participants self-reported experiences of social stigma in healthcare settings and previous HIV and STI testing. STI testing included HIV, herpes simplex virus-2 (HSV-2), syphilis, gonorrhea, and chlamydia. 205 MSM participated in the study. STI prevalence was HIV (10%), HSV-2 (4%), syphilis (13%), gonorrhea (34%), and chlamydia (19%). More than half (55%) of participants tested positive for at least one STI. Most participants had been previously tested for HIV or another STI (72%), with 24% previously receiving a positive result. Perceived and enacted social stigma in healthcare contexts was negatively associated with previous HIV or STI testing (adjusted prevalence odds ratio (aPOR): 0.22; 95% confidence interval (CI): 0.10-0.48). High prevalence of STIs was observed among Vietnamese MSM, and perceived and enacted stigma was related to HIV and STI testing. Our findings reaffirm the importance of regular STI screening among this population as well as additional outreach to promote safe HIV and STI healthcare engagement.


Serum paraoxonase and arylesterase activities of paraoxonase-1 (PON-1), mild cognitive impairment, and 2-year conversion to dementia: A pilot study.
Converging lines of evidence suggest that paraoxonase-1 (PON-1) may confer protection against inflammatory and oxidative challenge which, in turn, plays a key-role in the onset and progression of dementia. The aim of this study was to evaluate whether serum PON-1 paraoxonase/arylesterase activities might predict the clinical conversion of mild cognitive impairment (MCI) to late-onset Alzheimer's disease (LOAD) or vascular dementia (VAD). Serum paraoxonase and arylesterase activities were measured by spectrophotometric assays at baseline in 141 MCI patients (median age: 77 years; interquartile range 71-81) and in 78 healthy controls (median age: 76 years; interquartile range 73-79). After 2 years of follow-up, 86 MCI remained stable (MCI/MCI), 34 converted to LOAD (MCI/LOAD), whereas 21 converted to VAD (MCI/VAD). Baseline arylesterase activity was lower in all MCI groups compared with controls (all p < 0.01), whereas paraoxonase activity was lower in MCI/VAD group compared to controls (p < 0.05) and MCI/MCI patients (p = 0.009). Low paraoxonase and arylesterase activities (I quartile) were associated to higher risk of conversion to VAD (OR: 3.74, 95% CI: 1.37-10.25 and OR: 3.16, 95% CI: 1.17-8.56, respectively). Our results suggest that in MCI patients low PON-1 activity might contribute to identify individuals susceptible to develop vascular dementia.


Degraded perceptual and affective processing of racial out-groups: An electrophysiological approach.
Human beings process perceptual and affective information of racial out-groups in a degraded manner. Relative to racial in-group members, we lack perceptual individuation of racial out-group members and empathize their pain to a less degree. To date, however, the relationship between the deficiency of individuation and the impairment of empathy in responding to racial out-groups remains elusive. By recording event-related brain potentials in response to racial in-group and out-group faces portraying pain and neutral expressions, we simultaneously measured neural activity that underpinned individuation and empathy. Deficiency in individuating members of racial out-groups, manifesting as reduced reactivity of face-sensitive N170 in the occipitotemporal region of the brain, predicted attenuation of fronto-central empathic response to the suffering of racial out-groups. Further, the individuation bias mediated the influence of racial prejudice on racial in-group bias in empathic neural responses. These findings suggest an interplay between degraded perceptual and affective processing of racial out-groups.


Bioassay-guided evaluation of antinociceptive effect of N-salicyloyltryptamine: a behavioral and electrophysiological approach.
We investigated the antinociceptive and nerve excitability effects of the N-salicyloyltryptamine (NST) NST-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg (i.p.) were administered (i.p.). This effect was not antagonized by naloxone (1.5 mg/kg, i.p.). NST inhibited the licking response of the injected paw when 100 and 200 mg/kg were administered (i.p.) to mice in the first and second phases of the formalin test. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and showed that NST (3.57 mM) significantly reduced (29.2%) amplitude of the compound action potential (CAP) suggesting a sodium channel effect induced by NST. Our results demonstrated an antinociceptive activity of the NST that could be, at least in part, associated to the reduction of the action potential amplitude. NST might represent an important tool for pain management.


Keyhole approach in anterior circulation aneurysm: Current indication, advantages, technical limitations, complications and their avoidance.
Keyhole surgery recently evolved as a minimal invasive surgical approach for treatment of anterior circulation aneurysm. This review was done to evaluate the keyhole approach for anterior circulation aneurysms, their indications, advantages, technical limitations, complications and their avoidance. The literature review was performed with the phrase "keyhole approach for anterior circulation aneurysm" as a search term in PubMed central, Medline, Google scholar and Embase data base to identify all the articles published till December 2020. Out of 113 articles searched, 22 were included in this review after screening for eligibility. On analyzing these articles, there was total 2058 aneurysm in 1871 patients. Out of 2058 aneurysm, 988 were ruptured and 547 unruptured. In 5 studies, which include 344 aneurysms in 344 cases, aneurysm ruptured or unruptured status was not specified. The most frequent aneurysm site was anterior communicating artery (n=573). The size of the aneurysm mentioned in most of the study was <15 mm. The rate of complete occlusion was ranged from 93.6-100%. The range of intra operative rupture (IOR) was 0-28.6%. The mean operative time was ranged from 70 min-5.34 hours as reported in 13 studies. Good outcome [Glasgow outcome scale (GOS): 4-5] were seen in 75-100% cases. The frontalis muscle weakness has been reported in 3 studies and ranged from 0-1.99%. Keyhole surgery can be a safe and effective treatment modality for treatment of a selected anterior circulation aneurysm. In the experienced hand it has certain advantages over standard pterional craniotomy.


Demonstration of traumatic hepato-pleural-cutaneous defect by 131I-rose bengal.
A 19-year-old man was shot in the right chest about 2 cm below the nipple; bloody fluid was drained through a chest tube. Two days later sero-sanguineous fluid tinged with bile was seen to drain from the wound site. 131I-rose bengal, injected intravenously, collected in the dome of the liver and drained into a collection bag placed over the wound site, thus identifying a hepato-pleural-cutaneous fistula, which was confirmed at surgery.


Der p I, a major allergen of the house dust mite, proteolytically cleaves the low-affinity receptor for human IgE (CD23).
The nature of the proteases that cleave CD23 in vivo is of considerable interest, but remains unknown. Here, we demonstrate that Der p I, a major allergen of the house dust mite Dermatophagoides pteronyssinus, cleaves CD23 from the surface of cultured human B cells (RPMI 8866 B cell line). The cleavage of the receptor from the B cell surface was associated with a parallel increase in soluble CD23 (sCD23) in the culture supernatant. Furthermore, the proteolytic effect of Der p I was specific for CD23, since none of the other B cell markers tested (CD20, HLA-DR, CD71 and CD49d) were affected. Labeled antibody experiments and protease inhibition assays clearly demonstrate that Der p I is a cysteine protease that directly cleaves a 25-kDa fragment of CD23. These data suggest that the cysteine protease Der p I, in addition to being highly immunogenic, may up-regulate IgE synthesis by virtue of its ability to cleave CD23.


Interhemispheric transfer of colour and shape information in the presence and absence of the corpus callosum.
Two split-brained subjects, one (L.B.) with full forebrain commissurotomy and one (R.B.) with callosal agenesis, and a group of twenty neurologically intact subjects were tested in three discrimination tasks: a go-no go task, a two-choice task, and a three-choice task. The discriminations were based on colour in Experiment 1, and on shape in Experiment 2. The stimuli were presented in one or other visual field, and the subjects responded with the fingers of one or other hand, allowing the differences in reaction time between crossed and uncrossed responses (CUD) to be calculated. For the normal subjects the CUD tended to diminish with the complexity of the tasks, suggesting that both hemispheres were increasingly involved. Unlike R.B. and the normal controls, who made virtually no errors, L.B. had increasing difficulty as task complexity increased. He was better able to transfer information from the right to the left hemisphere than vice versa, but an analysis of his accuracy under the crossed conditions showed that the amount transferred was always well under one bit. This confirms previous evidence that L.B. has very limited subcortical transfer of either colour or shape.


[Quality assurance in dentistry].
An important subject regarding the quality of dental care is the development of a system of quality assurance. This system should be focused on preservation and improvement of the quality of dentistry. Activities like peer review, continuing dental education, (re-)registration and professional specialization could make a major contribution to the establishment of such a system.


Effect of dosing vehicle on the hepatotoxicity of CCl4 and nephrotoxicity of CHCl3 in rats.
There are conflicting results in the literature concerning the effect of gavage vehicle, corn oil (CO) versus aqueous suspension, on the toxicity of haloalkanes. The purpose of our study was to assess the influence of oral dosing vehicle on the acute hepatotoxicity of CCl4 and nephrotoxicity of CHCl3. Male Sprague-Dawley rats, fed ad libitum, were treated (po) with single doses of CCl4 or CHCl3 using corn oil (CO), or an aqueous preparation (5%) of Emulphor (EL620) or Tween-85 (Tw-85) as vehicle (10 ml/kg). Rats were killed 48 h after treatment. Blood was collected for plasma alanine aminotransferase (ALT) determination and renal cortical slices were prepared for p-aminohippuric acid (PAH) incorporation. The comparison, between gavage vehicles, of the slopes and ED50 of the dose-response curves, although not significantly different, indicated clear trends for enhanced potency with CO for CHCl3 nephrotoxicity but not for CCl4 hepatotoxicity. However, ALT values, a measure of the severity of effect for CCl4, also indicated that CO, when compared to EL620 and Tw-85, tended to enhance CCl4 hepatotoxicity at low toxicity incidence. Furthermore, CO clearly enhanced the severity of effect for CHCl3 nephrotoxicity, as measured by the slice-to-medium PAH ratios, at high dosage. The greater severity of the lesion produced by exposure to these chemicals, when administered in CO, is consistent with the trends observed for their potency (dose-response curves). Our results agree with an increased toxicity of haloalkanes by the gavage vehicle CO reported in the literature. Thus, CO should be considered a potential confounder in hepato- and nephrotoxicity assays.


Hinged elbow external fixators: indications and uses.
Hinged external fixation of the elbow joint can play an important role in managing complicated fracture-dislocations, joint instability after extensive contracture release, and distraction interposition arthroplasty. Application of these devices requires accurate alignment of the fixator axis with the anatomic axis of the elbow. The primary therapeutic goal is to allow joint motion while protecting the healing ligaments. Common complications include pin loosening, injury to adjacent neurovascular structures, cellulitis, and loss of reduction. Although reported data are limited, this technique is a useful adjunct in patients with complex elbow instability.


Assessment of performance of laboratories in determining acrylamide in crispbread.
A proficiency testing round was undertaken to assess the performance of laboratories to measure acrylamide in a sample of crispbread. Retail samples of crispbread were ground to a fine powder and after thorough mixing were packed in 40 g units for distribution. Ten samples were selected at random and analyzed in duplicate for acrylamide by liquid chromatography/mass spectrometry (LC/MS). Standard statistical tests showed that the material was homogeneous for the purposes of proficiency testing. Test samples were distributed to 55 laboratories in 16 countries in Europe, North America, Australia, and the Middle East. The results were analyzed by standard proficiency testing statistical procedures, and laboratories were awarded z-scores on the basis of their reported results. Based on a target standard deviation (sigmap value) taken from the Horwitz equation, for a robust mean value of 1.2 mg/kg acrylamide, satisfactory results (z-score within +/- 2 for those between 0.8 and 1.6 mg/kg) were obtained by 86% of the 37 laboratories that returned results. Only 1 laboratory was unsatisfactory and 4 had questionable results. About equal numbers of laboratories used gas chromatography (GC)/MS and LC/MS procedures with about 25% using MS/MS and one using GC with electron capture detection. There was no evident trend in performance or bias in results. GC/MS and LC/MS data were evenly distributed across the population of laboratories reporting results.


Prevalence of and factors associated with smoking among students in Sousse, Tunisia.
Within the framework of the fight against tobacco among young people, we conducted a descriptive cross-sectional study in 2013 to estimate the prevalence of smoking and to identify associated factors among students in Sousse. A questionnaire was administered to a representative sample of 556 students in 5 academic institutions in Sousse randomly drawn. The age of the participants was between 17 and 35 years. The prevalence of tobacco consumption in the past 12 months was 22.1% and consumption during the past 3 months was 65.3%. The average age of starting smoking was 17 years. Smoking prevalence was significantly higher for males (P < 0.001) and those aged over 25 years (P = 0.002). Students from 2 of the institutions were using more tobacco than their colleagues in the other institutions (P = 0.027). The high prevalence of smoking found among the students means that prevention measures are essential; this requires increasing self-esteem and evaluating intervention programmes implemented before smoking the first cigarette.


Citrullus colocynthis (L.) Schrad (Bitter Apple Fruit): Promising Traditional Uses, Pharmacological Effects, Aspects, and Potential Applications.
Health consciousness and increased knowledge about the side effects of synthetic drugs have enhanced interest in traditional medicines. Medicinal plants offer cures for various diseases, leading to improved living standards. This has brought ethnomedicinal studies into the spotlight and increased demand for herb-based medicines. Citrullus colocynthis is an herbaceous plant containing an abundance of nutrients that play a key role in the improvement of wellbeing. C. colocynthis has many biological properties, such as antioxidative, hypoglycemic, antibacterial, anti-cancerous, anti-inflammatory, analgesic, gastrointestinal tract, reproduction, protection, anti-microbial, antidiabetic, hypolipidemic, antineoplastic, profibrinolytic, anti-allergic, pesticidal, and immune-stimulatory. There are numerous bioactive compounds like cucurbitacin, flavonoids, and polyphenols in C. colocynthis that give it medicinal properties. Herein, we have extensively compiled, reviewed, and analyzed significant information on C. colocynthhis from the best published available evidence in PubMed, Scopus (Embase), Web of Science (Web of Knowledge), Cochrane Library, and Google Scholar, etc. Scientific literature evidenced that owing to the bioactive constituents, including cucurbitacin, polyphenols, flavonoids, and other potent molecules, C. colocynthis has many pharmacological and physiological functions. It possesses multi-beneficial applications in treating various disorders of humans and animals. So, the primary purpose of this comprehensive review is to provide an overview of the findings of positive impacts and risks of C. colocynthis consumption on human health, especially in poultry and veterinary fields. In the future, this narrative article will be aware of discoveries about the potential of this promising natural fruit and its bioactive compounds as the best nutraceuticals and therapeutic drugs in veterinary and human medicine.


Use of the Staged Development Tool for Assessing, Planning, and Measuring Progress in the Development of National Public Health Institutes.
The Staged Development Tool (SDT) was created to help national public health institutes (NPHIs) assess their current capacity and develop roadmaps for achieving a higher level of functioning. This article discusses the current use of the SDT by national public health institutes to establish baseline capacity and inform strategic planning and its proposed use in a 3-step sequence for measuring the impact of capacity-building interventions over time. The article also includes descriptions of how national public health institutes have been using the SDT to assess their baseline capacity in management issues and core public health functions. The first use of the SDT by a national public health institute provides essential baseline information on their capacities and levels of functioning and plans for addressing gaps. By repeating the SDT after time for the plans to be implemented, the SDT can be used to evaluate changes in capacity and the effectiveness of the interventions made. Because the SDT is built to be complementary to existing assessments and public health strengthening tools and guidelines, implementing the SDT provides concrete, complementary information that can help countries achieve global health security goals and address current and future threats to public health.


Relationship between preoperative endotoxin immune status, gut perfusion, and outcome from cardiac valve replacement surgery.
Endotoxin is a powerful trigger of systemic inflammation. Since cardiac surgery exposes patients to endotoxemia, this study was set up to define the relationship between preoperative endogenous endotoxin immune status, gut perfusion, and outcome following cardiac valve replacement surgery. Observational study. University hospital. Fifty-nine consecutive patients undergoing cardiac valve replacement. Blood was assayed for IgG and IgM endotoxin core antibody (EndoCAb) levels preoperatively, immediately postoperatively, and at 4 h and 24 h postoperatively. Intraoperative gut mucosal perfusion was assessed using gastric tonometry. Complications were assessed for groups above and below the median EndoCAb value of a healthy population (100 median units micro/mL). Of the 59 patients, 12 developed at least one of a set of predefined complications. Of these 12, all had preoperative levels of IgM EndoCAb below 100 MU/mL (p<0.025). Eleven had IgG EndoCAb levels below 100 MU/mL (0.05<p<0.1). There was no relationship between the fall in gastric intramucosal pH and exposure to endotoxin as implied by the fall in unbound IgM EndoCAb levels, although the specificity of tonometry for predicting complications could be improved by considering the patient's preoperative EndoCAb status. Preoperative EndoCAb levels were related to poor outcome following cardiac surgery and may be used to improve the specificity of GI tonometry in predicting postoperative complications.


Structural basis for thermophilic protein stability: structures of thermophilic and mesophilic malate dehydrogenases.
The three-dimensional structure of four malate dehydrogenases (MDH) from thermophilic and mesophilic phototropic bacteria have been determined by X-ray crystallography and the corresponding structures compared. In contrast to the dimeric quaternary structure of most MDHs, these MDHs are tetramers and are structurally related to tetrameric malate dehydrogenases from Archaea and to lactate dehydrogenases. The tetramers are dimers of dimers, where the structures of each subunit and the dimers are similar to the dimeric malate dehydrogenases. The difference in optimal growth temperature of the corresponding organisms is relatively small, ranging from 32 to 55 degrees C. Nevertheless, on the basis of the four crystal structures, a number of factors that are likely to contribute to the relative thermostability in the present series have been identified. It appears from the results obtained, that the difference in thermostability between MDH from the mesophilic Chlorobium vibrioforme on one hand and from the moderate thermophile Chlorobium tepidum on the other hand is mainly due to the presence of polar residues that form additional hydrogen bonds within each subunit. Furthermore, for the even more thermostable Chloroflexus aurantiacus MDH, the use of charged residues to form additional ionic interactions across the dimer-dimer interface is favored. This enzyme has a favorable intercalation of His-Trp as well as additional aromatic contacts at the monomer-monomer interface in each dimer. A structural alignment of tetrameric and dimeric prokaryotic MDHs reveal that structural elements that differ among dimeric and tetrameric MDHs are located in a few loop regions.


Intravascular Ultrasound-Guided Coronary Lithotripsy Treatment of In-Stent Restenosis in Saphenous Venous Graft.
To the best of our knowledge, this is the first description of intravascular-ultrasound guided coronary lithotripsy on saphenous vein graft because of severely calcific in-stent restenosis, showing good result without procedural complications.


Limited association between scalp psoriasis and psoriatic arthritis severity and treatment response.
We evaluated whether scalp psoriasis (PsO) is associated with psoriatic arthritis (PsA) severity and/or with treatment response to etanercept. Patients with moderate-to-severe PsO and active PsA received etanercept 50 mg once weekly for 24 weeks. Patients were stratified according to whether scalp PsO was present at baseline. Demographics and disease characteristics were compared at baseline and after 12 and 24 weeks of treatment with etanercept. Scalp PsO was present in 273/373 (73.2%) patients; they were significantly younger and a higher proportion were male versus those without scalp PsO. At baseline, the patient global assessment psoriasis score was significantly higher for patients with scalp PsO versus without (67.0 vs. 57.9, p<0.01); tender joint count was significantly higher for patients without scalp PsO (6.0 vs. 5.0, p<0.05). A higher proportion of patients without versus with scalp PsO achieved enthesitis ≤1 at Week 12 (91.5% vs. 81.7%, p<0.05) and dactylitis ≤1 at week 24 (93.9% vs. 85.6%, p<0.05). Patients with scalp PsO showed significantly greater improvements in fatigue and joint pain at weeks 12 and 24, and a greater proportion achieved a score ≤0.5 in the health assessment questionnaire at week 12 (65.2% vs. 53.0%, p<0.05). Scalp PsO was not clearly associated with PsA severity, and it did not affect treatment response. Patients without scalp PsO exhibited greater improvements in objective joint outcomes, whereas patients with scalp PsO experienced better outcomes in patient-reported outcomes.


Melanoma associated with ring chromosome 7.
We report the case of a 17-year-old girl with a constitutional chromosome anomaly (ring chromosome 7), associated with multiple pigmented skin lesions, who developed malignant melanoma. Eight other cases of ring chromosome 7 are described in the literature; all present vascular or pigmented skin lesions, but our patient was the first to develop a malignant tumor. Genetic studies in malignant melanoma are discussed, as well as the possible link between a constitutional anomaly of chromosome 7 and the occurrence of malignant melanoma. This association is possibly not fortuitous, particularly since most ring chromosome 7 patients reported to date have pigmented skin lesions.


Solitary neurofibroma of the floor of the mouth.
We present a case of neurofibroma in the floor of the mouth. A 74-year-old female complained of painless swelling in the right side of the floor of the mouth for 3 months. Clinical examination and CT revealed a tumor involving the right side of the floor of the mouth. Histological features were characteristic of a neurofibroma. Such a tumor arising in the area of the mouth is very rare. We review the clinical and pathological features of a neurofibroma arising in the mouth.


Advancing the Adverse Outcome Pathway for PPARγ Inactivation Leading to Pulmonary Fibrosis Using Bradford-Hill Consideration and the Comparative Toxicogenomics Database.
Pulmonary fibrosis is regulated by transforming growth factor-β (TGF-β) and peroxisome proliferator-activated receptor-gamma (PPARγ). An adverse outcome pathway (AOP) for PPARγ inactivation leading to pulmonary fibrosis has been previously developed. To advance the development of this AOP, the confidence of the overall AOP was assessed using the Bradford-Hill considerations as per the recommendations from the Organisation for Economic Co-operation and Development (OECD) Users' Handbook. Overall, the essentiality of key events (KEs) and the biological plausibility of key event relationships (KERs) were rated high. In contrast, the empirical support of KERs was found to be moderate. To experimentally evaluate the KERs from the molecular initiating event (MIE) and KE1, PPARγ (MIE) and TGF-β (KE1) inhibitors were used to examine the effects of downstream events following inhibition of their upstream events. PPARγ inhibition (MIE) led to TGF-β activation (KE1), upregulation in vimentin expression (KE3), and an increase in the fibronectin level (KE4). Similarly, activated TGF-β (KE1) led to an increase in vimentin (KE3) and fibronectin expression (KE4). In the database analysis using the Comparative Toxicogenomics Database, 31 genes related to each KE were found to be highly correlated with pulmonary fibrosis, and the top 21 potential stressors were suggested. The AOP for pulmonary fibrosis evaluated in this study will be the basis for the screening of inhaled toxic substances in the environment.


Nomogram Incorporating Multimodal Transvaginal Ultrasound Assessment at 20 to 24 Weeks' Gestation for Predicting Spontaneous Preterm Delivery in Low-Risk Women.
The majority of women who experience spontaneous preterm delivery (SPTD) have low-risk, asymptomatic pregnancies with a cervical length (CL) ≥25mm and no clear risk factors. Despite the fact that cervical elastography is a potential tool for predicting SPTD, there is currently no feasible solution to make a reliable prediction for preventing SPTD. The aim of this study was to construct a nomogram including multimodal transvaginal ultrasound parameters during the second trimester to predict SPTD in low-risk women. This multi-center study enrolled 1260 women with singleton pregnancies between 20 and 24 weeks' gestation. CL and cervical elastography data were obtained when they were undergoing the second-trimester anomaly scan. Univariate and multivariate Logistic regression were utilized to screen predictors independently related to SPTD from the maternal characteristics and multimodal ultrasound data. Then construct a nomogram to determine the likelihood of SPTD in pregnant women. A total of 66 pregnancies in the training cohort (7.8%, 66/842) and 37 pregnancies (8.9%, 37/418) in the validation cohort ended in SPTD. Age, uterine curettage, CL, and strain in the anterior lip of internal os were the independent predictors of SPTD (P < 0.001, < 0.001, = 0.007, and < 0.001, respectively). These predictors constituted a nomogram to predict the probability of SPTD for a pregnant woman in her second trimester. It showed good discrimination (C-index = 0.898 and 0.839), calibration (P = 0.258 and 0.115), and yielded net benefits both in the training and validation cohorts. The nomogram including data of multimodal transvaginal ultrasound at 20 to 24 weeks' gestation is expected to identify women with SPTD in the low-risk, asymptomatic population.


Single Virus Targeting Multiple Organs: What We Know and Where We Are Heading?
COVID-19 caused by SARS-CoV-2 has already infected more than 6. 3 million people worldwide as of 1st June 2020 and caused a global medical emergency. Healthcare professionals have been struggling to devise appropriate therapeutic strategies against the virus mainly due to the diverse range of symptoms and multiple-organ failure in infected patients. Several broad-spectrum antiviral drugs are being used for treatment; however, there is yet no specific drug or vaccine against the virus. Multiple-organ failure due to hyperactivity of the immune system resulting in cytokine storms is a major reason for death among the 5% critically ill patients. In this article, we have discussed the damage caused by COVID-19 on different organs of the human body.


Laser speckle for determining ametropia and accommodation response of the eye.
A method is described for. measuring ametropia and voluntary accommodation response of the eye using laser speckle patterns. An explanation of the movement of laser speckle patterns is given based on geometrical optics. Results of refraction measurements at various wavelengths across the visible spectrum are given. Results of accommodation response measurements at various wavelengths across the visible spectrum are given.


Steroid diagnostics of 21st century in the light of their new roles and analytical tools.
The determination of steroid hormones and subsequent interpretation of results is accompanied by a range of difficulties. The amount of information that current technology can provide on the circulating concentrations of more than a hundred various steroid compounds can lead to problems with interpretation. The aim of this study is to help provide orientation in this maze of data on steroid hormones. First we focus on specific aspects arising from the pre-analytical phase of steroid determination that need to be considered when planning sampling, whether for diagnostics or research. Then, we provide a brief summary of the characteristics and diagnostic relevance of several steroid hormones and/or their metabolites: pregnenolone, 17alpha-hydroxy-pregnenolone, dehydroepiandrosterone, hydroxyderivatives of dehydroepiandrosterone, androstenedione, testosterone, estrone, estradiol, estriol, cortisol, cortisone, which in our institute are determined with validated LC-MS/MS methods. For these steroids, we also provide newly calculated reference values in fertile women according to the phase of their menstrual cycle.


3-D Spiraling Self-Trapped Light Beams in Photochemical Systems.
A pair of visible laser beams self-trap and spiral about each other as they propagate through polymer gels undergoing two different photochemical reactions. When launched into gels that undergo photopolymerization of methacrylate substituents or photo-oxidation of iodide anion, two non-coplanar (skewed) Gaussian beams collide and spiral about each other as they advance through the evolving medium. In the absence of chemical reactions, the linearly polarized beams broaden naturally and propagate along their original, straight-pathed trajectories. By contrast, refractive index gradients generated by the photochemical reactions elicit self-trapping and introduce an attractive interaction between the self-trapped beams. The self-trapped beams spiral about each other when this mutual attraction perfectly counterbalances their original tendency to diverge away from each other. These findings show that the photochemically mediated interactions of incident optical fields within the gel medium impart a helical trajectory and angular velocity to the self-trapped beam pair.


[Protection of children born to hepatitis-B-infected mothers].
The vaccination schedule implemented on 1 March 2003 for the approximately 1000 Dutch children per year born to hepatitis-B-virus-infected mothers is under discussion. The Health Council of The Netherlands and TNO have both published reports which reveal that the current schedule does not fulfil its objectives, as too many children are completely missed and many of the vaccinated children do not receive their scheduled vaccinations on time. Furthermore, doubts have been expressed about the effectiveness of the present vaccination schedule. In line with one of the schedules proposed by the Health Council we suggest the introduction of a 4-dose vaccination, in which the first vaccination is given immediately after the birth of the child. The subsequent vaccinations can then take place after 2, 4 and 11 months. These are the ages at which other children are also vaccinated against hepatitis B in accordance with the Dutch national vaccination programme. Furthermore, we advise an improved surveillance to ensure compliance with the individual vaccination schedules for these children. If data from the hepatitis-B screening of pregnant women, the regional vaccination registers, and the vaccinations actually administered are linked, then it will be possible to take swift action if a child is late for a hepatitis-B vaccination. In our opinion, this can best be achieved if a single national organisation is made responsible for the entire process, starting from the collection of the hepatitis-B data of pregnant women up to concluding the scheme, whether or not the serologic response is checked.


Strecker stents in the femoropopliteal arteries: value of duplex ultrasonography in restenosis assessment.
Experience with Strecker stent implantation in the femoropopliteal arteries has been described; however, few of the reports were prospective studies, and none routinely used site-specific assessment methods for follow-up evaluation of stent patency. The purpose of this study was to evaluate 1-year Strecker stent patency using duplex ultrasound imaging to obtain a more precise delineation of stent restenosis than is possible with other noninvasive assessment modalities. A prospective study involved 52 patients with 57 sites treated by angioplasty and Strecker stent deployment in the femoropopliteal arteries. Assessment included clinical evaluation; ankle-brachial index (ABI) measurements at rest and after exercise; and duplex ultrasound imaging preprocedurally and at 3 and 12 months after the intervention. All 74 stents were deployed successfully in the 35 occluded arteries and 22 stenotic lesions. Acute reocclusion occurred in 6 (10%). At 3 months, primary patency was 81% and secondary patency 84%. Mean ( +/- SD) ABIs increased from 0.64 +/- 0.15 at rest and 0.32 +/- 0.17 after exercise to 0.89 +/- 0.14 and 0.68 +/- 0.23, respectively (p < 0.0001). At 12 months, primary patency was 79%, and secondary patency was 82%. Mean ABIs were 0.82 +/- 0.15 at rest and 0.52 +/- 0.22 after exercise at 12 months (p < 0.0002 compared with preprocedural ABIs). Analysis of the length of lesion treated showed betted results with shorter diseased segments, but this was not statistically significant (p > 0.05). Better outcomes were also obtained when one stent was used rather than two stents at 12 months (p = 0.15), but there was no difference at 3 months (p = 0.3). Thirty-four percent of the stented segments progressed from < 20% stenosis at 3 months to > 50% stenosis at 12 months. Overall, 19 (43%) of 44 segments progressed from < 50% stenosis at 3 months to a > 50% stenosis at 12 months. Restenosis seen at 3 months generally was in the native artery just proximal or distal to the stent, but at 12 months, restenosis was mainly inside the stent. Strecker stents at 1-year demonstrated satisfactory patency in the femoropopliteal arteries when deployed for angioplasty salvage or recurrent disease. The 3- and 12-month evaluations obtained with duplex ultrasound provided site-specific hemodynamic data for stent assessment. Resting ankle pressures were a poor index of restenosis.


Facile removal of high mannose structures prior to extracting complex type N-glycans from de-N-glycosylated peptides retained by C18 solid phase to allow more efficient glycomic mapping.
The relative amount of high mannose structures within an N-glycomic pool differs from one source to another, but quite often it predominates over the larger size complex type structures carrying biologically important glyco-epitopes. An efficient method to separate these two classes of N-glycans would significantly aid in detecting the lower abundant components by MS. Capitalizing on an initial observation that only high mannose type structures were recovered in the flow-through fraction when peptide-N-glycosidase F digested peptides were passed through a C18 cartridge in 0.1% formic acid, we demonstrated here that native complex type N-glycans can be retained by C18 cartridge and to be efficiently separated from both the smaller high mannose type structures, as well as de-N-glycosylated peptides by stepwise elution with increasing ACN concentration. The weak retention of the largely hydrophilic N-glycans on C18 resin is dependent not only on size but also increased by the presence of α6-fucosylation. This was shown by comparing the resulting N-glycomic profiles of the washed and low-ACN eluted fractions derived from both a human cancer cell line and an insect cell line.


Molecular dissection of zyxin function reveals its involvement in cell motility.
Spatially controlled actin filament assembly is critical for numerous processes, including the vectorial cell migration required for wound healing, cell- mediated immunity, and embryogenesis. One protein implicated in the regulation of actin assembly is zyxin, a protein concentrated at sites where the fast growing ends of actin filaments are enriched. To evaluate the role of zyxin in vivo, we developed a specific peptide inhibitor of zyxin function that blocks its interaction with alpha-actinin and displaces it from its normal subcellular location. Mislocalization of zyxin perturbs cell migration and spreading, and affects the behavior of the cell edge, a structure maintained by assembly of actin at sites proximal to the plasma membrane. These results support a role for zyxin in cell motility, and demonstrate that the correct positioning of zyxin within the cell is critical for its physiological function. Interestingly, the mislocalization of zyxin in the peptide-injected cells is accompanied by disturbances in the distribution of Ena/VASP family members, proteins that have a well-established role in promoting actin assembly. In concert with previous work, our findings suggest that zyxin promotes the spatially restricted assembly of protein complexes necessary for cell motility.


Cerebrovascular resistance and blood flow velocity changes after carotid endarterectomy.
To study the pattern of cerebral blood flow velocity and cerebral resistance changes after carotid endarterectomy. In 81 patients (mean age +/- SD, 64 +/- 8 years) with unilateral carotid endarterectomy (CEA) the systolic, diastolic and mean blood velocities, and the pulsatility index (PI) were recorded in both middle cerebral arteries preoperatively and repetitively postoperatively with the use of transcranial Doppler ultrasound (TCD). In the middle cerebral artery ipsilateral to CEA mean blood velocity was increased 6 hours (64 +/- 25 cm/sec; p < 0.005) and 7 days (54 +/- 15 cm/sec; p < 0.05) after CEA and had returned to the preoperative level (49 +/- 11 cm/sec) after 3 months. Compared to preoperatively (0.86 +/- 22), the PI was significantly increased at 6 hours examination (1.03 +/- 23, p < 0.005), and remained increased thereafter. A pathologically increased mean blood velocity (> 83 cm/sec) 6 hours after CEA occurred in 11 patients, two of them developed a slight hyperperfusion syndrome. In the contralateral middle cerebral artery, only the diastolic blood velocity showed significant changes (preoperatively, 35 +/- 12 cm/sec; 3 months after CEA, 33 +/- 8 cm/sec; p < 0.05). Using TCD, hemodynamic changes occur predominantly in the middle cerebral arteries ipsilateral to CEA. Early postoperative TCD studies may be of help to identify patients at risk to develop a hyperperfusion syndrome.


Multi-vicinal fluoroalkanes: a new class of organofluorine compounds.
"Multi-vicinal fluoroalkanes" are straight-chain alkanes in which each adjacent carbon atom is bonded to one fluorine atom. Such molecules may be regarded as intermediate in structure between alkanes and perfluoroalkanes. The alternate fluoromethylene groups also generate stereogenic centres, which need to be controlled during synthesis. This review will describe our recent progress in the preparation of such single isomer motifs and the study of the conformational behaviour of this new class of organofluorine compounds.


Vienna phrenic pacemaker--experience with diaphragm pacing in children.
Eight children, five boys and three girls, aging from 2 to 13 years (M = 9 +/- 3) were treated with the "Vienna phrenic pacemaker". Indication for implantation was central alveolar hypoventilation syndrome (CAH) in one case and total ventilatory insufficiency due to high cervical cord or brain stem lesion (SCI) in seven cases. Four electrodes were applied to each phrenic nerve via sternotomy. Both hemidiaphragms were paced synchronously with increasing duty cycles to condition the diaphragms for continuous electrophrenic respiration (EPR). EPR could be performed successfully in all children but one. Four children could achieve chronical EPR, one is in conditioning period. Two patients could not be discharged from hospital due to parental neglect and died after two and three years of intermittent stimulation. Six children could be discharged from hospital, two of them died after one and four years of chronic pacing. In one case tracheotomy could be closed definitively. Ventilatory insufficiency due to CAH and SCI can be treated even in children with diaphragm pacing, provided the indication for implantation, containing medical and social aspects, was made correctly. Diaphragm pacing probably will not lengthen life of severely injured children but it can increase the quality of their life and therefore should be preferred to positive pressure mechanical ventilation.


Genetically-Guided Medical Nutrition Therapy in Type 2 Diabetes Mellitus and Pre-diabetes: A Series of n-of-1 Superiority Trials.
Type 2 diabetes mellitus (T2DM) is a heterogeneous metabolic disorder of multifactorial etiology that includes genetic and dietary influences. By addressing the latter, medical nutrition therapy (MNT) contributes to the management of T2DM or pre-diabetes toward achieving glycaemic control and improved insulin sensitivity. However, the clinical outcomes of MNT vary and may further benefit from personalized nutritional plans that take into consideration genetic variations associated with individual responses to macronutrients. The aim of the present series of n-of-1 trials was to assess the effects of genetically-guided vs. conventional MNT on patients with pre-diabetes or T2DM. A quasi-experimental, cross-over design was adopted in three Caucasian adult men with either diagnosis. Complete diet, bioclinical and anthropometric assessment was performed and a conventional MNT, based on the clinical practice guidelines was applied for 8 weeks. After a week of "wash-out," a precision MNT was prescribed for an additional 8-week period, based on the genetic characteristics of each patient. Outcomes of interest included changes in body weight (BW), fasting plasma glucose (FPG), and blood pressure (BP). Collectively, the trials indicated improvements in BW, FPG, BP, and glycosylated hemoglobin (HbA1c) following the genetically-guided precision MNT intervention. Moreover, both patients with pre-diabetes experienced remission of the condition. We conclude that improved BW loss and glycemic control can be achieved in patients with pre-diabetes/T2DM, by coupling MNT to their genetic makeup, guiding optimal diet, macronutrient composition, exercise and oral nutrient supplementation in a personalized manner.


Telomere length changes in colorectal cancers and polyps.
Telomere shortening and telomerase activation occur frequently in cases of colorectal carcinoma. In this study, we correlated the clinicopathological parameters with the telomere length in colorectal carcinomas, colonic polyps, and normal colonic tissues. We also investigated whether the telomere length changes reflect the biologic behavior of tumors and different modes of tumor development. Telomere length was determined by terminal restriction fragment Southern blot analysis in 20 invasive colorectal carcinomas and normal mucosa from the same patients. We also examined 20 colonic polyps and associated normal mucosa. Telomere shortening was detected in 16/20 (80%), and telomere elongation in 2/20 (10%) cases of colorectal carcinoma, and no changes in 2 subjects. In the colonic polyp patients, shortening was detected in 4/20 (20%), elongation in 6/20 (30%), and no change in 10/20 (50%). The frequency of telomere shortening was significantly different between colorectal carcinoma and polyp groups. Decreased telomere length was noted in 92.9% (13/14) of Dukes' C and 50% (3/6) of Dukes' B. The difference between these two sub-groups was statistically significant. This study suggests that the telomere length in colorectal carcinomas is decreased upon the development of malignancy. A significant difference in telomere length between polyps and invasive colorectal carcinomas may reflect a different biologic behavior of colorectal carcinomas.


We'll always have Paris The Paris System for Reporting Urinary Cytology 2022.
Following the amazing acceptance of The Paris System for Reporting Urinary Cytology (TPS), the second edition (TPS 2.0) was inevitable. Based on new studies since the publication of the first edition, diagnostic criteria are refined, and pitfalls discussed. In addition to reinforcing the mandate that the focus of diagnostic urinary cytology is the detection of high-grade urothelial carcinoma, other issues are addressed. Low-grade lesions are included in the category of negative for high-grade urothelial cancer. The rationale for that decision is strongly supported by evidence from the authors' experiences as well as the recent literature. A new chapter on urine cytology of the upper tract, a rarely addressed topic, explores the challenges involved. Furthermore, the issue of cellular degeneration is discussed in the criteria of all diagnostic categories. Most importantly, data defining the risk of high-grade malignancy (ROHM) for each diagnostic category informs clinical management. The 65 authors are recognized authorities from 33 countries, attesting to the global impact of TPS 2.0.


Craniofacial Fibrous Dysplasia of the Skull Assisted by Virtual Surgical Planning.
Craniofacial fibrous dysplasia (FD) involves thickening of the skull and facial bones, causing asymmetry and distortion of overlying soft tissues. Surgical contouring is often performed with rotary bur or osteotome, with the goal of matching contralateral unaffected anatomy. This is made technically challenging by having no direct visualization of contralateral structures, and the desire to control depth of resection to match the contour of the unaffected side. In our report, a 13-year-old male presented for surgical evaluation of craniofacial FD affecting the right parietal/temporal bones. A novel virtual surgical planning approach of premade drilling template with numerous pilot guide holes was used to assist bone debulking. The pilot holes allowed precise burring of the dysplastic bone. The patient achieved excellent calvarial contour symmetry without unintended intracranial extension. We believe that virtual surgical planning and drilling depth guides are effective tools in the reconstruction of craniofacial FD.


Stereoselective Synthesis of the Spirocyclic γ-Lactam Core of the Ansalactams.
Ansalactam A is an ansa macrolide natural product that contains a densely functionalized spiro-γ-lactam core containing three contiguous stereocenters. This unusual motif distinguishes it from other members of this family and represents a significant synthetic challenge. Herein, we report the development of a stereoselective formal [3+2] cycloaddition reaction for the construction of this key spiro-γ-lactam motif for the first time, thereby enabling access to the northern domain of ansalactam A.


[Mitral flow responses to two-week salt loading in elderly hypertensive patients].
The effects of a two-week high sodium diet on mitral flow pattern were assessed in 29 patients with essential hypertension (81.9 +/- 6.9 years). Transmitral flow was recorded during different rates of salt intake; 7 g/day for 8 weeks and 20 g/day for 2 weeks. With sodium loading, 25 patients whose mean blood pressure (MBP) increased by 10 percent or more were termed salt-sensitive (SS) group, and 4 patients whose MBP did not change or increased by less than 10 percent were termed non-salt-sensitive (NSS) group with mitral flow velocity integral, cardiac output (CO) and total peripheral resistance (TPR) were calculated. Thirteen of the SS patients were defined as "SST" in which an increase in TPR was greater than that in CO with sodium repletion. In the remaining 12 SS patients termed "SSc", the increase in CO was greater than that in TPR with salt loading. CO increased significantly in the SSc patients, but did not change in the SST or NSS group with sodium loading. TPR increased significantly in the SST and NSS subjects, and decreased significantly in the SSc patients. Peak velocity of transmitral flow in the rapid filling phase (R) decreased significantly in the SST and NSS patients, and increased significantly in the SSc group. On the other hand peak velocity of transmitral flow in the atrial contraction phase (A) increased significantly in the SST and SSc groups, but remained unchanged in the NSS patients. There was a significant increase in A/R in the SSt group and a significant decrease in A/R in the SSc patients with sodium loading.


Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors.
Elicitation of broadly neutralizing antibodies remains a long-standing goal of HIV vaccine research. Although such antibodies can arise during HIV-1 infection, gaps in our knowledge of their germline, pre-immune precursor forms, as well as on their interaction with viral Env, limit our ability to elicit them through vaccination. Studies of broadly neutralizing antibodies from the VRC01-class provide insight into progenitor B cell receptors (BCRs) that could develop into this class of antibodies. Here, we employed high-throughput heavy chain variable region (VH)/light chain variable region (VL) deep sequencing, combined with biophysical, structural, and modeling antibody analyses, to interrogate circulating potential VRC01-progenitor BCRs in healthy individuals. Our study reveals that not all humans are equally predisposed to generate VRC01-class antibodies, not all predicted progenitor VRC01-expressing B cells can bind to Env, and the CDRH3 region of germline VRC01 antibodies influence their ability to recognize HIV-1. These findings will be critical to the design of optimized immunogens that should consider CDRH3 interactions.


Combination of Nanomaterials in Cell-Based Drug Delivery Systems for Cancer Treatment.
Cell-based drug delivery systems have shown tremendous advantages in cancer treatment due to their distinctive properties. For instance, delivery of therapeutics using tumor-tropic cells like neutrophils, lymphocytes and mesenchymal stem cells can achieve specific tumor targeting due to the "Trojan Horse" effect. Other circulatory cells like erythrocytes and platelets can greatly improve the circulation time of nanoparticles due to their innate long circulation property. Adipocytes, especially cancer-associated adipocytes, play key roles in tumor development and metabolism, therefore, adipocytes are regarded as promising bio-derived nanoplatforms for anticancer targeted drug delivery. Nanomaterials are important participants in cell-based drug delivery because of their unique physicochemical characteristics. Therefore, the integration of various nanomaterials with different cell types will endow the constructed delivery systems with many attractive properties due to the merits of both. In this review, a number of strategies based on nanomaterial-involved cell-mediated drug delivery systems for cancer treatment will be summarized. This review discusses how nanomaterials can be a benefit to cell-based therapies and how cell-derived carriers overcome the limitations of nanomaterials, which highlights recent advancements and specific biomedical applications based on nanomaterial-mediated, cell-based drug delivery systems.


Complement activation by propofol and its effect during propofol anaesthesia.
We have examined whether propofol activates complement. In the first study, blood was mixed with saline, propofol or the lipid solvent for propofol, and the activated complement 3 (C3a) and 4 (C4a) concentrations in the supernatant were assayed. In the second study, blood and propofol were mixed with various levels of nafamostat mesilate (anti-complement agent) up to 0.3 mmol/l and the C3a was assayed. In the third study, the time course of plasma C3a concentration in patients during propofol anaesthesia was examined. The results showed that the lipid solvent activated complement and produced similar levels of C3a to propofol, probably via both the classical and alternative pathways. This activation was not inhibited by any of the nafamostat concentrations used. There was no significant change in plasma C3a concentration during propofol anaesthesia. These results suggest that C3a is generated by the lipid solvent, but its accumulation during propofol anaesthesia is minimal.


Effect of lipoic acid and α-glyceryl-phosphoryl-choline on astroglial cell proliferation and differentiation in primary culture.
Lipoic acid plays a crucial role as antioxidant and metabolic component of enzymes involved in glucose metabolism of different cell types. Choline alphoscerate (α-glyceryl-phosphoryl-choline [αGPC]) is a semisynthetic derivative of phosphatidylcholines representing, among acetilcholine precursors, a cholinergic drug. In the present study, we evaluated the expression of some proliferation and differentiation markers in 15 or 21 DIV astrocyte cultures treated with 50 μM (+)lipoic acid or (+/-)lipoic acid and/or 10 mM αGPC for 24 hr. In addition, we evaluated the possible genoprotective effect by analysis of DNA status detected by alkaline comet assay. The addition of single drugs [(+)lipoic acid, (+/-)lipoic acid, or αGPC] induced an "upward modulation" of the expression of biomarkers used in our study. On the contrary, the cotreatment with either (+)lipoic acid + αGPC or (+/-)lipoic + αGPC surprisingly showed no significant modification or even a downregulation of the above-mentioned biomarkers. This latter finding demonstrated no additional effect after the cotreatment with both drugs with respect to the single treatments alone. Further studies are necessary to clarify the specific mechanism evoked by the processing of these neuroprotective agents in our in vitro models. Finally, these preliminary findings may represent a good tool with which to clarify the antioxidant and metabolic roles played by lipoic acid in proliferating and differentiating astroglial cell cultures, during an interactive cross-talk between glial and neuronal cells, after brain lesions or damage correlated with oxidative stress that may occur in some degenerative diseases.