Boric-Acid-Functional Lanthanide Metal-Organic Frameworks for Selective Ratiometric Fluorescence Detection of Fluoride Ions.
Here, we report that boric acid is used to tune the optical properties of lanthanide metal-organic frameworks (LMOFs) for dual-fluorescence emission and improves the selectivity of LMOFs for the determination of F- ions. The LMOFs are prepared with 5-boronoisophthalic acid (5-bop) and Eu3+ ions as the precursors. Emission mechanism study indicates that 5-bop is excited with UV photons to produce its triplet state, which then excites Eu3+ ions for their red emission. This is the general story of the antenna effect, but electron-deficient boric acid decreases the energy transfer efficiency from the triplet state of 5-bop to Eu3+ ions, so dual emission from both 5-bop and Eu3+ ions is efficiently excited at the single excitation of 275 nm. Moreover, boric acid is used to identify fluoride specifically as a free accessible site. The ratiometric fluorescent detection of F- ions is validated with the dual emission at single excitation. The LMOFs are very monodisperse, so the determination of aqueous F- ions is easily achieved with high selectivity and a low detection limit (2 μM). For the first time, we reveal that rational selection of functional ligands can improve the sensing efficiency of LMOFs through tuning their optical property and enhancing the selectivity toward targets.


Changing incidence of abdominal aortic aneurysms: a population-based study.
The apparent incidence of abdominal aortic aneurysms among Rochester, Minnesota residents increased seven-fold between 1951 and 1980, while the incidence of thoracic aortic aneurysms declined somewhat. Rates for abdominal aneurysms rose with age and were greater among men. The overall incidence in 1971-1980 was 36.5 per 100,000 person-years. While all clinical classes of abdominal aortic aneurysms became more frequent, the greatest rise in incidence was for small, asymptomatic, and uncomplicated aneurysms which suggested an important role for more complete case ascertainment in recent years. The secular trend in abdominal aortic aneurysm incidence seems to be different from that observed for stroke or for coronary heart disease in the same community.


Idiopathic Acute Compartment Syndrome of the Leg with Incidental Deep Venous Thrombosis: A Case Report.
Acute compartment syndrome (ACS) is an emergency. The majority of cases are caused by underlying trauma, especially fractures. Idiopathic atraumatic ACS of the leg is very rare. The diagnosis and management of ACS should focus on the clinical presentation to avoid delay in fasciotomy for limb salvage. ACS of the leg can be caused by massive proximal iliofemoral thrombosis and rarely occlusive popliteal vein thrombosis with total or near total occlusion. Nonocclusive distal popliteal vein thrombosis, especially if chronic, does not cause ACS and when seen in a patient with ACS, it is likely an incidental finding rather than the cause of the compartment syndrome. This is a case of idiopathic ACS of the right leg occurring in the presence of an incidental right chronic nonocclusive distal popliteal vein thrombosis.


Substrate specificity of glycinamide ribonucleotide synthetase from chicken liver.
Several analogs of glycinamide ribonucleotide and phosphoribosylamine have been prepared and evaluated as substrates for glycinamide ribonucleotide synthetase purified from chicken liver. Glycinamide ribonucleotide analogs include side chain modifications wherein the glycine side chain (R = CH2NH2) has been replaced by R = CH2NHCH3 and R = CH2CH2NH2, ribose ring replacement by chiral cyclopentane and cyclopentene derivatives, and phosphate replacement by phosphonates. All of these, with the exception of the O-phosphonate, served as substrates for the reverse enzymatic reaction, with Vmax values comparable to that obtained with glycinamide ribonucleotide, although the Km values ranged from 21 to 118 times the Km for glycinamide ribonucleotide. Analogs of phosphoribosylamine examined as substrates for the forward reaction consist of chiral derivatives of cyclopentane and cyclopentene and a chiral carbocyclic phosphonate. These also served as substrates, with Km values ranging from 5 to 23 times the Km for phosphoribosylamine and with diminished Vmax values. These studies have begun to define the structural features of the nucleotide substrate necessary to support enzymatic activity. Sarcosine (N-methylglycine) and beta-alanine were also accepted as substrates, albeit with reduced affinity compared with glycine.


Outbreak of Shigella flexneri linked to salad prepared at a central commissary in Michigan.
In August 1992, the Michigan Department of Public Health was notified of a cluster of persons with Shigella flexneri infections, all of whom had eaten at different outlets of a single restaurant chain. The chain prepared many foods at a central kitchen. A matched case-control study to determine risk factors for illness among patrons of the restaurant chain was undertaken. An inspection of the commissary and a review of commissary inspection and employee records were conducted. Of the 46 patients identified, 44 had eaten tossed salad versus 33 of the 71 controls (matched odds ratio = 56.9; 95 percent confidence interval 5.0, 648.1). Improper salad preparation techniques were used, and the salad preparation area had not been inspected in several years. Some salad preparers had been ill shortly before the outbreak but continued to work. The greater use of central kitchens could lead to larger outbreaks of illness related to improper food handling. Raw vegetables are a potential vehicle for transmission of shigellosis. Coordination of all agencies responsible for inspecting commissaries should be assured. Assuring restriction of ill food handlers will require management to take an active role in identification of ill employees and in the development of incentives to report illness.


Molecular Insights on the Therapeutic Effect of Selected Flavonoids on Diabetic Neuropathy.
One of the common clinical complications of diabetes is diabetic neuropathy affecting the nervous system. Painful diabetic neuropathy is widespread and highly prevalent. At least 50% of diabetes patients eventually develop diabetic neuropathy. The four main types of diabetic neuropathy are peripheral neuropathy, autonomic neuropathy, proximal neuropathy (diabetic polyradiculopathy), and mononeuropathy (Focal neuropathy). Glucose control remains the common therapy for diabetic neuropathy due to limited knowledge on early biomarkers that are expressed during nerve damage, thereby limiting the cure through pharmacotherapy. Glucose control dramatically reduces the onset of neuropathy in type 1 diabetes but proves to be less effective in type 2 diabetes. Therefore, the focus is on various herbal remedies for prevention and treatment. There is numerous research on the use of anticonvulsants and antidepressants for the management of pain in diabetic neuropathy. Extensive research is being conducted on natural products, including the isolation of pure compounds like flavonoids from plants and their effect on diabetic neuropathy. This review focuses on the use of important flavonoids such as flavanols (e.g., quercetin, rutin, kaempferol, and isorhamnetin), flavanones (e.g., hesperidin, naringenin and class eriodictyol), and flavones (e.g., apigenin, luteolin, tangeretin, chrysin, and diosmin) for the prevention and treatment of diabetic neuropathy. The mechanisms of action of flavonoids against diabetic neuropathy by their antioxidant, anti-inflammation, anti-glycation properties, etc., are also covered in this review article.


Survival of Enterohemorrhagic Escherichia coli O104:H4 Strain C227/11Φcu in Agricultural Soils Depends on rpoS and Environmental Factors.
The consumption of contaminated fresh produce caused outbreaks of enterohemorrhagic (EHEC) Escherichia coli. Agricultural soil might be a reservoir for EHEC strains and represent a contamination source for edible plants. Furthermore, the application of manure as fertilizer is an important contamination route. Thus, the German fertilizer ordinance prohibits the use of manure 12 weeks before crop harvest to avoid pathogen transmission into the food chain. In this study, the survival of E. coli O104:H4 strain C227/11Φcu in soil microenvironments with either diluvial sand or alluvial loam at two temperatures was investigated for more than 12 weeks. It was analyzed whether the addition of cattle manure extends EHEC survival in these microenvironments. The experiments were additionally performed with isogenic ΔrpoS and ΔfliC deletion mutants of C227/11Φcu. The survival of C227/11Φcu was highest at 4 °C, whereas the soil type had a minor influence. The addition of cattle manure increased the survival at 22 °C. Deletion of rpoS significantly decreased the survival period under all cultivation conditions, whereas fliC deletion did not have any influence. The results of our study demonstrate that EHEC C227/11Φcu is able to survive for more than 12 weeks in soil microenvironments and that RpoS is an important determinant for survival.


Impact of the COVID-19 pandemic on the activity of advanced-practice nurses on a reference unit for inflammatory bowel disease.
To report the impact of the COVID-19 pandemic on the activity of nurses working on an inflammatory bowel disease (IBD) unit and to identify reasons for telehealth care and its relationship to certain characteristics. The COVID-19 pandemic had led to an increase in demand for remote care in patients with inflammatory bowel disease who require monitoring and frequent access to health services. A retrospective study of all activity (in person and by phone call or email) done on the unit during the acute phase of the pandemic at a reference hospital in Spain. Numbers of activities done by nurses, reasons for telehealth care and sociodemographic and clinical data were collected. Statistical analysis was performed using frequency, chi-squared and analysis of variance tests. A total of 1095 activities for 561 patients who received care were reported. Among them, 1042 (95.2%) were telemedicine activities, amounting to a 47.3% increase over the prior year. COVID-19-related activities numbered 588 (59.5%). Consultations due to disease flare-up numbered 134 (13.7%), representing a 145% increase compared to 2019. Significant differences were found between reasons for using telemedicine and diagnosis, occupational status, contact week and treatment. The acute phase of the pandemic has changed the activity managed by the nursing staff on the unit. Identifying and analysing these changes has yielded valuable information to achieve more efficient management and better care quality for patients in special situations.


Ischemic Conditioning Ameliorated Hypertension and Vascular Remodeling of Spontaneously Hypertensive Rat via Inflammatory Regulation.
Vascular remodeling is an initial step in the development of hypertension. Limb remote ischemic conditioning (LRIC) is a physiological treatment that induces endogenous protective effect during acute ischemic injury. However, the impact of long-term LRIC on hypertension, a chronic disease, is unknown. In this study, we aimed to investigate the LRIC effect on blood pressure and vascular remodeling in spontaneously hypertensive rat (SHR) model and patients with prehypertension and early-stage hypertension. LRIC of rats was performed once a day for 6-weeks. Blood pressure, vascular remodeling (cross-sectional area, extracellular deposition, and smooth muscle cell area), inflammation (inflammatory factors, and inflammatory cells) were compared among normotensive Wistar-Kyoto rats (WKY), WKY RIC group, SHR control group, and SHR RIC. Long-term LRCI treatment (twice a day for 4-weeks) was performed on patients with prehypertension or early-stage hypertension. Blood pressure and pulse wave velocity (PWV) were analyzed before and after LRIC treatment. LRIC treatment decreased blood pressure in SHR (n = 9-10). LRIC ameliorated vascular remodeling by decreasing cross-sectional area, suppressing deposition of the extracellular matrix, and hypertrophy of smooth muscle cell in conduit artery and small resistance artery (n = 7). LRIC decreased proinflammatory factors while increasing the anti-inflammatory factors in the circulation (n = 5). LRIC decreased circulating monocyte and natural killer T-cell levels (n = 5). Furthermore, LRIC treatment decreased blood pressure and improved vascular stiffness in patients (n = 20). In conclusion, long term LRIC could decrease blood pressure and ameliorate vascular remodeling via inflammation regulation. LRIC could be a preventive treatment for people with blood pressure elevation or prehypertension.


Anesthetic Management of a Patient With Distal Acquired Demyelinating Symmetric (DADS) Neuropathy Under General Anesthesia.
Distal acquired demyelinating symmetric (DADS) neuropathy is a form of chronic inflammatory demyelinating polyradiculopathy (CIDP) which can present many risks to patients undergoing anesthesia. There are currently no specific guidelines for the management of patients with any form of CIDP. This case report describes a 65-year-old male with DADS neuropathy who underwent elective total hip arthroplasty. General, total IV anesthesia was used in combination with other short-acting drugs and the patient endured a successful procedure with an uneventful post-operative course. This case may provide future insight into the anesthetic management of patients with similar comorbidities.


Brain proton magnetic resonance spectroscopy studies in recently abstinent alcoholics.
Chronic alcohol-dependent patients have reduced brain volumes and concomitant neurobehavioral deficits that may recover during abstinence. In 10 chronic alcoholic patients, using localized proton magnetic resonance spectroscopy, we found reliable increases during the first 3-4 weeks of abstinence in the concentrations within the superior cerebellar vermis of choline (Cho)-containing compounds relative to the neuronal marker, N-acetylaspartate (NAA). Lesser changes were observed following 1 month of abstinence, and in one of the patients studied longitudinally over 3 months, a marked reduction in the Cho/NAA ratio was associated with relapse. After detoxification, the Cho/NAA ratio correlated with a composite clinical impression of brain functions. The lowest Cho/NAA was observed in a patient with persisting alcoholic dementia, in striking contrast to reduced relative concentrations of NAA reported in dementia of the Alzheimer's type. Possible molecular explanations for these brain metabolic changes are discussed.


Effects of oxidized phospholipids on gene expression in RAW 264.7 macrophages: a microarray study.
Oxidized phospholipids (oxPLs) are components of oxidized LDL (oxLDL). It is known that oxLDL activates expression of a series of atherogenic genes and their oxPLs contribute to their biological activities. In this study we present the effects of 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on gene expression in RAW 264.7 macrophages using cDNA microarrays. PGPC affected the regulation of 146 genes, whereas POVPC showed only very minor effects. PGPC preferentially influenced expression of genes related to cell death, angiogenesis, cholesterol efflux, procoagulant mechanisms, atherogenesis, inflammation, and cell cycle. Many of these effects are known from studies with oxLDL or oxidized 1-hexadecanoyl-2-eicosatetra-5',8',11',14'-enoyl-sn-glycero-3-phosphocholine (oxPAPC), containing PGPC in addition to other oxPL species. It is known that POVPC efficiently reacts with proteins by Schiff base formation, whereas PGPC only physically interacts with its biological targets. POVPC seems to affect cell physiology to a great extent on the protein level, whereas PGPC gives rise to both the modulation of protein function and regulation on the transcriptional level.


Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study-experience with 14C-labeled (R)-6-[amino(4- chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1- methyl-2(1H)-quinolinone (R115777), a farnesyl transferase inhibitor.
Accelerator mass spectrometry (AMS) has been used in a human mass balance and metabolism study to analyze samples taken from four healthy male adult subjects administered nanoCurie doses of the farnesyl transferase inhibitor 14C-labeled (R)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone ([14C]R115777). Plasma, urine, and feces samples were collected at fixed timepoints after oral administration of 50 mg [14C]R115777 (25.4 Bq/mg or 687 pCi/mg i.e., equivalent to 76.257 x 10(3) dpm) per subject. AMS analysis showed that drug-related (14)C was present in the plasma samples with C(max) values ranging from 1.6055 to 2.9074 dpm/ml (1.0525-1.9047 microg/ml) at t(max) = 2 to 3 h. The C(max) values for acetonitrile extracts of plasma samples ranged from 0.3724 to 0.7490 dpm/ml in the four male subjects. Drug-related 14C was eliminated from the body both in the urine and the feces, with a mean total recovery of 79.8 +/- 12.9% in the feces and 13.7 +/- 6.2% in the urine. The majority of drug-related radioactivity in urine and feces was excreted within the first 48 h. High-performance liquid chromatography (HPLC)-AMS profiles were generated from radioactive parent drug plus metabolites from pooled diluted urine, plasma, and methanolic feces extracts and matched to retention times of synthetic reference substances, postulated as metabolites. All HPLC separations used no more than 5 dpm injected on-column. The radioactive metabolite profiles obtained compared well with those obtained using liquid chromatography/tandem mass spectometry. This study demonstrates the use of AMS in a human phase I study in which the administered radioactive dose was at least 1000-fold lower than that used for conventional radioactive studies.


Acute mountain sickness in children at 2835 meters.
Acute mountain sickness has been described in adults but little is known concerning its occurrence in children. Our objective was to determine the incidence of acute mountain sickness in children. A survey questionnaire was completed by 558 children (aged 9 to 14 years) after they ascended from 1600 to 2835 m and from 405 similarly aged children after travel at sea level. Three or more of the following symptoms in the high-altitude setting were considered as the case definition of acute mountain sickness: headache, loss of appetite, vomiting, fatigue, insomnia, shortness of breath, and dizziness. One hundred fifty-six (28%) of the children at 2835 m developed acute mountain sickness. Three or more symptoms developed in a smaller, but nonetheless considerable, number (86 [21%]) of children at sea level. Headache, shortness of breath, and dizziness were reported more frequently at high altitude than at low altitude, whereas the other symptoms occurred with equal frequency at the two locations. More than one fourth of the children visiting high altitude developed acute mountain sickness. A high proportion (21%) of children at sea level developed similar symptoms, suggesting that an appreciable portion of the symptoms present were due to factors other than altitude, such as travel, anxiety, or disruption of daily routine.


A monoclonal antibody that defines p24, a core protein of adult T-cell leukemia virus, and its precursor.
A mouse hybridoma cell line, H15, produced monoclonal antibody reacting with all the adult T-cell leukemia (ATL) virus (ATLV)-bearing cell lines but none of the ATLV-negative cell lines tested. Binding of H15 antibody to ATLV-bearing cell surfaces was specifically blocked by anti-ATLV positive human sera. Radioimmunoprecipitation analyses revealed that the antigen detected by H15 antibody was p24, a core protein of ATLV. Pulse-chase experiments using H15 antibody led to the identification of a protein, p53, which could be a precursor of p24.


Allosteric regulation of HIV-1 reverse transcriptase by ATP for nucleotide selection.
Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a DNA polymerase that converts viral RNA genomes into proviral DNAs. How HIV-1 RT regulates nucleotide selectivity is a central issue for genetics and the nucleoside analog RT inhibitor (NRTI) resistance of HIV-1. Here we show that an ATP molecule at physiological concentrations acts as an allosteric regulator of HIV-1 RT to decrease the K(m) value of the substrate, decrease the k(cat) value, and increase the K(i) value of NRTIs for RT. Computer-assisted structural analyses and mutagenesis studies suggested the positions of the ATP molecule and NRTI-resistance mutations during a catalytic reaction, which immediately predict possible influences on nucleotide insertion into the catalytic site, the DNA polymerization, and the excision reaction. These data imply that the ATP molecule and NRTI mutations can modulate nucleotide selectivity by altering the fidelity of the geometric selection of nucleotides and the probability of an excision reaction.


gamma-Aminobutyric acid enhances the light response of ganglion cells in the trout pineal organ.
Electrical recordings from achromatic second order neurons of intact superfused pineal organs of the rainbow trout were used to investigate the role of gamma-aminobutyric acid (GABA) in the transmission of photoreceptor signals onto centrally projecting ganglion cells. Bath-applied GABA decreased the spike discharge rate of 98% of achromatic ganglion cells in a dose-dependent manner. GABA was also active if applied during synaptic blockade, demonstrating the presence of GABAergic receptors at the ganglion cell level. Responsiveness of ganglion cells to light was reversibly enhanced by GABA. The light response curve of ganglion cells, which was obtained by plotting spike rate versus light intensity, was significantly shifted to lower frequencies by GABA, indicating that GABA is an important inhibitory modulator of ganglion cell activity in the trout pineal organ.


Improving Environmental Efficiency of Reverse Filling Cementitious Materials through Packing Optimization and Fiber Incorporation.
To improve the environmental efficiency of the reverse filling system, three strategies aim to optimize the packing density, and the mechanical property were adopted in this study. Based on the compressive packing model (CPM), the relationship between the D50 ratio and maximum theoretical packing density for a reverse filling system with 25% and 30% superfine Portland cement was established. For comparison, silica fume and steel fiber were also added to the reverse filling system, respectively. The improvement of packing density by adjusting the D50 ratio was verified through the minimum water demand method, CPM, and modified Andreasen and Andersen (MAA) model. Compared to the reverse filling system added with 3 wt % silica fume, which possesses a comparable mechanical property with the optimized group (adjusted D50 ratio), the incorporation of steel fiber shows a more significant increase. The environmental efficiency of all the samples was quantified into five aspects through the calculation based on the mix proportion, compressive strength, and hydration degree. The comprehensive evaluation demonstrated that the optimized reverse filling system exerts a lower environmental impact and possesses a much higher cement use efficiency compared to the majority of ultra-high performance concrete (UHPC)/ ultra-high performance fiber-reinforced concrete (UHPFRC) reported in published papers.


Travelers' diarrhea among United States military personnel during joint American-Egyptian armed forces exercises in Cairo, Egypt.
A study was conducted of travelers' diarrhea in a United States military population on deployment in Cairo, Egypt, during July and August 1987. Acute diarrhea requiring medical attention developed in 183 (4%) of 4,500 troops. A possible etiologic agent was identified in 49% of all diarrhea cases. Enteric pathogens associated with cases of diarrhea included: Enterotoxigenic Escherichia coli (17% ST-producers, 13% LT-producers, and 3% LT/ST-producers); Shigella (9%); Campylobacter spp. (2%); Salmonella (2%); and Vibrio cholerae non-01 serogroup (2%). Other enteric pathogens isolated from one episode each of diarrhea included Aeromonas hydrophila group, Plesiomonas shigelloides, and Bacillus cereus. Yersinia enterocolitica, enteroinvasive E. coli, intoxications by Clostridium perfringens and Clostridium difficile, and pathogenic enteric parasites were not found in any of the 183 patients with diarrhea. A survey of military personnel not requesting medical care indicated that up to 40% of troops may have had diarrhea during this deployment. Acute gastroenteritis is a potential cause of substantial morbidity in U.S. military personnel deployed to Egypt.


The katE gene, which encodes the catalase HPII of Mycobacterium avium.
Disseminated Mycobacterium avium-Mycobacterium intracellulare disease is a prevalent opportunistic infection in patients with acquired immune deficiency syndrome (AIDS). These pathogens are generally resistant to isoniazid (INH), a powerful antituberculosis drug. It is now generally accepted that the INH susceptibility of Mycobacterium tuberculosis results from the transformation of the drug into a toxic derivative, as a result of the action of the enzyme catalase-peroxidase (HPI), encoded by the katG gene. It has been speculated that the presence of a second catalase (HPII) in some mycobacterial species, but lacking in M. tuberculosis, may impair the action of INH. In this report, the nucleotide sequence of the M. avium katE gene, encoding catalase HPII, is described. This enzyme shows strong similarity to Escherichia coli catalase HPII and eukaryotic catalases. All amino acids previously postulated as participating directly in catalysis by liver catalase and most of the amino acids binding the prosthetic group are conserved in M. avium catalase HPII. The enzyme is expressed in E. coli and is inhibited by 3-amino-1,2,4-triazole (AT). Furthermore, Southern blot hybridizations and polymerase chain reaction experiments demonstrate the distribution of katE gene in several mycobacterial species. To evaluate the potentially antagonistic effect of HPII catalase on INH susceptibility, the katE gene was transformed into M. tuberculosis H37Rv and the minimum inhibitory concentration (MIC) for INH was determined. Despite strong expression of the katE gene, no change in MIC was observed, thus ruling out a possible contribution of this enzyme to the natural resistance of M. avium to the drug. The availability of the gene probe, encoding the second mycobacterial catalase HPII, should open the way for the development of new drugs and diagnostic tests to combat drug-resistant pathogen strains.


Autophagy-related Proteins as a Prognostic Factor of Patients With Colorectal Cancer.
Autophagy plays a dual role in tumorigenesis. In the initial stages, it promotes cell survival and suppresses carcinogenesis, whereas in cancer development, it induces cancer cell survival. In this study, we investigate the role of autophagy as a protective or tumor suppressor mechanism in colorectal cancer (CRC) cell lines and evaluate its role as a potential biomarker in human tumor samples. The data of 68 patients with CRC treated at our Department from January 1 to December 31, 2016 were analyzed. Immunohistochemistry evaluation of p62, LC3B, Beclin-1, and Rab-7 in formalin-fixed paraffin-embedded tissue samples was performed and their expression was correlated with clinicopathologic characteristics, mutation status, and therapeutic approach. The χ was used to test an association among categorical variables. Survival curves were estimated using the Kaplan-Meier method and differences were assessed using the log-rank test. Colo-205, HT29, SW-480, and Caco-2 cell lines were also used so as to test the autophagy markers with oxaliplatin, irinotecan, hydroxychloroquine, and 3-methyladenine. Overexpression of Beclin-1 is associated with poor survival (P=0.001) in patients with CRC treated with chemotherapy, irrespective of the stage and mutational status. Rab-7 is also correlated with progression-free survival (PFS) (P=0.088). Oxaliplatin (10 and 20 μΜ) and irinotecan (10 and 20 μΜ) inhibit autophagy in microsatellite stable (MSS) CRC cell lines. The inhibition of autophagy in MSS CRC cell lines after treatment with oxaliplatin and irinotecan is further identified through monodancylcadaverine staining. Moreover, inhibition of autophagy with molecules such as hydroxychloroquine (20 μΜ) and 3-methyladenine (5 mM) was identified by the accumulation of p62 and LC3B. Beclin-1 is an independent prognostic factor of overall survival and PFS. Also, Rab-7 is identified as an independent prognostic factor of PFS. Besides, several chemotherapeutic drugs such as oxaliplatin and irinotecan inhibit autophagy in MSS CRC cell lines in a similar way like hydroxychloroquine and 3-methyladenine. Thus, in MSS patients who develop chemoresistance, a combination of other therapies that include an autophagy inhibitor could be more beneficial. Further clinical trials are needed to investigate these therapeutic strategies.


Organogelation by 4-(N-tetradecanoyl)aminohydroxybutyric acids: effect of hydrogen-bonding group in the amphiphile head.
The major driving force for organogelation is known to be hydrogen bonding for gelators containing functional groups capable of forming hydrogen bond(s). In order to examine this, we have investigated the gelation behavior of two 4-(N-tetradecanoyl)aminohydroxybutanoic acid amphiphiles in a series of organic solvents and compared with those of the corresponding unsubstituted amphiphile 4-(N-tetradecanoyl)aminobutanoic acid (C14-ABA). The gelation ability of the nonhydroxyl amphiphile C14-ABA was found to be better than the hydroxyl group substituted amphiphiles. An attempt was also made to correlate gelation abilities of the amphiphiles with the solvent polarity parameters. The driving force for the gelation was studied by Fourier transform infrared and (1)H NMR spectroscopy. The organogels were characterized by electron microscopy and XRD. The thermal stability of the gels was investigated by measuring the sol-to-gel transition temperature. Rheological measurements were performed in order to determine the mechanical stability of the organogels. The gelation ability and thermal and mechanical stability of the organogels were correlated with the intermolecular hydrogen-bonding interactions between amphiphile head groups.


Interrupted coarsening in a driven kinetically constrained Ising chain.
We introduce a driven version of the one-dimensional kinetically constrained spin chain [J. Jackle and S. Eisinger, Zeitschr. Phys. B 84, 115 (1991)]. In its original undriven version, this model shows anomalous coarsening following a quench to a low temperature, with an equilibration time that diverges as approximately exp(1/T(2)) for T-->0. We show that driving of constant rate gamma; interrupts coarsening and stabilizes the chain in a state analogous to that of a coarsening chain of age 1/gamma;. We present an analytical theory for this steady state, and demonstrate it to be in excellent agreement with our simulation results.


Seed size and capitulum position drive germination and dormancy responses to projected warming for the threatened dune endemic Cirsium pitcheri (Asteraceae).
Among coastal plant species at risk from rapid environmental changes is the North American Great Lakes dune endemic Cirsium pitcheri. Despite being listed as federally threatened, little is known about how C. pitcheri seed attributes influence germination and dormancy-break patterns in the context of climate change. Following a previous work where we found differences in the number and weight of C. pitcheri seeds among capitulum positions and study sites, here we examine the effects of seed attributes (capitulum position, seed weight, and site of origin) on the proportion and timing of C. pitcheri seed germination under temperature treatments that simulate projected warming in the Great Lakes (20/10, 25/10, and 30/10°C day/night). Our results demonstrate that C. pitcheri produces diverse cohorts of seeds with seed attributes that significantly influence the timing and probability of germination over a 3-year soil seed bank. Cirsium pitcheri seed germination proportions were highest at 20°C and decreased successively at 25 and 30°C. Seeds from terminal capitula also had higher germination proportions and took longer to germinate than those from secondary capitula. Lastly, the effect of seed weight on germination probability depended on site of origin and capitulum position, with all effects varying in size and significance over time. Ultimately, our results highlight the considerable differences in germination patterns exhibited by seeds from different capitulum positions and sites of origin and provide insight into the dormancy-break patterns that C. pitcheri might experience under predicted temperature rise in the Great Lakes region of North America.


Inhibitory effect of rhodamine 123 on the growth of the rodent malaria parasite, Plasmodium yoelii.
The effect of the cationic permeant fluorescent dye, rhodamine 123 (R123), on the in vivo growth of Plasmodium yoelii was examined. Plasmodium yoelii-infected mouse erythrocytes were incubated in vitro with R123 and injected intravenously into mice. Examination of daily parasitemias showed that R123 delayed parasite growth whereas rhodamine 110, a neutral compound, and fluorescein, a negatively charged fluorescent dye, did not. Infected erythrocytes treated with R123 were not cleared from the circulation even 7 h after injection. Quantitation of cell-associated R123 by spectrophotometry revealed that infected cells with increased levels of R123 considerably prolonged the 2% prepatent period, the time required for the parasite to develop a 2% parasitemia. Degenerating parasites within and outside the host erythrocytes were observed on day 1 of infection in the mice. Thus it follows that R123, which accumulated in infected erythrocytes, inhibits the growth of P. yoelii; moreover, when R123-labeled infected erythrocytes were treated with 1-10 microM carbonylcyanide m-chlorophenylhydrazone (CCCP), a proton ionophore, to release R123 from the cells, the inhibitory effect on the growth rate of P. yoelii was partially reversed.


Apoptosis of astrocytes with enhanced lysosomal activity and oligodendrocytes in white matter lesions in Alzheimer's disease.
Cerebral white matter lesions in Alzheimer's disease (AD) consist of subcortical degeneration and ischaemic-hypoxic changes. Glial changes are intimately associated with the white matter lesions, and regressive changes in astrocytes and loss of oligodendroglial cells have been reported. We quantitatively compared glial changes including apoptosis and enhanced lysosomal activity in the frontal and temporal white matter by using terminal dUTP nick end labelling (TUNEL) and immunohistochemistry for glial markers, lysosomes and apoptosis-regulating proteins in non-familial AD brains. The degree of myelin pallor and axonal loss varied considerably in both the frontal and temporal white matter but fibrillary gliosis in demyelinated lesions tended to be less prominent in the temporal white matter in AD cases. A morphometric study with planimetric methods for cross-sectional areas of frontal and temporal white matter revealed that the white matter of AD cases manifested atrophy with significant reduction in frontal (11.9%) and temporal (29.4%) white matter compared to normal controls. Double immunolabelling for glial fibrillary acidic protein (GFAP) and KP1 (CD68) revealed KP1-positive fragmented structures within the weakly GFAP-labelled astrocytes. These KP1-positive structures correspond to process fragmentation and cytoplasmic vacuoles, which in turn indicate enhanced lysosomal activity during regressive changes in astrocytes. The KP1-modified astrocytes were not found in Pick's disease and corticobasal degeneration. The density of apoptotic glial cells, largely oligodendroglial, was significantly higher in the temporal than in the frontal white matter, and most GFAP-positive astrocytes with regressive changes were apoptotic. GFAP-positive astrocyte density was statistically the same in the frontal and temporal white matter, but the density of KP1-modified astrocytes was higher in the temporal than in the frontal white matter. The rate of white matter shrinkage was significantly correlated with the density of apoptotic glial cells and the density of KP1-modified astrocytes in the temporal lobe in AD cases. An increase in apoptotic glial cell density was found to contribute to GFAP-positive astrocytes with regressive changes in temporal white matter, while apoptosis of vascular smooth muscle cells did not show topographical accentuation. Astrocytes labelled with beta amyloid protein were not apoptotic, and the density of apoptotic cells labelled with CD95 and caspase-3 was too low in both types of white matter to be statistically evaluated. Our results imply that regressive changes in astrocytes and glial apoptosis are, to some extent, associated with white matter lesions, particularly of the temporal lobe in AD brains. The presence of apoptotic astrocytes with evidence of regressive change could therefore be a histological hallmark for white matter degeneration in AD.


[Are invitations to mammography screening a reasonable basis for informed consent?-- Secondary publication].
There is a delicate balance between the benefits and harms of mammography screening, and women should decide for themselves, on an informed basis. The invitation to have a mammography is the only source of information provided to all eligible women, and we explored whether it provides such a basis. We collected invitations from English-speaking and Scandinavian countries. The major benefit of screening, a reduction in breast cancer mortality, was mentioned in 30 of 31 invitations, whereas the most important harms, overdiagnosis and overtreatment, were not mentioned in any of the invitations.


Stroke after chiropractic manipulation as a result of extracranial postero-inferior cerebellar artery dissection.
To describe a case of dissection of the postero-inferior cerebellar artery (PICA) after cervical manipulation. After cervical manipulation, a 42-year-old woman had a cerebellar syndrome related to an infarct in the area supplied by the PICA, confirmed by computed tomography of the brain. Cerebral angiography showed a normal appearance of the vertebral artery, a cervical extradural origin of PICA, and a dissection of the latter at the C1-C2 level. Anticoagulant treatment with heparin was implemented. A positive outcome was achieved after 3 weeks. Anatomical variations of the vertebral arteries and their branches are not infrequent and may constitute a predisposing factor to complications after neck manipulation.


COVID-19 in a state of Brazilian Northeast: Prevalence and associated factors in people with flu-like syndrome.
To estimate the prevalence and associated factors of COVID-19 in people with flu-like syndrome in Ceará, Brazil. COVID-19 is an infectious disease that has led to a worldwide public health emergency. More than 30,000 cases were confirmed in Brazil, especially in the States of São Paulo, Rio de Janeiro and Ceará. The capital of the Ceará State is the one with the highest incidence of COVID-19 in Brazil. Estimating the prevalence of the disease and its associated factors is important to offer adequate health care. A cross-sectional study with secondary data of people notified with flu-like syndrome and COVID-19 test results. 19,967 cases of flu-like syndrome were analysed according to the result of the COVID-19 test. Predictive variables were as follows: age range, sex, women in puerperium, presence or absence of cardiovascular diseases, diabetes, haematological illness, immunodeficiencies, neurological diseases, obesity, renal diseases and Down syndrome. Robust Poisson regression models estimated the prevalence ratios of COVID-19. The research was reported via STROBE guidelines for cross-sectional studies. The prevalence of COVID-19 in the population was 10.37%. In the final model, the following variables were associated with COVID-19: aged people, male sex, cardiovascular diseases and diabetes. Among the flu-like syndrome cases, COVID-19 prevalence was high. In the Ceará State, clinical factors such as aged people, male sex, cardiovascular diseases and diabetes can enhance the prevalence of COVID-19 by up to 2.57 times. The identification of factors that are associated with the enhanced prevalence of COVID-19 facilitates early diagnosis, and adequate and prompt treatment. This knowledge may avoid an unfavourable prognosis of the disease.


Destruction of bulk ordering by surface randomness.
We demonstrate that the arbitrarily weak quenched disorder on the surface of a system of continuous symmetry destroys long-range order in the bulk, and, instead, quasi-long-range order emerges. Correlation functions are calculated exactly for the two- and three-dimensional XY models with surface randomness via the functional renormalization group. Even at strong quenched disorder the three-dimensional XY model possesses topological order. We also determine roughness of a domain wall in the presence of surface disorder.


Regulatory and effector T cell activation levels are prime determinants of in vivo immune regulation.
Little is known about the in vivo conditions in which CD4+CD25+ regulatory T cells (T(reg)) exert their suppressive effect in nonlymphopenic mice. To this end, we analyzed T(reg)-mediated suppression of expansion and cytokine production at different levels of Ag-specific CD4+CD25- T cell activation. Using Ab-mediated depletion of endogenous T(reg), we show that basal immunosuppression is dependent on effector T cell activation. These polyclonal T(reg), which were poorly activated in our immunization conditions, were effective in weak but not high T cell activation context. In contrast, the same immunization conditions led to proliferation of cotransferred Ag-specific T(reg). Those efficiently inhibited T cell proliferation and cytokine production even in strong T cell activation context. Interestingly, T(reg) selectively suppressed expansion or cytokine production depending on the experimental approach. The importance of the immune context for efficient suppression is further supported by the observation that T(reg) depletion exacerbated diabetes of NOD mice only at the early stage of the disease. Overall, our study suggests that T(reg)-mediated suppression depends on the relative activation of T(reg) and effector T cells in vivo. This balance may be a critical factor in the regulation of immune responses.


Atypical squamous cells of undetermined significance. Current laboratory practices of participants in the College of American Pathologists Interlaboratory. Comparison Program in Cervicovaginal Cytology.
To evaluate current laboratory practices and rates for atypical squamous cells of undetermined significance (ASCUS), a category of epithelial cell abnormality in the Bethesda System. Questionnaire surveys were mailed in December 1993 and March 1994. Cytopathology laboratory participants in the College of American Pathologists Interlaboratory Comparison Program in Cervicovaginal Cytology (PAP). Most responding laboratories (82.5%) limited the use of "atypia" terminology to abnormalities of undetermined significance. Nearly half of the laboratories employed only the term ASCUS for squamous epithelial changes in this category. The median rate of ASCUS in 1993 was 2.8%, with 10% of laboratories reporting rates greater than 9.0%. The median squamous intraepithelial lesion rate was 2.0%, with a median ASCUS-squamous intraepithelial lesion ratio of 1.3. The majority of laboratories qualified a portion of ASCUS cases and issued recommendations for follow-up when appropriate. Fifty-six percent of laboratories surveyed included patients diagnosed with ASCUS in follow-up programs. Laboratories estimated that about 20% (median response) of patients with ASCUS smears had a squamous intraepithelial lesion or equivalent diagnosis made within a year's follow-up. The ASCUS category is used by the majority of laboratories as recommended by the Bethesda System, but reporting rates vary. The results of this survey and associated surveys provide laboratories with useful benchmark figures for interlaboratory comparison of ASCUS practices.


[Metabolic considerations in the treatment of coronary disease in diabetic patients].
Coronary heart disease represents the first cause of death in diabetic patients. The poor outcome of this ischemic disease is multifactorial. The abnormalities in myocardial energy metabolism encountered by the diabetic heart explain both the ischemic severity and the worsening of reperfusion lesions. The metabolic abnormalities in diabetic heart consist in both an impairment of glucose metabolism (diminished glucose uptake, reduced glycolysis, decreased glucose oxidation...) and an increase in fatty acid oxidation. During ischemia, glucose oxidation is reduced and anaerobic glycolysis becomes the main ATP substrate. Lactate accumulate in myocardial cells, inducing both a metabolic acidosis and an intracellular calcium overload. During reperfusion, intracellular homeostasis is restored very slowly in diabetic heart. Several therapeutic approaches are used to correct these metabolic disturbances. Glucose--insulin--potassium infusion in acute myocardial infarction leads to a significant reduction in the mortality relative risk in diabetic patients (ECLA and DIGAMI studies). The benefit is greater in diabetic patients who where non-insulin-treated prior to ischemia followed by myocardial reperfusion therapy. Others more direct pharmacological approaches improve glucose oxidation during myocardial ischaemia and myocardial reperfusion. The reference drug remains trimetazidine for which one of the fundamental mechanism of action was discovered recently. This specific metabolic, non haemodynamic approach, complete the gold-standard treatment of coronary heart disease in diabetic patients (e.g. aspirin, beta-blockers, ACE inhibitors and statins).


Distinctive Tropical Forest Variants Have Unique Soil Microbial Communities, But Not Always Low Microbial Diversity.
There has been little study of whether different variants of tropical rainforest have distinct soil microbial communities and levels of diversity. We compared bacterial and fungal community composition and diversity between primary mixed dipterocarp, secondary mixed dipterocarp, white sand heath, inland heath, and peat swamp forests in Brunei Darussalam, Northwest Borneo by analyzing Illumina Miseq sequence data of 16S rRNA gene and ITS1 region. We hypothesized that white sand heath, inland heath and peat swamp forests would show lower microbial diversity and relatively distinct microbial communities (compared to MDF primary and secondary forests) due to their distinctive environments. We found that soil properties together with bacterial and fungal communities varied significantly between forest types. Alpha and beta-diversity of bacteria was highest in secondary dipterocarp and white sand heath forests. Also, bacterial alpha diversity was strongly structured by pH, adding another instance of this widespread pattern in nature. The alpha diversity of fungi was equally high in all forest types except peat swamp forest, although fungal beta-diversity was highest in primary and secondary mixed dipterocarp forests. The relative abundance of ectomycorrhizal (EcM) fungi varied significantly between forest types, with highest relative abundance observed in MDF primary forest. Overall, our results suggest that the soil bacterial and fungal communities in these forest types are to a certain extent predictable and structured by soil properties, but that diversity is not determined by how distinctive the conditions are. This contrasts with the diversity patterns seen in rainforest trees, where distinctive soil conditions have consistently lower tree diversity.


Assessment of incomplete clipping of aneurysms intraoperatively by a near-infrared indocyanine green-video angiography (Niicg-Va) integrated microscope.
The objective of this article was to assess the clinical use and the completeness of clipping with total occlusion of the aneurysmal lumen, real-time assessment of vascular patency in the parent, branching and perforating vessels, intraoperative assessment of blood flow, image quality, spatial resolution and clinical value in difficult aneurysms using near infrared indocyanine green video angiography integrated on to an operative Pentero neurosurgical microscope (Carl Zeiss, Oberkochen Germany). Thirteen patients with aneurysms were operated upon. An infrared camera with near infrared technology was adapted on to the OPMI Pentero microscope with a special filter and infrared excitation light to illuminate the operating field which was designed to allow passage of the near infrared light required for excitation of indocyanine green (ICG) which was used as the intravascular marker. The intravascular fluorescence was imaged with a video camera attached to the microscope. ICG fluorescence (700-850 nm) from a modified microscope light source on to the surgical field and passage of ICG fluorescence (780-950 nm) from the surgical field, back into the optical path of the microscope was used to detect the completeness of aneurysmal clipping Incomplete clipping in three patients (1 female and 2 males) with unruptured complicated aneurysms was detected using indocyanine green video angiography. There were no adverse effects after injection of indocyanine green. The completeness of clipping was inadequately detected by Doppler ultrasound miniprobe and rigid endoscopy and was thus complemented by indocyanine green video angiography. The operative microscope-integrated ICG video angiography as a new intraoperative method for detecting vascular flow, was found to be quick, reliable, cost-effective and possibly a substitute or adjunct for Doppler ultrasonography or intraoperative DSA, which is presently the gold standard. The simplicity of the method, the speed with which the investigation can be performed, the quality of the images, and the outcome of surgical procedures have all reduced the need for angiography. This technique may be useful during routine aneurysm surgery as an independent form of angiography and/or as an adjunct to intraoperative or postoperative DSA.


On the clinico-pathological significance of multinucleated giant neurons in the hypothalamic arcuate nucleus.
Several multinucleated giant neurons were demonstrated in the arcuate nucleus of hypothalamus in 5 of 35 autopsied patients. In the 2 male patients, these cells showed intranuclear cytoplasmic inclusions characteristic of a persistent humoro-neural feedback effect in gonadal atrophy. Presumably, they had no pathologic effect on the neuroendocrine function of the arcuate nucleus. In the remaining 3 patients, markedly obese females, multinucleated giant neurons showed dysgenetic, dysplastic features but no evidence of feedback effect. Since severe adiposity associated with giant neurons were present in only these 3 patients, the question of a special form of hypothalamic obesity arises. Likewise, neuronal hypertrophy of the pars subventricularis of the arcuate nucleus, as demonstrated in anorexia nervosa [Hart 1971], suggests a possible participation of this nucleus in the regulation of nutrition and of body weight. Until now, it has been attributed to the ventromedial nucleus and to the lateral portions of the hypothalamus. This appears to support the proposed interpretation in our cases.


Management of peritoneal tear during endoscopic extraperitoneal inguinal hernioplasty.
Peritoneal tear during endoscopic extraperitoneal inguinal hernioplasty (TEP) results in pneumoperitoneum and loss of extraperitoneal space. To avoid bowel adhesions, internal herniation, and mesh migration, closure of the peritoneal opening is preferred. The present study was conducted to evaluate the efficacy of various operative techniques for the closure of peritoneal laceration. Between April 2000 and May 2001, 100 consecutive patients undergoing 123 TEPs were recruited for the present study. The incidence of peritoneal tear and techniques for the closure of peritoneal opening were documented. Operative time and postoperative morbidity were compared among groups for which different closure methods of peritoneal laceration were used. The incidence of peritoneal tear was 47%. The mean operative times of unilateral TEPs with and without peritoneal laceration were 66 min and 53 min, respectively (p<0.05). Techniques for the closure of the peritoneal opening included endoscopic stapling (n = 12), endoscopic suturing (n = 14), and pretied suture loop ligation (n = 21). The mean operative times for unilateral TEPs with endoscopic stapling, pretied suture loop ligation, and endoscopic suturing of peritoneal tear were 53, 64, and 82 min, respectively (p<0.05). Comparison of postoperative morbidity showed no significant differences among the three groups. Peritoneal tear is a frequent and challenging intraoperative event during TEP. Its occurrence significantly prolongs the length of operation. Endoscopic stapling and pretied suture loop ligation are safe and quick techniques for the closure of peritoneal tear during TEP.


The risk of endophthalmitis following intravitreal triamcinolone injection in the DRCRnet and SCORE clinical trials.
To report the incidence of endophthalmitis following intravitreal injection using a standardized injection procedure. Two randomized clinical trials. Nonpreserved intravitreal triamcinolone acetonide in prefilled syringes (Allergan, Inc, Irvine, California, USA) was injected intravitreally in the Diabetic Retinopathy Clinical Research Network (DRCR net) and the Standard Care vs COrticosteroid for REtinal Vein Occlusion (SCORE) clinical trials. The standardized injection procedure did not include the use of topical antibiotics during the days prior to the injection. As of December 31, 2006, 1,378 intravitreal injections (538 eyes) have been administered in the Diabetic Retinopathy Clinical Research Network Diabetic Macular Edema trial and 631 injections (301 eyes) in Standard Care vs COrticosteroid for REtinal Vein Occlusion. There was one case of endophthalmitis in the 2,009 injections to date (0.05%, 95% confidence interval 0.001% to 0.277%). A low rate of endophthalmitis is achievable using a standardized procedure for intravitreal injection without prescribing antibiotic prophylaxis on the days prior to the injection.


Primers on molecular pathways - lipoxygenases: their role as an oncogenic pathway in pancreatic cancer.
Different evidence supports a functional role of enzymes involved in lipid metabolic pathways, such as lipoxygenases (LOXs) and their metabolite derivatives, in carcinogenesis. LOX enzymes catalyze the dioxygenation of arachidonic acid into hydroxyperoxyeicosatetraenoic acids, which is followed by their conversion to their corresponding eicosanoids as hydroxyeicosatetraenoic acids, leukotrienes, lipoxins and hepoxilins, which in turn act as cellular messengers. Subcellular LOX enzyme localization varies according to the LOX and cellular type regulating different cell functions. LOX enzymes or their products may exert their biological effects in different modes, either intracellular or in other cells. Numerous clinical studies on expression of LOXs in human tumors as well as in animal models indicate different roles of distinct LOX isoforms in carcinogenesis. In fact, different LOXs exhibit either protumorigenic or antitumorigenic activities and modulate the tumor response in a tissue-specific manner. Moreover, the LOX pathways are involved in the spread and metastasis of several cancers, including pancreas, through the activation of several cellular signaling pathways which modify gene expression affecting cellular proliferation, survival, migration and extracellular matrix production. In this review we focus on the important role and different mechanisms of action of LOX pathways in the regulation of pancreatic cancer initiation and progression. A novel approach for pancreatic cancer chemoprevention would involve targeting LOX activities, alone or in combination with other pathways as a major anticancer strategy.


A recoverable enzymatic microgel based on biomolecular recognition.
The enzyme beta-galactosidase has been immobilized through incorporation into a selectively soluble microgel, prepared from DNA, biotinylated peptide nucleic acid (PNA), and the protein avidin. The enzyme was conjugated to avidin, allowing it to be integrated directly into the microgel network. Efficient hydrolysis of a small-molecule substrate occurred at 37 degrees , but cooling and centrifuging led to precipitation of the microgels and product separation. The microgels were then reconstituted by adding fresh buffer and shaking. The enzymatic activity was completely recovered through repeated cycles. This method should be generalizable to a wide variety of other enzymes and substrates.


Treatment of high-risk acute lymphoblastic leukemia in children using the AL851 and ALHR88 protocols: a report from the Kyushu-Yamaguchi Children's Cancer Study Group in Japan.
A total of 125 children, who were diagnosed as having high-risk acute lymphoblastic leukemia (ALL), were treated with two consecutive protocols designated as AL851 (1985-1988) and ALHR88 (1988-1990). All patients received induction therapy consisting of vincristine (VCR), prednisolone (PSL), daunorubicin (DNR), and I-asparaginase (I-Asp). In the ALHR88 protocol, the patients whose blasts in the bone marrow (BM) were > or = 25% on day 14 of induction therapy and who were classified into T-cell type received additional cytosine arabinoside (AraC). After consolidation with intermediate-dose methotrexate (MTX), reinduction therapy including VCR, dexamethasone, and adriamycin followed by high-dose AraC was done for all patients. Intrathecal MTX and 24Gy of cranial irradiation were used to prevent central nervous system leukemia. A maintenance therapy consisting of 6-mercaptopurine, cyclophosphamide, MTX, DNR, VCR, and AraC was administered for 3 years after achieving a complete remission (CR). CR was achieved in 51/55 (92.7%) for AL851 and 68/70 (97.1%) for ALHR88. The 5-year event-free survival rates were 49.1 +/- 6.7% in AL851 and 62.5 +/- 6.1% in ALHR88. The factors related to a poor prognosis were a high initial leukocyte count of greater than 50 x 10(9)/L (P < 0.001), an L2 morphology of leukemic cells by FAB classification (P = 0.009), the chromosomal abnormality (P = 0.004) and high residual leukemic cells in BM (> or = 25%) on day 14 of induction therapy (P < 0.001). Taking these factors into consideration, more intensive protocols were started in 1990 for the patients with high-risk ALL.


Neuroligins and Neurodevelopmental Disorders: X-Linked Genetics.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that results in social-communication impairments, as well as restricted and repetitive behaviors. Moreover, ASD is more prevalent in males, with a male to female ratio of 4 to 1. Although the underlying etiology of ASD is generally unknown, recent advances in genome sequencing have facilitated the identification of a host of associated genes. Among these, synaptic proteins such as cell adhesion molecules have been strongly linked with ASD. Interestingly, many large genome sequencing studies exclude sex chromosomes, which leads to a shift in focus toward autosomal genes as targets for ASD research. However, there are many genes on the X chromosome that encode synaptic proteins, including strong candidate genes. Here, we review findings regarding two members of the neuroligin (NLGN) family of postsynaptic adhesion molecules, NLGN3 and NLGN4. Neuroligins have multiple isoforms (NLGN1-4), which are both autosomal and sex-linked. The sex-linked genes, NLGN3 and NLGN4, are both on the X chromosome and were among the first few genes to be linked with ASD and intellectual disability (ID). In addition, there is a less studied human neuroligin on the Y chromosome, NLGN4Y, which forms an X-Y pair with NLGN4X. We will discuss recent findings of these neuroligin isoforms regarding function at the synapse in both rodent models and human-derived differentiated neurons, and highlight the exciting challenges moving forward to a better understanding of ASD/ID.


DMPP-evoked increases in postganglionic sympathetic nerve activity and blood pressure occurs by two mechanisms in the rat.
1. Intravenous administration of the ganglionic nicotinic receptor agonist DMPP (1,1-dimethyl-4-phenylpiperazinium iodide) into urethane-anaesthetized rats evoked dose-dependent increases in mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). 2. The ganglionic nicotinic receptor antagonists pentolinium and hexamethonium either alone or combined did not inhibit the increase in RSNA and MAP evoked by 50 to 200 micrograms kg-1 doses of DMPP. The increase in renal sympathetic nerve activity evoked by DMPP occurred as a brief burst in firing. 3. The increase in MAP, but not RSNA, evoked by DMPP in the presence of pentolinium was inhibited by the selective alpha 1-adrenergic receptor antagonist prazosin. 4. The non-selective alpha-adrenoceptor and NPY receptor antagonist benextramine also inhibited the increase in MAP without inhibiting the increase in RSNA. Surprisingly, the combination of benextramine and pentolinium, or benextramine and hexamethonium, completely blocked the DMPP-evoked increase in RSNA and thus the increase in MAP. 5. The uptake1 antagonist desipramine combined with pentolinium did not affect the DMPP-evoked increases in MAP or RSNA when compared to the responses evoked in the presence of pentolinium alone. 6. Adding the selective M1 muscarinic receptor antagonist telenzepine to pentolinium and prazosin did not inhibit the increase in RSNA evoked by a 100 micrograms kg-1 dose of DMPP. 7. While the DMPP-evoked increase in MAP in the presence of ganglionic nicotinic receptor antagonists is primarily dependent upon activation of alpha 1-adrenoceptors, the increase in RSNA occurs via activation of ganglionic nicotinic receptors and activation of a mechanism susceptible to blockade by benextramine.


Chronic amphotericin B nephrotoxicity in the rat: protective effect of calcium channel blockade.
Amphotericin B is used despite predictable nephrotoxicity because it remains the most efficacious agent currently available for systemic fungal infections. It has been previously shown that calcium channel blockade prevents renal vasoconstriction and blunts the fall in glomerular filtration rate during acute amphotericin B infusion in the rat. Therefore, the effect of cotreatment with diltiazem on nephrotoxicity during chronic daily amphotericin therapy in rats was studied. Rats were given diltiazem (45 mg/kg, 1 h before and 1 h after amphotericin) or vehicle by gastric tube; and amphotericin B (5 mg/kg/day i.p.) for 10 days. Control rats received corresponding vehicles by gastric tube and daily i.p. infection. Renal function was determined 24 h after the last dose of amphotericin or vehicle. Serum creatinine rose significantly in rats receiving amphotericin alone (initial versus final, 0.50 +/- 0.07 versus 1.09 +/- 0.20 mg/dL; P less than 0.05) but not with amphotericin plus diltiazem (0.54 +/- 0.11 versus 0.84 +/- 0.23 mg/dL; P was not significant). Amphotericin rats had a marked decrease in glomerular filtration rate (amphotericin versus control, 0.28 +/- 0.04 versus 1.23 +/- 0.08 mL/min/g kidney wt; P less than 0.05) and renal plasma flow (1.63 +/- 0.19 versus 3.50 +/- 0.40 mL/min/g kidney wt; P less than 0.05). These adverse renal hemodynamic effects were prevented by cotreatment with diltiazem (amphotericin plus diltiazem; glomerular filtration rate, 0.82 +/- 0.18 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control; renal plasma flow, 3.24 +/- 0.63 mL/min/g kidney wt; P less than 0.05 versus amphotericin; P was not significant versus control).(ABSTRACT TRUNCATED AT 250 WORDS)


Light bullets in moiré lattices.
We predict that photonic moiré lattices produced by two mutually twisted periodic sublattices in a medium with Kerr nonlinearity can support stable three-dimensional (3D) light bullets localized in both space and time. The stability of light bullets and their properties are closely connected with the properties of linear spatial eigenmodes of moiré lattices that undergo localization-delocalization transition (LDT) upon the increase of the depth of one of the sublattices forming the moiré lattice, but only for twist angles corresponding to incommensurate, aperiodic moiré structures. Above the LDT threshold, such incommensurate moiré lattices support stable light bullets without an energy threshold. In contrast, commensurate-or periodic-moiré lattices arising at Pythagorean twist angles, whose eigenmodes are delocalized Bloch waves, can support stable light bullets only above a certain energy threshold. Moiré lattices below the LDT threshold cannot support stable light bullets for our parameters. Our results illustrate that the periodicity/aperiodicity of the underlying lattice is a crucial factor in determining the stability properties of the nonlinear 3D states.


A MecA paralog, YpbH, binds ClpC, affecting both competence and sporulation.
ComK, the master regulator of competence, is degraded by the general stress-related protease ClpCP but must be targeted to this protease by binding to the adapter protein MecA. The genome of Bacillus subtilis contains a paralog of mecA, ypbH. We show in the present study that YpbH, like MecA, binds ClpC and that its elimination or overproduction affects competence and sporulation.


Sexual abuse in irritable bowel syndrome: to ask or not to ask -- that is the question.
Irritable bowel syndrome (IBS) is a common and costly disorder in Canada. The paucity of medical treatment underscores the importance of examining every element of the management approach. Data exist supporting an increased prevalence of abuse among individuals with IBS. Importantly, the pathophysiology underlying the link between abuse and IBS is increasingly understood. Treatment recommendations by opinion leaders support an abuse inquiry. However, many clinicians view abuse inquiry as an ethical dilemma. Canadian gastroenterologists were surveyed to determine current practice patterns and to identify barriers to inquiry. Barriers cited by clinicians were explored within an ethical context. Abuse inquiry is not universally practised in Canada. Fifty-four per cent of the membership of Canadian Association of Gastroenterologists responded to the survey. They reported inquiring into abuse histories in approximately 50% of patients with IBS. The frequency of inquiry declined when male patients were considered. The primal barriers cited were time constraints (25%), personal comfort with abuse issues (25%) and lack of resources for addressing the abuse (33%). Importantly, only a minority (10%), cited abuse history as irrelevant to the management of the patient. Physicians identify significant barriers to pursuing an inquiry into abuse. However, a minority cited 'clinical irrelevance' as a primal barrier, the implicit statement being that the abuse history has clinical relevance. This view is consistent with opinion leaders and published treatment recommendations. Therefore, by not inquiring into the abuse history, physicians are not fulfilling their ethical responsibility to the patient. Physicians need to resolve their barriers to inquiry. Furthermore, they need to familiarize themselves with treatment recommendations and include this review in their consultation.


STIMPY mediates cytokinin signaling during shoot meristem establishment in Arabidopsis seedlings.
The establishment of the primary meristems through proliferation after germination is essential for plant post-embryonic development. Cytokinins have long been considered a key regulator of plant cell division. Here we show that cytokinins are essential for early seedling development of Arabidopsis. Loss of cytokinin perception leads to a complete failure of meristem establishment and growth arrest after germination. We also present evidence that cytokinin signaling is involved in activation of the homeobox gene STIMPY (STIP or WOX9) expression in meristematic tissues, which is essential for maintaining the meristematic fate. Cytokinin-independent STIP expression is able to partially compensate for the shoot apical meristem growth defects in mutants that cannot sense cytokinin. These findings identify a new branch of the cytokinin signaling network, linking cytokinin to the process of meristem and seedling establishment.


Scaffold percolative efficiency: in vitro evaluation of the structural criterion for electrospun mats.
Fibrous scaffolds of engineered structures can be chosen as promising porous environments when an approved criterion validates their applicability for a specific medical purpose. For such biomaterials, this paper sought to investigate various structural characteristics in order to determine whether they are appropriate descriptors. A number of poly(3-hydroxybutyrate) scaffolds were electrospun; each of which possessed a distinguished architecture when their material and processing conditions were altered. Subsequent culture of mouse fibroblast cells (L929) was carried out to evaluate the cells viability on each scaffold after their attachment for 24 h and proliferation for 48 and 72 h. The scaffolds' porosity, pores number, pores size and distribution were quantified and none could establish a relationship with the viability results. Virtual reconstruction of the mats introduced an authentic criterion, "Scaffold Percolative Efficiency" (SPE), with which the above descriptors were addressed collectively. It was hypothesized to be able to quantify the efficacy of fibrous scaffolds by considering the integration of porosity and interconnectivity of the pores. There was a correlation of 80% as a good agreement between the SPE values and the spectrophotometer absorbance of viable cells; a viability of more than 350% in comparison to that of the controls.


Molecular mechanisms of protein kinase C-induced apoptosis in prostate cancer cells.
Protein kinase C (PKC) isozymes, a family of serine-threonine kinases, are important regulators of cell proliferation and malignant transformation. Phorbol esters, the prototype PKC activators, cause PKC translocation to the plasma membrane in prostate cancer cells, and trigger an apoptotic response. Studies in recent years have determined that each member of the PKC family exerts different effects on apoptotic or survival pathways. PKCdelta, one of the novel PKCs, is a key player of the apoptotic response via the activation of the p38 MAPK pathway. Studies using RNAi revealed that depletion of PKCdelta totally abolishes the apoptotic effect of the phorbol ester PMA. Activation of the classical PKCalpha promotes the dephosphorylation and inactivation of the survival kinase Akt. Studies have assigned a pro-survival role to PKCepsilon, but the function of this PKC isozyme remains controversial. Recently, it has been determined that the PKC apoptotic effect in androgen-dependent prostate cancer cells is mediated by the autocrine secretion of death factors. PKCdelta stimulates the release of TNFalpha from the plasma membrane, and blockade of TNFalpha secretion or TNFalpha receptors abrogates the apoptotic response of PMA. Molecular analysis indicates the requirement of the extrinsic apoptotic cascade via the activation of death receptors and caspase-8. Dissecting the pathways downstream of PKC isozymes represents a major challenge to understanding the molecular basis of phorbol ester-induced apoptosis.


Distinct Homologous and Variant-Specific Memory B-Cell and Antibody Response Over Time After Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccination.
The durability of protective humoral immunity after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection is largely dependent on the generation and persistence of antigen-specific isotype-switched memory B cells (MBCs) and long-lived plasma cells that reside in the bone marrow and secrete high-affinity neutralizing antibodies. The reactivity of vaccine-induced MBCs to emerging clinically significant SARS-CoV-2 variants of concern (VoCs) is largely unknown. In a longitudinal cohort study (up to 6 months following coronavirus disease 2019 messenger RNA vaccination), we measured MBCs in concert with other functional antibody measures. We found statistically significant differences between the frequencies of MBCs responding to homologous and VoC (Beta, Gamma, and Delta) receptor-binding domains after vaccination that persisted over time. In concert with a waning antibody response, the reduced MBC response to VoCs could translate to a weaker subsequent recall immune response and increased susceptibility to the emerging SARS-CoV-2 variant strains after vaccination.


Evolutionary insights into DNA methylation in insects.
Epigenetic information affects gene function and plays a critical role in development. DNA methylation is one of the most widespread epigenetic marks and has been linked to developmental plasticity in insects. Here, we review the patterns and functions of DNA methylation in insects. We specifically focus on how the application of an evolutionary framework has led to important insights into the role of DNA methylation. We discuss the importance of evolutionary variation in DNA methylation among insect taxa and show how comparative analyses have revealed conservation in targets of DNA methylation. We then show how the distribution of DNA methylation in insect genomes has been linked to evolutionary conserved patterns of histone modifications and variants. We conclude by discussing how the evolutionary conservation and variability of DNA methylation in insects can provide insight into the function of DNA methylation across eukaryotic systems.


Tracheo-innominate fistula formation; a rare complication of tracheostomy.
Fistula formation between trachea and the innominate artery is a life-threatening complication of tracheostomy. The overall incidence of tracheo-innominate artery fistula (TIF) has been reported to be 0.3- 0.7%. Several such cases occur in the first three weeks after tracheostomy and its hallmark is massive arterial bleeding either through or around the tracheostomy site. Mechanisms of fistula formation include mucosal necrosis due to pressure exerted by the cuff of the tracheostomy tube, high-cuff pressure, abnormally high innominate artery, low-placed tracheostomy (4 tracheal ring or below) and excessive head movement. Immediate surgical attention is the key to managing this fatal complication. We present herein patient who developed TIF and died as a consequence of massive haemorrhage into the tracheobronchial tree and asphyxia. It is a rare case and to our knowledge no case of TIF or any case series concerning this rare complication has recently been reported from Pakistan.


[The use of molecular biology in the modeling of Pseudomonas aeruginosa strains recovered from nosocomial infections].
Different methods of molecular typing (ribotyping, genomic DNA RFLP and RAPD) were tested on Pseudomonas aeruginosa strains isolated in Polish hospitals in order to elaborate a reliable typing scheme for epidemiological investigations. The combined RAPD analysis with the use of two different primers, RAPD-4 and RAPD-7, was found to have the highest discriminatory power which considering also the easiness and low time-consumption has suggested its high usefulness in studies of outbreaks caused by P. aeruginosa. Ribotyping was shown to be the least discriminatory, however, especially with the use of the PvuII restriction enzyme, this method can be very useful in revealing the genetic structure of P. aeruginosa populations persisting in hospital environments over longer periods. Clonal relations within populations of strains isolated in four different hospitals were revealed. In two of the hospitals P. aeruginosa populations demonstrated a very high diversity which suggested that infections had been caused by strains of different origins, probably introduced from other environments. P. aeruginosa strains from two remaining hospitals were found to form some clonally related clusters what revealed that in these hospitals epidemic strains of this microorganism have been circulating for prolonged periods and infecting predisposed patients.


A PCR-based method to amplify DNA with random primers: determining the chromosomal content of porcine flow-karyotype peaks by chromosome painting.
We present here a new PCR-based technique that allows the production of several micrograms of DNA from only 300 flow-sorted chromosomes. During the first two PCR cycles, the annealing temperature is decreased to 30 degrees C, and numerous random loci are amplified under nonspecific conditions. As demonstrated here for pig chromosomes 1 and 18, the PCR products may be used to identify the chromosomal content of the flow-karyotype peaks of any species by fluorescence in situ hybridization.


Comparative Analysis between Ecotoxicity of Nitrogen-, Phosphorus-, and Potassium-Based Fertilizers and Their Active Ingredients.
This study aimed to analyze the ecotoxicity of nitrogen-, phosphorus-, and potassium-based compounds to organisms of two different trophic levels in order to compare the toxic effect between high-purity substances and these substances as components of fertilizers. Dilutions were made with the fertilizers' potassium chloride, potassium nitrate, superphosphate, urea, and their equivalent reagents, to conduct assays to establish the acute lethal concentration for half of the population (LC50). Ten individuals of the benthic snail Biomphalaria glabrata and the fish Danio rerio were exposed to each concentration of tested compounds. As a result, the toxicity levels of potassium chloride, potassium nitrate, and urea were obtained for B. glabrata and D. rerio, with the fish being more susceptible to potassium chloride in the fertilizer and the snail to potassium nitrate and urea, in both commercial and reagent forms. Regarding superphosphate, no significant toxicity was found. This study concluded that among the tested substances, KNO₃ and KCl were the most toxic substances and urea the least toxic. It was not possible to establish the most sensitive species since, for KCl, the fish were more susceptible to the fertilizer and the snail to the reagent, while for KNO₃ the opposite was observed.


Bipolar disorder and identity. Systematic review.
The article was written with the intention of filling the gap in the Polish psychiatric literature, which has not yet found room for the analysis of the phenomenon of bipolar disorder (BD) in terms of consequences that it may have for identity of people diagnosed with it. In order to do that, taking into account absence of the research in Poland, an attempt was made to find all previous reports on this subject in English-language professional journals and monographs. As a result, a detailed description with commentaries was made on five thorough studies of essentially qualitative nature. Although the .identity' was operationalized a little differently in each of them, it addressed each time the question: "Who am I?", both in phenomenological terms, most often manifested in the loss of a sense of continuity, and cognitive terms, associated with the key elements of self-image. The presented studies revealed a number of threats to identity, more or less specific for BD. The nature of these studies does not allow the generalization of their results, nor answer the question of a scale of the phenomenon. On the other hand, the relative similarity of these results reveals previously overlooked difficulties, potentially frequent and important to more holistic understanding and therapy of people with BD, for which the implications have been summarized in the final part of the text.


Michael additions versus cycloaddition condensations with ethyl nitroacetate and electron-deficient olefins.
Ethyl nitroacetate (1) reacts with electron-poor olefins in the presence of a base to give either the Michael adducts 3 or the isoxazoline cycloadducts 4, resulting from water elimination. The proportions of the two products depend on the reaction conditions and change in the course of the process. Kinetic profiles for the two reactions show that the cycloaddition-condensations require long induction times that dramatically decrease upon addition of a copper salt to the catalytic system: the drops in the induction time cause increases in the proportion of cycloadducts 4, which are often the sole reaction products. This is the first report on the selective formation of products 3 and 4 from primary nitro compounds through modulation of the catalytic system.


Enhancing pressure ulcer prevention using wound dressings: what are the modes of action?
Recent clinical research has generated interest in the use of sacral wound dressings as preventive devices for patients at risk of ulceration. This study was conducted to identify the modes of action through which dressings can add to pressure ulcer prevention, for example, shear and friction force redistribution and pressure distribution. Bench testing was performed using nine commercially available dressings. The use of dressings can reduce the amplitude of shear stress and friction reaching the skin of patients at risk. They can also effectively redirect these forces to wider areas which minimises the mechanical loads upon skeletal prominences. Dressings can redistribute pressure based upon their effective Poisson ratio and larger deflection areas, providing greater load redistribution.


[Direct and reverse transport of RNA in a system of isolated HeLa cell nuclei].
In a system containing isolated HeLa cell nuclei the release of RNA from the nuclei may be paralleled with the antagonistic process, i. e., RNA translocation into the nuclei. The RNA release from the nuclei depends on incubation time, pH, Mg2+ and nucleoside triphosphate concentration. The rate of reverse transport depends on pH, size of RNA to be translocated and the physiological state of the nuclear membrane. Low molecular weight RNAs (less than 10 S) are translocated into the nuclei most effectively. The nuclei of synchronized HeLa cells in the G1-period are more "permeable" for translocated RNA as compared with the S-phase HeLa cell nuclei.


Investigating the relationship between the dimensions of mindfulness and maternal attachment to the fetus during pregnancy.
Maternal attachment to the fetus is a term used to describe the emotional relationship between mother and fetus. This emotional connection increases during pregnancy and is reflected in her feelings, perceptions, and behaviors. Mindfulness is important as one of the factors affecting the mental health of people during pregnancy. Therefore, the present study was conducted to determine the relationship between the dimensions of mindfulness and maternal attachment to the fetus during pregnancy. The present study was performed on 500 pregnant mothers referred to health centers affiliated to Isfahan University of Medical Sciences. The samples were entered into the study by available sampling method and if they had inclusion criteria and no exclusion criteria. The research instruments were the Fetal Attachment Questionnaire and the Bauer Mindfulness Questionnaire. The collected data were analyzed by SPSS software version 22. The results of the data showed that there was no significant relationship between the overall score of mindfulness and the overall score of maternal attachment to the fetus (P = 0.62). While from the dimensions of mindfulness such as "action with awareness" there was a significant negative relationship (P = 0.03) with maternal attachment to the fetus and a significant positive relationship "observation" with maternal attachment to the fetus (P = 0.03). According to the results of this study, there is a relationship between maternal attachment to the fetus during pregnancy and a number of dimensions of mindfulness. For this purpose, since mindfulness can increase the mother's interactions with the fetus, and this interaction begins during pregnancy and with the mother's attachment to the fetus, it is important to pay attention to this.


Fanconi's anaemia associated with multicentric Bowen's disease and decreased NK cytotoxicity.
We report a patient with Fanconi's anaemia and multiple lesions of vulvo-anal Bowen's disease. She was thrombocytopenic and lymphopenic, and NK-mediated cytotoxicity was undetectable. The vulvar lesions did not contain papillomavirus DNA. In vitro studies showed a possible benefit from acitretin treatment on bone marrow stem cells. However, low-dose acitretin given for 14 months did not prevent the development of an anal squamous carcinoma. Acitretin therapy was, however, associated with a sustained rise in the platelet count.


A systematic review of the biological mechanisms linking physical activity and breast cancer.
Epidemiological evidence has shown that leisure-time physical activity and structured exercise before and after breast cancer diagnosis contribute to reducing the risk of breast cancer recurrence and mortality. Thus, in this review, we aimed to summarize the physical activity-dependent regulation of systemic factors to understand the biological and molecular mechanisms involved in the initiation, progression, and survival of breast cancer. We systematically reviewed the studies on 1) the relationship between physical activity and the risk of breast cancer, and 2) various systemic factors induced by physical activity and exercise that are potentially linked to breast cancer outcomes. To perform this literature review, PubMed database was searched using the terms "Physical activity OR exercise" and "breast cancer", until August 5th, 2020; then, we reviewed those articles related to biological mechanisms after examining the resulting search list. There is strong evidence that physical activity reduces the risk of breast cancer, and the protective effect of physical activity on breast cancer has been achieved by long-term regulation of various circulatory factors, such as sex hormones, metabolic hormones, inflammatory factors, adipokines, and myokines. In addition, physical activity substantially alters wholebody homeostasis by affecting numerous other factors, including plasma metabolites, reactive oxygen species, and microRNAs as well as exosomes and gut microbiota profile, and thereby every cell and organ in the whole body might be ultimately affected by the biological perturbation induced by physical activity and exercise. The understanding of integrative mechanisms will enhance how physical activity can ultimately influence the risk and prognosis of various cancers, including breast cancer. Furthermore, physical activity could be considered an efficacious non-pharmacological therapy, and the promotion of physical activity is probably an effective strategy in primary cancer prevention.


Synthesis, Reverse Transcription, Replication, and Inter-Transcription of 2'-Modified Nucleic Acids with Evolved Thermophilic Polymerases: Efforts toward Multidimensional Expansion of the Central Dogma.
In the past decades, various xenobiotic nucleic acids (XNAs), including 2'-modified nucleic acids, have been developed as novel genetic materials and demonstrated great potential in synthetic biology and biotechnology. Enzymatic polymerization and replication of these artificial polymers are obviously the prerequisite to make full use of them, and DNA and RNA polymerases from different families have thus been extensively engineered for these purposes. However, the performance of engineered XNA polymerases is still far from satisfactory, especially in terms of the efficiency of synthesizing XNA with bigger lengths and the capability of directly replicating XNAs or transcribing one XNA to another. In this work, we tailored a mutant of Stoffel fragment of Taq DNA polymerase, SFM4-3, by engineering a key residue pair on the surfaces of fingers and thumb domains, and successfully obtained mutants with significantly enhanced efficiency for the synthesis of fully 2'-OMe-modified DNA with bigger lengths. Remarkably, we also found that these polymerase mutants are capable of synthesizing, reverse transcribing, and even replicating RNA and different fully 2'-modified XNAs, as well as transcribing one of these nucleic acids to another, with varied efficiencies. The application of these activities for producing DNA strands end-protected by XNA duplexes was then demonstrated. These results clearly suggest that the genetic information can be stored in and transmitted among DNA, RNA, and different 2'-modified XNAs with the assistance of polymerase mutants, and the central dogma of life can be expanded to higher dimensions via the development of XNAs together with engineering their polymerases.


Polymorphisms of IL-17 and ICAM-1 and their expression in Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is an acute inflammatory, autoimmune disorder of peripheral nervous system. Interleukin-17 (IL-17) and intercellular adhesion molecule-1 (ICAM-1) polymorphisms with higher expression levels have already been studied in many inflammatory and autoimmune diseases. However, the possible role of IL-17 and ICAM-1 polymorphisms in GBS remains unknown. Therefore, the current study investigated IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms. In this study, total 80 GBS patients and 75 normal healthy controls were included. IL-17 (His161Arg and Glu126Gly) and ICAM-1 (Gly241Arg) polymorphisms were performed using polymerase chain reaction -restriction fragment length polymorphism analysis. Further, the expression of ICAM-1 and IL-17 was determined by reverse-transcriptase PCR and enzyme-linked immunosorbent assay. IL-17 (Glu126Gly) mutant and ICAM-1 (Gly241Arg) heterozygous genotypes were strongly associated with increased risk of GBS (p < 0.016; OR = 3.706, 95% CI = 1.28-10.67; p < 0.001; OR = 4.148, 95% CI = 2.119-8.119, respectively). IL-17 and ICAM-1 genes showed significantly higher expression in GBS when compared with healthy controls. IL-17 and ICAM-1 polymorphisms showed significant association with GBS and their enhanced expressions have possible role in GBS development. IL-17 and ICAM-1 polymorphisms could be genetic markers to GBS susceptibility.


The strange case of East African annual fishes: aridification correlates with diversification for a savannah aquatic group?
Annual Nothobranchius fishes are distributed in East and Southern Africa and inhabit ephemeral pools filled during the monsoon season. Nothobranchius show extreme life-history adaptations: embryos survive by entering diapause and they are the vertebrates with the fastest maturation and the shortest lifespan. The distribution of Nothobranchius overlaps with the East Africa Rift System. The geological and paleoclimatic history of this region is known in detail: in particular, aridification of East Africa and expansion of grassland habitats started 8 Mya and three humid periods between 3 and 1 Mya are superimposed on the longer-term aridification. These climatic oscillations are thought to have shaped evolution of savannah African mammals. We reconstructed the phylogeny of Nothobranchius and dated the different stages of diversification in relation to these paleoclimatic events. We sequenced one mitochondrial locus and five nuclear loci in 63 specimens and obtained a robust phylogeny. Nothobranchius can be divided in four geographically separated clades whose boundaries largely correspond to the East Africa Rift system. Statistical analysis of dispersal and vicariance identifies a Nilo-Sudan origin with southwards dispersion and confirmed that these four clades are the result of vicariance events In the absence of fossil Nothobranchius, molecular clock was calibrated using more distant outgroups (secondary calibration). This method estimates the age of the Nothobranchius genus to be 8.3 (6.0 - 10.7) My and the separation of the four clades 4.8 (2.7-7.0) Mya. Diversification within the clades was estimated to have started ~3 Mya and most species pairs were estimated to have an age of 0.5-1 My. The mechanism of Nothobranchius diversification was allopatric and driven by geographic isolation. We propose a scenario where diversification of Nothobranchius started in rough coincidence with aridification of East Africa, establishment of grassland habitats and the appearance of the typical African bovid fauna of the savannah. Although confidence intervals for the estimated ages of the four Nothobranchius clades are quite large, this scenario is compatible with the biology of extant Nothobranchius that are critically dependent on savannah habitats. Therefore, Nothobranchius diversification might have been shaped by the same paleoclimatic events that shaped African ungulate evolution.


[In-migration and the labor market in Tijuana, Baja California].
This interpretative essay on the status of migrant workers in the Tijuana labor market sets up a theoretical framework and specifies the data sources used, including a survey of 672 families in Tijuana in 1982. To define the sphere of analysis, the author discusses demographic behavior and the evolution of the labor market in Tijuana. Within this context, an examination of the work status of migrants is conducted by comparing it to that of the native population, taking into account the characteristics of their regions of origin and factors related to that work status. It is shown that 1) migrants come from areas which are relatively more developed; 2) their work experience is directly related to the nature of the relative degree of development of their regions of origin; 3) there is no difference between the migrants and the native population with regard to the sectors and positions in which they are inserted; and 4) the type of migration tends to be similar to migration taking place in industrialized countries, rather than that characterizing developing countries.


Nonsurgical Management of Osteoarthritis of the Knee: What You Should Be Injecting Now and in the Future.
Osteoarthritis of the knee affects many Americans. With the aging of the population and increasing comorbidities (eg, obesity, diabetes, hypertension, heart disease), the use of oral or topical NSAIDs is often contraindicated. Injectable treatment options are advantageous because of the ability to decrease or avoid the unwanted systematic adverse effects of NSAIDs. Injectable treatment options for osteoarthritis of the knee go back to the 1950s, beginning with corticosteroids, which remain widely used despite concerns that they may have adverse effects on articular chondrocytes and short duration of efficacy. The recent (FDA approval in 2017) introduction of a sustained-release corticosteroid (triamcinolone acetonide extended-release) offers significantly longer benefit than standard cortisone products and with substantially lower concentration levels of chondrocyte exposure to the steroid. Hyaluronic acid was added to the options for intra-articular injection in osteoarthritis of the knee in the late 1990s and remains widely used despite some controversy over its efficacy. Although guidelines for the use of hyaluronic acid for management of osteoarthritis of the knee have varied widely, careful analysis of the data and patient's perceived efficacy indicate its continued and important role in managing osteoarthritis of the knee. Finally, the past 15 years have seen an explosion in the use of biologics including platelet-rich plasma and pluripotential (often termed stem) cells. The science behind their use and efficacy is evolving and continued study is warranted.


Möbius syndrome: evidence for a vascular etiology.
We report five infants with restricted lateral gaze, facial diplegia, feeding difficulty, and/or respiratory disorders without significant pulmonary disease. Viral studies were negative in all patients. Two children had radiologic findings that included brain-stem hypoplasia and symmetric calcification in the dorsal tectum at the junction of the midbrain and pons. Autopsy of one of these two children demonstrated capillary telangiectasia in the mesencephalon and pons. The other three children had normal computed tomographic (CT) scans. However, their autopsies revealed focal brain-stem necrosis with calcifications but without vascular malformation. We suggest that the capillary malformations in one of our patients directly resulted in a vascular-induced necrosis and the manifestation of Möbius sequence. The similarity of symmetric neuropathologic findings in the three other patients and the CT scan in the one surviving patient suggest focal hemodynamic changes restricted to the posterior circulation, indirectly supporting a vascular theory of embryopathogenesis.