Treatment strategies for isolated systolic hypertension in elderly patients.
Hypertension is a major and modifiable risk factor for cardiovascular disease. Its prevalence is rising as the result of population aging. Isolated systolic hypertension mostly occurs in older patients accounting for up to 80% of cases. The authors systematically review published studies to appraise the scientific and clinical evidence supporting the role of blood pressure control in elderly patients with isolated systolic hypertension, and to assess the influence of different drug treatment regimens on outcomes. Antihypertensive treatment of isolated systolic hypertension significantly reduces the risk of morbidity and mortality in elderly patients. Thiazide diuretics and dihydropyridine calcium-channel blockers are the primary compounds used in randomized clinical trials. These drugs can be considered as first-line agents for the management of isolated systolic hypertension. Free or fixed combination therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and calcium-channel blockers or thiazide-like diuretics should also be considered, particularly when compelling indications such as coronary artery disease, chronic kidney disease, diabetes, and congestive heart failure coexist. There is also hot scientific debate on the optimal blood pressure target to be achieved in elderly patients with isolated systolic hypertension, but current recommendations are scarcely supported by evidence.


Copper-Catalyzed Decarboxylative Radical Silylation of Redox-Active Aliphatic Carboxylic Acid Derivatives.
A decarboxylative silylation of aliphatic N-hydroxyphthalimide (NHPI) esters using Si-B reagents as silicon pronucleophiles is reported. This C(sp3 )-Si cross-coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional-group tolerance is generally excellent, and α-heteroatom-substituted substrates also participate well. This enables, for example, the synthesis of α-silylated amines starting from NHPI esters derived from α-amino acids. The new method extends the still limited number of C(sp3 )-Si cross-couplings of unactivated alkyl electrophiles.


The herd effects of infant PCV7/PCV13 sequential implementation on adult invasive pneumococcal disease, six years post implementation; a nationwide study in Israel.
Introduction of pneumococcal conjugate vaccine (PCV) has nearly eliminated vaccine-type (VT) invasive pneumococcal disease (IPD) in children, yet the reported resulting reduction of adult IPD is variable. We present the indirect impact of sequential PCV7/PCV13 implementation in Israel on adult IPD. An ongoing nationwide active surveillance was initiated on July 2009 when PCV7 was implemented (with Catch-up). PCV7 was gradually replaced by PCV13 since November 2010. Comorbidity and outcome data were collected from medical files. Incidence rates were calculated for overall and vaccine-type IPD. A total of 2579 IPD cases were diagnosed among a population of 5.0-5.5 million adults >18y (2009-2015). Incidence rates were 9.15/100,000 and 10.16/100,000 in the first and second study years, respectively. However, after PCV13 implementation, the rates decreased to 7.19 within four years, and remained stable in the two following years. Within 6years, PCV7-VT-IPD incidence decreased from 2.52 to 0.52 (79%) and PCV13-VT-IPD from 6.15 to 1.81 (71%). Concurrently, non-VT13 incidence increased from 2.99 to 5.25. Approximately 50% of all patients were adults ≥65y, in whom the decrease in PCV13-VT-IPD incidence was smaller and slower (65% vs. >80% decrease in adults <50y). Despite continued reduction in PCV13-VT-IPD, overall IPD was stable during the last two years due to serotype replacement. Yet, the significant decrease in adult IPD, six years post-PCV7/13 implementation emphasizes the importance of indirect protection in achieving overall population impact and should be considered when discussing the potential additional benefits of direct adult PCV vaccination.


Systematic review of studies on drug-delivery systems for management of temporomandibular-joint osteoarthritis.
Temporomandibular-joint osteoarthritis (TMJOA) management is a major challenge. Minimally invasive therapies (based mainly on injections) have been developed to increase local efficacy and limit adverse systemic effects. However, the requirement for repeat injections due to a short duration of action and expensive healthcare costs have pushed researchers to develop, via tissue engineering, drug-delivery systems (DDSs). In this literature systematic review, we aim to provide an overview of studies that tested DDSs on a TMJOA model. We searched on PubMed for articles published from November 1965 to March 2021 on DDSs using a TMJOA model. We highlighted the different DDSs and the active molecule employed. Route of drug administration, model type, test duration, and efficacy duration were assessed. To evaluate the quality of each study, a protocol bias was tested using QUADAS-2™. Of the 10 studies that were full text-screened, four used a poly(lactic-co-glycolic acid)-based delivery system. The other DDSs employed chitosan-based hydrogels, microneedles patches, nanostructured lipid carriers, or poloxamer micelles. Hyaluronic acid, nonsteroidal anti-inflammatory drugs, and analgesics were used as active molecules in five studies. The main way to administer DDSs was intra-articular injection and the most used model was the rat. Various DDSs and active molecules have been studied on a TMJOA model that could aid TMJOA management. Further works using longer test durations are necessary to validate these advances.


Troxerutin, a plant flavonoid, protects cells against oxidative stress-induced cell death through radical scavenging mechanism.
Troxerutin (TRX) is a flavonoid present in tea, coffee, cereal grains, various fruits and vegetables have been reported to exhibit radioprotective, antithrombotic, nephro and hepato-protective effects. A systematic study was undertaken to evaluate its free radical scavenging ability and anti-apoptotic activity in cell-free and cellular systems. TRX scavenged superoxide, nitric oxide and also other model stable radicals like 1,1-diphenyl-2-picryl-hydazyl, and 2,2'-azinobis3-ethylbenzothiazoline-6-sulfonic acid. It reacted with hydroxyl radicals, carbonate and thiocyanate anions, as evaluated by pulse radiolysis and stopped flow techniques. TRX protected different cell types (epithelial cells, fibroblasts and lymphocytes) against peroxyl radical-induced apoptosis, necrosis and mitotic death. It scavenged intracellular basal and inducible ROS levels and also restored depletion of intracellular GSH levels, suggesting that free radical scavenging ability may be responsible for the observed cytoprotection of different cell types. TRX may find application as an adjuvant in treating various diseases attributed to oxidative stress.


Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease.
First identified as a powerful vasoconstrictor, endothelin has an extremely diverse set of actions that influence homeostatic mechanisms throughout the body. Two receptor subtypes, ET(A) and ET(B), which usually have opposing actions, mediate the actions of endothelin. ET(A) receptors function to promote vasoconstriction, growth, and inflammation, whereas ET(B) receptors produce vasodilation, increases in sodium excretion, and inhibit growth and inflammation. Potent and selective receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contradictory and complicated because of the tissue-specific vasoconstrictor actions of ET(B) receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo. Considerable questions remain regarding whether ET(A)-selective or nonselective ET(A)/ET(B) receptor antagonists would be useful in a range of clinical settings.


Polyethylene Glycol Confined in SiO2-Modified Expanded Graphite as Novel Form-Stable Phase Change Materials for Thermal Energy Storage.
Form-stable phase change materials (FSPCMs) composed of poly(ethylene glycol) (PEG) encapsulated in SiO2-modified expanded graphite (EG@SiO2) were prepared and investigated for thermal energy storage behaviors. The modification of SiO2 on EG was done using a simple sol-gel method, and then the resulting EG@SiO2 was introduced to confine PEG at varying content (60-90 wt %). Surface properties (including microstructure, morphology, and functional groups), PEG adsorptivity, leakage-proof ability, and thermal energy storage of the prepared materials were thoroughly characterized and discussed. The EG@SiO2 with 15 wt % SiO2 outstandingly adsorbed PEG as compared to the pristine EG, showing up >80 wt % of PEG. As a result, PEG was well stabilized in EG@SiO2 porous network without leakage, owing to capillary force, surface tension, and hydrogen bonding interactions. The optimal 80 wt % PEG/EG@SiO2 composite possessed high crystallinity (93.5%), high thermal energy storage capacity (132.5 J/g), and excellent thermal conductivity (4.086 W/m·K). In addition, it exhibited good cycling durability after 500 repeated melting/crystallization cycles. The high thermal efficacy and inexpensiveness would make the PEG/EG@SiO2 FSPCMs suitable for scale-up applications in thermal energy storage.


Botulism in Brazil, 2000-2008: epidemiology, clinical findings and laboratorial diagnosis.
Botulism is a rare and potentially lethal illness caused by Clostridium botulinum neurotoxin. We describe the findings of a laboratorial investigation of 117 suspected cases of botulism reported to the surveillance system in Brazil from January 2000 to October 2008. Data on the number and type of samples analyzed, type of toxins identified, reporting of the number of botulism cases and transmission sources are discussed. A total of 193 clinical samples and 81 food samples were analyzed for detection and identification of the botulism neurotoxin. Among the clinical samples, 22 (11.4%) presented the toxin (nine type A, five type AB and eight with an unidentified type); in food samples, eight (9.9%) were positive for the toxin (five type A, one type AB and two with an unidentified type). Of the 38 cases of suspected botulism in Brazil, 27 were confirmed by a mouse bioassay. Laboratorial botulism diagnosis is an important procedure to elucidate cases, especially food-borne botulism, to confirm clinical diagnosis and to identify toxins in food, helping sanitary control measures.


Nitric oxide pathway presumably does not contribute to antianxiety and memory retrieval effects of losartan.
Nitric oxide (NO) and angiotensin (AT) receptors have demonstrated well-established interactions in various physiological phenomena. AT1 receptors can play a part in stress-induced activation of the hypothalamic-pituitary-adrenal axis; also, angiotensinergic neurotransmission plays a pivotal role in stress-evoked physiological responses. On the basis of the stress-modulating characteristics of NO, AT1, and AT2 receptors, the present study evaluated the roles of NO and AT1 receptors in the attenuation of stress-induced anxiety-like behaviors after administration of losartan, an AT1 antagonist. Male Wistar rats were exposed to the communication stress box, using a novel method to induce physical or emotional stress, and losartan (10 mg/kg), losartan+L-NG-nitroargininemethyl ester (L-NAME), L-NAME (1, 10, and 100 mg/kg), and normal saline-treated groups were compared. Losartan had reduced behavioral changes induced by both types of stressor and enhanced memory retrieval. Anxiety-like behaviors were significantly attenuated by administration of losartan, to a greater extent in the emotional rather than physical stress group. None of the injected dosages of L-NAME reversed the antianxiety and memory retrieval effects of losartan. Our results indicate that losartan probably improves memory retrieval and lessens anxiety-like behaviors through mechanisms other than the NO pathway.


AIDS related knowledge and behaviours among college students, Gondar, Ethiopia: a comparative study.
AIDS-related knowledge and behaviours among students at the Gondar College of Medical Sciences, Gondar, Ethiopia were evaluated based on identical surveys conducted in 1990 and 1992. One hundred three second year students provided information in 1992. Analysis indicated that 49% were engaged in sexual intercourse and only a third of these group used condom despite their improved knowledge and belief on condom compared to their previous position in 1990 (p < 0.004). On the other hand, their sexual behaviours regarding sexual contact with high risk individuals decreased compared to 1990 (p < 0.0005). Their general level of AIDS-related preventive knowledge increased over time (p < 0.002), although there was no significant difference in knowledge observed among different sexes and departments. Among the sexually active, a large proportion of students (22%) still had sexual contact with high risk individuals and only 33% of them were using safer methods. Continuing efforts, including peer education, specific health education interventions are still crucially needed to bring a positive change in sexual behaviour.


Hospital admissions for acute painful crisis in Trinidad and Tobago. Are the British Committee for Standards in Haematology (BCSH) guidelines applicable?
We observed consecutive hospital admissions for acute painful crisis (APC) among adults with Sickle Cell Disease (SCD) over a 6-month period in Trinidad and Tobago. Episodes (111) of APC resulted in 82 admissions of 59 patients. The most common site for pain was the trunk. Patients ranged in age from 17 to 53 years (median: 25). Median length of hospital stay was 4 days. Total dose of Pethidine given per admission ranged from 100 to 1650 mg (median: 525). The mean dose of morphine was 70 mg. Six (7%) of patients were readmitted within 10 days of discharge. Twenty-five (30%) of patients had chest pain at presentation of whom 10 (12%) had consolidation on chest X-ray, defining the acute chest syndrome (ACS). There was one death caused by biliary sepsis. The study revealed seemingly low opiate usage for in-hospital treatment of APC with acceptable rates of readmission. The BCSH 2003 guidelines seemed applicable apart for the choice and route of fluid for rehydration and opiate analgesia.


Potential nitrosamine formation and its prevention during biological denitrification of red beet juice.
High nitrate intake has been shown to result in an increased risk of endogenous formation of N-nitroso compounds. Certain vegetables and vegetable juices contain high concentrations of nitrate. Biological denitrification using strains of Paracoccus denitrificans (P.d.) has been proposed as effective means to reduce nitrate contents in such vegetable juices. During this bacterial denitrification process, substantial nitrite concentrations are transiently formed. This study investigated whether N-nitrosation reactions might occur. The easily nitrosatable amine morpholine was added to red beet juice at high concentration (100 ppm) during denitrification 10 different batches of red beet juice served as raw material. Each batch was submitted to denitrification in the presence and absence of ascorbic acid. In the absence of ascorbic acid, formation of N-nitrosomorpholine (NMOR) was observed in the low ppb range (0.5-8 ppb). Addition of ascorbic acid (500 mg/litre) inhibited the formation of NMOR, except for those instances where the pH was less than 6 and/or nitrate turnover was low (< 200 mg NO3-/litre/hr). Under conditions leading to high rates of nitrate turnover (> 200 mg NO3-/litre/hr), nitrosamine formation can reliably be prevented by ascorbic acid. The results show that bacterial denitrification of red beet juice high in nitrate can be accomplished without the risk of nitrosamine formation.


Validity/reliability of PHQ-9 and PHQ-2 depression scales among adults living with HIV/AIDS in western Kenya.
Depression greatly burdens sub-Saharan Africa, especially populations living with HIV/AIDS, for whom few validated depression scales exist. Patient Health Questionnaire-9 (PHQ-9), a brief dual-purpose instrument yielding DSM-IV diagnoses and severity, and PHQ-2, an ultra-brief screening tool, offer advantages in resource-constrained settings. To assess the validity/reliability of PHQ-9 and PHQ-2. Observational, two occasions 7 days apart. A total of 347 patients attending psychosocial support groups. Demographics, PHQ-9, PHQ-2, general health perception rating and CD4 count. Rates for PHQ-9 DSM-IV major depressive disorder (MDD), other depressive disorder (ODD) and any depressive disorder were 13%, 21% and 34%. Depression was associated with female gender, but not CD4. Construct validity was supported by: (1) a strong association between PHQ-9 and general health rating, (2) a single major factor with loadings exceeding 0.50, (3) item-total correlations exceeding 0.37 and (4) a pattern of item means similar to US validation studies. Four focus groups indicated culturally relevant content validity and minor modifications to the PHQ-9 instructions. Coefficient alpha was 0.78. Test-retest reliability was acceptable: (1) intraclass correlation 0.59 for PHQ-9 total score, (2) kappas 0.24, 0.25 and 0.38 for PHQ-9 MDD, ODD and any depressive disorder and (3) weighted kappa 0.53 for PHQ-9 depression severity categories. PHQ-2 > or =3 demonstrated high sensitivity (85%) and specificity (95%) for diagnosing any PHQ-9 depressive disorder (AUC, 0.97), and 91% and 77%, respectively, for diagnosing PHQ-9 MDD (AUC, 0.91). Psychometrics were also good within four gender/age (18-35, 36-61) subgroups. PHQ-9 and PHQ-2 appear valid/reliable for assessing DSM-IV depressive disorders and depression severity among adults living with HIV/AIDS in western Kenya.


18F-AlF-NOTA-Octreotide Outperforms 68Ga-DOTATATE/NOC PET in Neuroendocrine Tumor Patients: Results from a Prospective, Multicenter Study.
18F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors (NETs), given their logistic advantages. Recently, 18F-AlF-NOTA-octreotide (18F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18F-AlF-OC compared with 68Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68Ga-DOTATATE (n = 56) or 68Ga-DOTANOC (n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18F-AlF-OC and 68Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10-5). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUVmax were observed (P = 0.067), but mean tumor-to-background ratio was significantly higher with 18F-AlF-OC than with 68Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.


Effects of restraint and naltrexone on the biphasic heart rate response to morphine in rats.
The effect of several doses of morphine (0, 0.5, 2, 5 or 10 mg/kg, i.v.) on heart rate was assessed in restrained and freely-moving rats. Morphine produced a dose-dependent bradycardia followed by tachycardia. The magnitude and duration of bradycardia were greater in restrained rats, whereas the magnitude and duration of tachycardia were greater in unrestrained rats. Naltrexone (5 mg/kg) pretreatment completely blocked the biphasic heart rate response to morphine (8 mg/kg). When naltrexone was given after the bradycardic portion of the response, tachycardia declined to baseline levels. These results suggest that one or both components of the biphasic response are mediated by opioid receptors.


[Biomaterials and tissues material in the treatment of prosthetic grafts infections].
An article is presented the treatment of vascular prosthetic grafts infections. An the graft infection treated by the replacement of infected prosthesis with autogenic venous material or with venous and arterial allograft harvested from brain-dead organ donors together with multiple organ procurement is presented. Autogenous material has an ability a better healing in infected tissues and used with absorbable sutures may lead to complete recovery from vascular graft infection - a severe and often lethal complication. An article is presented the treatment of vascular prosthetic grafts infections with the use of more resistant prostheses of infection - silver coated prosthesis, prosthesis with antibiotic and polytetrafluoroethylene prostheses.


[Breast reconstruction using a rectus abdominis myocutaneous flap: analysis of 234 cases].
The pedicled rectus abdominis myocutaneous flap is a very sophisticated form of breast reconstruction. Provided the indications are carefully set out and a perfect mastery of the technique, the rate of complications is consequently very low (9 reinterventions for 234 cases: 3.8%). The authors stress one particular point which they deem important: the preliminary vascular preparation to improve arterial flow and venous drainage of the internal mammary pedicled. The high rate of good results and of patient satisfaction--84% in the reported series--makes this form of reconstruction the prime method to choose in the case of patients with different types of carcinoma and more particularly in the early stages of breast cancer or when there is a need for prophylactic mastectomy.


Assessment of the factors involving in the development of hypothyroidism in HIV-infected patients: a case-control study.
Increased prevalence of thyroid dysfunction has been reported in HIV-infected patients, and recent studies have shown hypothyroidism as the most common thyroid function abnormality in this population, especially after treatment with antiretroviral drugs (HAART). The aim of this study is to assess risk factors of hypothyroidism in HIV-infected patients in Iran. This case-control study was conducted among 15 hypothyroid (cases) and 70 euthyroid (control group) HIV-infected outpatients. Serum Free T4, Free T3, and TSH levels were measured, and data on age, sex, body mass index, opium addiction or injection of illicit drugs, duration of HIV infection and HAART, disease stage, CD4-cell count, opportunistic infection (OI) or malignancy, HCV co-infection, and drug use were collected. We found no association between hypothyroidism in HIV-infected patients and any parameters measured, and P value was not significant for receipt of HAART (0.141), CD4-cell count (0.094), duration of HIV infection (0.474), duration of HAART (0.418), HCV co-infection (0.146), OI (0.566), or receipt of rifampin (0.816). In this study, age, sex, HAART, mean CD4- cell count, duration of HIV infection, HCV co-infection, and OI were not significant risk factors of hypothyroidism in HIV-infected patients. The occurrence of hypothyroidism may be related to other factors or HIV infection itself. Therefore, hypothyroidism should be considered in all HIV-infected patients.


Incidence of bilateral testicular germ cell cancer in Denmark, 1960-84: preliminary findings.
The incidence of a second primary testicular germ cell cancer in the contralateral testicle among 2338 men with a first primary testicular germ cell cancer diagnosed in the years 1960-79 in Denmark was established in this preliminary report. The material represents 83% of the total cohort followed until 31 December 1984. The relative risk for a patient with testicular cancer to get yet another testicular cancer was studied, taking into account the histology of the first primary testicular germ cell cancer. Based on fifty-eight nonsimultaneous contralateral testicular cancer cases and 19,995 'person-years at risk', the overall relative risk of invasive germ cell cancer in the contralateral testicle following a first germ cell testicular cancer was found to be 23.3 (95% confidence interval: 18-30). Among men with nonseminoma the risk was higher (relative risk = 27.5) than among men with seminomas (relative risk = 20.1). Overall, sixty-two (2.7%) patients developed a second cancer. In four of these patients bilateral tumours occurred simultaneously.


Ethical Aspects of Human Induced Pluripotent Stem Cells and Alzheimer's Disease: Potentials and Challenges of a Seemingly Harmless Method.
Dementia currently affects more than 55 million people worldwide, and scientists predict that this number will continue to rise. The most common form is Alzheimer's disease (AD), which is triggered, among other things, by dysfunctional cells in the human brain. Stem cell research attempts to counteract neurodegenerative processes, for example by replacing or treating diseased cells. In addition to human embryonic stem cells, since the successes of Takahashi and Yamanaka in 2006, there has been an increased focus on human induced pluripotent stem cells (hiPS cells). These cells avoid ethically challenging questions about the moral status of human embryos, but there are numerous problems, such as high production costs, side effects from the reprogramming process, or a potentially new moral status. These ethical issues will be examined primarily in relation to AD. The first part will be a discussion of hiPS cells and their importance for stem cell research, after which the focus turns to AD. Based on scientific studies, the relationship between hiPS cells and AD will be outlined as well as ethical implications presented. While potential limitations of hiPS cells have been discussed by numerous authors, an ethical perspective on the link between hiPS cells and AD seems to be neglected in the scientific community. The following risk analysis aims to identify a possible research agenda. In conclusion, the focus on individuals with AD may help to adopt an ethical stance that recognizes existing limitations and constructively engages with the possibilities of research.


Apoptotic machinery diversity in multiple myeloma molecular subtypes.
Multiple myeloma (MM) is a plasma-cell (PC) malignancy that is heterogeneous in its clinical presentation and prognosis. Monoclonal gammopathy of undetermined significance (MGUS) consistently preceded development of MM. The presence of primary IgH translocations and the universal overexpression of cyclin D genes led to a molecular classification of MM patients into different disease subtypes. Since Bcl-2 family proteins determine cell fate, we analyzed a publicly available Affymetrix gene expression of 44 MGUS and 414 newly diagnosed MM patients to investigate (1) the global change of Bcl-2 family members in MM versus MGUS (2) whether the four major subtypes defined as hyperdiploid, CyclinD1, MAF, and MMSET, display specific apoptotic machineries. We showed that among the main anti-apoptotic members (Bcl-2, Bcl-xL, and Mcl-1), Mcl-1 up-regulation discriminated MM from MGUS, in agreement with the prominent role of Mcl-1 in PC differentiation. Surprisingly, the expression of multi-domain pro-apoptotic Bak and Bax were increased during the progression of MGUS to MM. The combined profile of Bcl-2, Bcl-xL, and Mcl-1 was sufficient to distinguish MM molecular groups. While specific pro-apoptotic members expression was observed for each MM subtypes, CyclinD1 subgroup, was identified as a particular entity characterized by a low expression of BH3-only (Puma, Bik, and Bad) and multi-domain pro-apoptotic members (Bax and Bak). Our analysis supports the notion that MM heterogeneity is extended to the differential expression of the Bcl-2 family content in each MM subgroup. The influence of Bcl-2 family profile in the survival of the different patient groups will be further discussed to establish the potential consequences for therapeutic interventions. Finally, the use of distinct pro-survival members in the different steps of immune responses to antigen raises also the question of whether the different Bcl-2 anti-apoptotic profile could reflect a different origin of MM cells.


Adjuvanticity of plasmid DNA encoding cytokines fused to immunoglobulin Fc domains.
Plasmid DNAs encoding cytokines enhance immune responses to vaccination in models of infectious diseases and cancer. We compared DNA adjuvants for their ability to enhance immunity against a poorly immunogenic self-antigen expressed by cancer. DNAs encoding cytokines that affect T cells [interleukin (IL)-2, IL-12, IL-15, IL-18, IL-21, and the chemokine CCL21] and antigen-presenting cells [granulocyte macrophage colony-stimulating factor (GM-CSF)] were compared in mouse models as adjuvants to enhance CD8+ T-cell responses and tumor immunity. A DNA vaccine against a self-antigen, gp100, expressed by melanoma was used in combination with DNA encoding cytokines and cytokines fused to the Fc domain of mouse IgG1 (Ig). We found that (a) cytokine DNAs generally increased CD8+ T-cell responses against gp100; (b) ligation to Fc domains further enhanced T-cell responses; (c) adjuvant effects were sensitive to timing of DNA injection; (d) the most efficacious individual adjuvants for improving tumor-free survival were IL-12/Ig, IL-15/Ig, IL-21/Ig, GM-CSF/Ig, and CCL21; and (e) combinations of IL-2/Ig+IL-12/Ig, IL-2/Ig+IL-15/Ig, IL-12/Ig+IL-15/Ig, and IL-12/Ig+IL-21/Ig were most active; and (f) increased adjuvanticity of cytokine/Ig fusion DNAs was not related to higher tissue levels or greater stability. These observations support the potential of cytokine DNA adjuvants for immunization against self-antigens expressed by cancer, the importance of timing, and the enhancement of immune responses by Fc domains through mechanisms unrelated to increased half-life.


Denial of hostility and psychopathology in the evaluation of child molestation.
We administered the Buss-Durkee Hostility Inventory (Buss & Durkee, 1957) and the Minnesota Multiphasic Personality Inventory (Hathaway & McKinley, 1967) to 82 alleged child molesters. Denial of hostility was significantly associated both with minimization of psychopathology and with denial of charges of sex offense. No subjects who denied charges acknowledged psychopathology, whereas one third of admitters acknowledged psychopathology. Our results suggest that alleged sex offenders may show complex patterns of impression management and that self-report hostility inventories are highly vulnerable to response bias.


Metabolites identification of berberine in rats using ultra-high performance liquid chromatography/quadrupole time-of-flight mass spectrometry.
Berberine (BBR), the principle component for many medicinal plants such as Coptis chinensis Franch., Phellodendron chinense Schneid., and Mahonia bealei (Fort.) Carr., possesses diverse pharmacological activities, including anti-bacterial, anti-inflammatory, antitumor, hypolipidemic and antidiabetic activities. In this study, a rapid and reliable method using a five-step strategy based on the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS), and metabolynx™ software with mass defect filter (MDF) technique was developed to investigate the metabolism of BBR. Plasma, bile, urine and feces samples were collected from rats after oral administration of BBR with a dose of 100mg/kg/day for three consecutive days and analyzed to characterize the metabolic profile of BBR. By comparing the molecular weights and MS fragmentations of the metabolites with those of the parent drug and reference standards, a total of 97 metabolites were identified, including 68 metabolites in urine, 45 metabolites in plasma, 44 metabolites in bile and 41 metabolites in feces. Demethylation, demethylenation, reduction, hydroxylation, and subsequent glucuronidation, sulfation and methylation were the major metabolic pathways of BBR in vivo.


Diphyllobothriasis: update on human cases, foci, patterns and sources of human infections and future considerations.
Diphylobothriasis is a well documented disease of humans. On a world scale new infections are reported regularly, especially from Russia and parts of Japan. Globally, new species have been discovered and the etiology of the disease may be changing. Human infections appear to be in decline but it is not clear if the sources of infection are also in decline or if public health awareness has improved. In North America there has been a decline in human cases while in South America an increase in reports from fish, especially salmonids suggests high levels in these fish species. The history of human infections of Diphyllobothrium latum is primarily associated with the consumption of the northern circumpolar distributed pike and percids and is often considered a parasite of humans only. Indeed some researchers believe that D. latum was introduced to North America by northern European immigrants. The more benign human infections of D. dendriticum appears to be primarily associated with salmonids and coregonid fishes and fish eating birds. Although the early cases of diphyllobothriasis in the 1930s in North America came from fish originating in Lake Winnipeg, Manitoba, there was general belief that it was declining in fish populations and therefore of little significance to humans in the area. However, high levels of a plerocercoid in the flesh of walleyes and pike led to rejection of commercially harvested walleye and pike in Manitoba and northern Ontario, Canada, and a financial loss to Aboriginal fishers. D. latum is widely distributed in fishes of Manitoba and is infective to humans where it is not pathogenic and has a life span up to 4.5 years. The distribution and potential infection routes has not changed in a century and is still well established in natural hosts in the boreal regions of North America. Evidence is building for an old pre-European presence in North America, involving the Beringian land bridge and later involvement of susceptible hosts (northern European immigrants).


The "learning curve" in videoscopic Heller myotomy.
In the early 1990s, minimally invasive videoscopy was applied to numerous operations. After undertaking more than 50 "open" Heller myotomies, our experience with videoscopic Heller myotomy began in 1992. We sought to determine whether the outcome following videoscopic Heller myotomy is influenced by surgeon experience. Seventy-eight patients with severe dysphagia secondary to achalasia underwent videoscopic Heller myotomy between 1992 and 1998. Intraoperative endoscopy was utilized to ensure adequate myotomy in all patients. Patients were stratified into 3 groups: the first 25 patients (group I), the second 25 patients (group II), and the last 28 patients (group III). Clinical outcome was based on length of stay, incidence of intraoperative complications, conversion to an 'open' procedure, and postoperative symptoms. Perioperative complications occurred in 20% of patients in group I compared with 8% and 12% in groups II and III, respectively (P = NS). Only 3 patients required conversion to an 'open' procedure, all in group I (P <0 .05). Symptomatic improvement was achieved in 80% of patients in group I, 100% in group II, and 96% in group III (P < 0.05). Significant reductions in conversions to open, length of stay, and postoperative symptoms were seen after 20 myotomies were undertaken. Outcome following videoscopic Heller myotomy, like other videoscopic operations, improves as surgeons progress along the videoscopic "learning curve." After approximately 20 videoscopic Heller myotomies, surgeons can expect fewer conversions to open procedures, shorter hospital stays, and better symptomatic relief.


[Comparative studies of methods of salmonella enrichment (author's transl)].
Eight different methods of salmonella enrichment were compared in two series of experiments involving 100 samples of whole-egg powder and 80 samples of frozen whole liquid egg, respectively. 66 out of a total of 100 samples of whole-egg powder had been artificially infected with varying numbers of S. typhi-murium; 60 out of 80 samples of frozen whole liquid egg were found to be naturally infected with various salmonella species. 3 of the 8 methods (Table 1) were compared within an international collaborative study with 14 laboratories in 11 countries participating. A reduction of the pre-enrichment period from 18 to 6 hours and of volumes used in pre-enrichment and selective enrichment from 10 and 100 ml, respectively to 1 and 10 ml, respectively were found to have adverse influence upon the result of isolations, in particular in the case of weakly infected samples. In contrast, extended incubation over 48 hours as well as preparation of two sub-cultures on solid selective media following incubation of enrichment cultures over 18-24 hours and 42-48 hours, respectively always resulted in a certain increase of salmonella yield which, however, exhibited gradual differences for the individual methods examined. Preparation of a 2nd sub-culture meant, in particular, a decisive improvement of the result of isolations from artificially infected samples if selenite-cystine enrichment volumes were 10 and 100 ml, respectively. The best results could be obtained by means of the following methods of enrichment: Pre-enrichment of material in buffered peptone water at 37 degrees C over 18 hours; pipetting of 10 ml inoculated and incubated pre-enriched material into 100 ml selenite-cystine or tetrathionate enrichment medium according to MULLER-KAUFFMANN; onward incubation of the enrichment culture at 43 degrees C over 48 hours; and preparation of sub-cultures on solid selective media after 24 and 48 hours. The method using tetrathionate enrichment medium was found to be most expensive, results, however, were the most consistent ones.


Congenital mitral stenosis by multimodality cardiac imaging.
This vignette illustrates a classic case of congenital mitral stenosis (Ruckman-VanPraagh type 1) presenting in adulthood and demonstrates the benefits of multimodality cardiac imaging prior to successful surgical intervention.


The effect of high protein diet on the regulatory properties of AMP deaminase from chicken liver.
Feeding high protein diet for 5 days caused a 3,5-fold and 2-fold increase of the activity of xanthine dehydrogenase (EC 22.214.171.124) and 5-nucleotidase (EC 126.96.36.199) respectively, in chicken liver. Six hours after feeding the high protein diet there was no change in either enzyme activity although a 3-fold increase in the level of serum uric acid was observed. High protein diet considerably decreased the activity of AMP deaminase at low, but not at high substrate concentration. The activity ratio, measured at 10.0 and 0.16 mM AMP increased from 14:1 (low protein diet) to 23:1 and 24:1 after 6 h and 5 days of high protein diet, respectively. It has been suggested that feeding birds a high protein diet may cause transformation of liver AMP deaminase (EC 184.108.40.206) from a low Km form toward a high Km form.


Plasma cadmium and zinc and their interrelationship in adult Nigerians: potential health implications.
Zinc (an essential trace element) and cadmium (a ubiquitous environmental pollutant with acclaimed toxicity) have been found to occur together in nature, with reported antagonism between the two elements. The present study aimed at determination of plasma levels of zinc (Zn) and cadmium (Cd) and their interrelationship in adult Nigerians. The series comprised adults (n=443) aged ≥18 yrs (mean ± SD 38.4±13.7 yrs), consisting of 117 males, 184 non-pregnant and 140 pregnant females. Sociodemographic data were collected by questionnaire while anthropometrics were determined using standard methods. Plasma Cd and Zn were determined by using an atomic absorption spectrophotometer. The mean plasma zinc and cadmium were 94.7±18.1 μg/dl and 0.150±0.548 μg/dl, respectively. Age, sex, pregnancy, and parity had no effect on either plasma Zn or Cd. Although educational level had no effect on plasma Zn, it had a significant effect on Cd; subjects possessing either secondary or tertiary education had significantly lower plasma Cd than subjects without formal education. Moreover, there seemed to be an inverse relationship between Cd and Zn, but this was not statistically significant (r=-0.089; p=0.061). Although plasma Zn was not related to BMI (r=0.037; p=0.432), Cd was significantly negatively correlated with BMI (r=-0.124; p=0.009). It may be concluded that adult Nigerians in Ebonyi State have elevated plasma levels of Cd, with apparent impact on the levels of plasma Zn. This has important public health implications considering the essential roles of Zn in the protection of Cd mediated adverse health effects. While food diversification is recommended to improve plasma Zn, efforts should be made to reduce exposure to Cd to mitigate partially its possible adverse effects.


An ex-vivo comparative study of root-end marginal adaptation using grey mineral trioxide aggregate, white mineral trioxide aggregate, and Portland cement under scanning electron microscopy.
Where nonsurgical endodontic intervention is not possible, or it will not solve the problem, surgical endodontic treatment must be considered. A major cause of surgical endodontic failures is an inadequate apical seal, so the use of the suitable substance as root-end filling material that prevents egress of potential contaminants into periapical tissue is very critical. The aim of the present ex-vivo study was to compare and evaluate the three root-end filling materials of mineral trioxide aggregate (MTA) family (white MTA [WMTA], grey MTA [GMTA] and Portland cement [PC]) for their marginal adaptation at the root-end dentinal wall using scanning electron microscopy (SEM). Sixty human single-rooted teeth were decoronated, instrumented, and obturated with Gutta-percha. After the root-end resection and apical cavity preparation, the teeth were randomly divided into three-experimental groups (each containing 20 teeth) and each group was filled with their respective experimental materials. After longitudinal sectioning of root, SEM examination was done to determine the overall gap between retrograde materials and cavity walls in terms of length and width of the gap (maximum) at the interface. Descriptive statistical analysis was performed to calculate the means with corresponding standard errors, median and ranges along with an analysis of variance and Tukey's test. The least overall gap was observed in GMTA followed by PC and WMTA. While after statistically analyzing the various data obtained from different groups, there was no significant difference among these three groups in terms of marginal adaptation. GMTA showed the best overall adaptation to root dentinal wall compared to PC and WMTA. Being biocompatible and cheaper, the PC may be an alternative but not a substitute for MTA.


Deciphering Key Foreign Body Reaction-Related Transcription Factors and Genes Through Transcriptome Analysis.
Background: Silicone implants are widely used in the field of plastic surgery for wound repair and cosmetic augmentation. However, molecular mechanisms and signaling pathways underlying the foreign body reaction (FBR) of a host tissue to the silicone require further elucidation. The purpose of this study was to identify key FBR-related transcription factors (TFs) and genes through transcriptome analysis. Methods: We used a rat model with a subcutaneous silicone implant in the scalp and performed high throughput sequencing to determine the transcriptional profiles involved in the FBR. The function was analyzed by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-enrichment analysis. A protein-protein interaction (PPI) network of differentially expressed mRNAs (DEmRNAs) was constructed to identify the hub genes and key modules and to determine the regulatory TF-mRNA relationships. In addition, the hub gene and transcript expression levels were determined by Quantitative Reverse Transcription polymerase Chain Reaction (qRT-PCR). Myofibroblasts differentiation and macrophage recruitment were identified by immunofluorescence. The protein expression of MMP9 was detected by immunohistochemistry and Western blot. Results: We identified ten hub genes (Fos, Spp1, Fn1, Ctgf, Tlr2, Itgb2, Itgax, Ccl2, Mmp9, and Serpine1) and 3 TFs (FOS, IRF4, and SPI1) that may be crucial (particularly FOS) for the FBR. Furthermore, we identified multiple differentially expressed genes involved in several important biological processes, including leukocyte migration, cytokine‒ cytokine receptor interaction, phagocytosis, extracellular matrix (ECM) organization, and angiogenesis. We also identified potentially significant signaling pathways, including cytokine‒cytokine receptor interaction, phagosome, ECM‒receptor interaction, complement and coagulation cascades, the IL-17 signaling pathway, and the PI3K‒Akt signaling pathway. In addition, qRT-PCR confirmed the expression patterns of the TFs and hub genes, Western blot and immunohistochemistry validated the expression patterns of MMP9. Conclusion: We generated a comprehensive overview of the gene networks underlying the FBR evoked by silicone implants. Moreover, we identified specific molecular and signaling pathways that may perform key functions in the silicone implant-induced FBR. Our results provide significant insights into the molecular mechanisms underlying silicone-induced FBR and determine novel therapeutic targets to reduce complications related to silicone implantation.


Confined multilamellae prefer cylindrical morphology. A theory of myelin formation.
By evaporating a drop of lipid dispersion we generate the myelin morphology often seen in dissolving surfactant powders. We explain these puzzling nonequilibrium structures using a geometric argument: the bilayer repeat spacing increases and thus the repulsion between bilayers decreases when a multilamellar disk is converted into a myelin without gain or loss of material and with number of bilayers unchanged. Sufficient reduction in bilayer repulsion can compensate for the cost in curvature energy, leading to a net stability of the myelin structure. A numerical estimate predicts the degree of dehydration required to favor myelin structures over flat lamellae.


Cloning and expression of chicken p54c-ets cDNAs: the first p54c-ets coding exon is located into the 40.0 kbp genomic domain unrelated to v-ets.
We have isolated cDNA clones of chicken c-ets mRNA the longest of which, designated pCk E54A, contained approximately 2.0 kb of a c-ets mRNA species. Nucleotide sequencing of this clone revealed a single long open reading frame, extending from the first ATG codon (nucleotide +1) to a TGA termination codon at nucleotide 1324. The predicted translation product contains 441 amino acid residues and its molecular weight is 48 kd. Expression in COS-1 cells of this clone resulted in the synthesis of polypeptides immunologically indistinguishable from the authentic p54c-ets after one-dimensional gel electrophoresis. Comparison of the nucleotide sequence of this cDNA to that of v-ets of avian acute leukemia virus E26 showed that both sequences are almost colinear with the exception of five point mutations but present striking differences in their 5' and 3' parts. 79 nucleotides downstream of the first ATG codon in c-ets cDNA are not found in the 5' part of v-ets where they are replaced by 223 different nucleotides. The 3' parts of v-ets and the coding region of the chicken c-ets cDNAs are also different: the last 13 codons of the cDNA are replaced by 16 different codons in v-ets. Thus our results precisely define the structural differences between the ets encoded domain of E26 viral transforming protein (P135 gag-myb-ets) and the normal cellular protein p54c-ets expressed at high levels in chicken thymocytes and bursal lymphocytes. They also suggest the possibility of alternative splicing of different 5' exons to a common set of 3' exons.


Structural studies of two mutants of amicyanin from Paracoccus denitrificans that stabilize the reduced state of the copper.
Mutation of Pro94 to phenylalanine or alanine significantly alters the redox properties of the type I copper center of amicyanin. Each mutation increases the redox midpoint potential (E(m)) value by at least 140 mV and shifts the pK(a) for the pH dependence of the E(m) value to a more acidic value. Atomic resolution (0.99-1.1 A) structures of both the P94F and P94A amicyanin have been determined in the oxidized and reduced states. In each amicyanin mutant, an electron-withdrawing hydrogen bond to the copper-coordinating thiolate sulfur of Cys92 is introduced by movement of the amide nitrogens of Phe94 and Ala94 much closer to the thiolate sulfur than in wild-type amicyanin. This is the likely explanation for the much more positive E(m) values which result from each of these mutations. The observed decrease in the pK(a) value for the pH dependence of the E(m) value that is seen in the mutants seems to be correlated with steric hindrance to the rotation of the His95 copper ligand which results from the mutations. In wild-type amicyanin the His95 side chain undergoes a redox and pH-dependent conformational change which accounts for the pH dependence of the E(m) value of amicyanin. The reduced P94A amicyanin exhibits two alternate conformations with the positions of the copper 1.4 A apart. In one of these conformations, a water molecule appears to have replaced Met98 as a copper ligand. The relevance of these structures to the electron transfer properties of P94F and P94A amicyanin are also discussed.


Teaching geriatric fellows how to teach: a needs assessment targeting geriatrics fellowship program directors.
The entire healthcare workforce needs to be educated to better care for older adults. The purpose of this study was to determine whether fellows are being trained to teach, to assess the attitudes of fellowship directors toward training fellows to be teachers, and to understand how to facilitate this type of training for fellows. A nine-question survey adapted from a 2001 survey issued to residency program directors inquiring about residents-as-teachers curricula was developed and administered. The survey was issued electronically and sent out three times over a 6-week period. Of 144 ACGME-accredited geriatric fellowship directors from geriatric, internal medicine, and family medicine departments who were e-mailed the survey, 101 (70%) responded; 75% had an academic affiliation, 15% had a community affiliation, and 10% did not report. Academic and community programs required their fellows to teach, but just 55% of academic and 29% of community programs offered teaching skills instruction as part of their fellowship curriculum; 67% of academic programs and 79% of community programs felt that their fellows would benefit from more teaching skill instruction. Program directors listed fellow (39%) and faculty (46%) time constraints as obstacles to creation and implementation of a teaching curriculum. The majority of fellowship directors believe that it is important for geriatric fellows to become competent educators, but only approximately half of programs currently provide formal instruction in teaching skills. A reproducible, accessible curriculum on teaching to teach that includes a rigorous evaluation component should be created for geriatrics fellowship programs.


Y:X sperm ratio in boron-exposed men.
Several epidemiologic investigations have shown shifts in sex ratios at birth toward females in populations with relatively high boron exposure. To investigate the paternal origin of these shifts, we assayed sperm Y:X ratio in men exposed to a range of environmental and workplace boron. Participants included 63 workers in boron industry: 39 men living in an area of high environmental boron but not employed in boron industry, and 44 controls living in an area of low environmental boron. Total daily boron exposure was calculated as the sum of boron in 24-hour duplicate food and fluid intakes plus personal air sampling for workplace inhalable dust. Internal dose was measured in blood, urine, and semen. Sperm were analyzed by fluorescence in situ hybridization for Y- versus X-bearing cells. Potential confounders were identified using a questionnaire. Total exposure was correlated with internal dose (Pearson correlation for total exposure and boron in blood = 0.63, P < .0001; semen = 0.80, P < .001; and urine = 0.79, P < .0001). Linear regression of logged boron in biologic fluids on Y:X ratio was significant for blood P = .02, semen P = .0003, and urine P = .005. Additionally, when subjects were categorized by exposure group, decreased Y:X sperm ratio was found for boron workers compared with men in a high boron environment and controls (P < .0001). Exogenous environmental or workplace boron exposures were associated with decreases in Y- versus X-bearing sperm. This may explain earlier findings from us and others showing changes in offspring sex ratios at birth for men exposed to boron.


Integrating fluoroquinolones into the hospital formulary.
With the increasing availability of new agents, selection of fluoroquinolones for formulary inclusion can be difficult. Appropriate evaluation of the important characteristics (pharmacokinetic and pharmacodynamic properties, antimicrobial activity, efficacy, tolerability, cost) of these agents should allow selection of the most cost-effective ones. Evidence from in vitro studies and clinical trials indicates differences exist among fluoroquinolones, especially in terms of activity against gram-positive, aerobic organisms. For selected clinical situations, it may be important to choose an agent that is available in both intravenous and oral formulations. Comparative drug costs, as well as costs associated with potential clinical failure and adverse events, should be evaluated carefully. Dosage regimens should be considered, as shorter durations of therapy and less frequent dose administration may lead to reduced labor costs and increased patient compliance, thereby improving effectiveness and economic efficiency.


A second 5-carboxyvanillate decarboxylase gene, ligW2, is important for lignin-related biphenyl catabolism in Sphingomonas paucimobilis SYK-6.
A lignin-related biphenyl compound, 5,5'-dehydrodivanillate (DDVA), is degraded to 5-carboxyvanillate (5CVA) by the enzyme reactions catalyzed by DDVA O-demethylase (LigX), meta-cleavage oxygenase (LigZ), and meta-cleavage compound hydrolase (LigY) in Sphingomonas paucimobilis SYK-6. 5CVA is then transformed to vanillate by a nonoxidative 5CVA decarboxylase and is further degraded through the protocatechuate 4,5-cleavage pathway. A 5CVA decarboxylase gene, ligW, was isolated from SYK-6 (X. Peng, E. Masai, H. Kitayama, K. Harada, Y, Katayama, and M. Fukuda, Appl. Environ. Microbiol. 68:4407-4415, 2002). However, disruption of ligW slightly affected the 5CVA decarboxylase activity and the growth rate on DDVA of the mutant, suggesting the presence of an alternative 5CVA decarboxylase gene. Here we isolated a second 5CVA decarboxylase gene, ligW2, which consists of a 1,050-bp open reading frame encoding a polypeptide with a molecular mass of 39,379 Da. The deduced amino acid sequence encoded by ligW2 exhibits 37% identity with the sequence encoded by ligW. Based on a gas chromatography-mass spectrometry analysis of the reaction product from 5CVA catalyzed by LigW2 in the presence of deuterium oxide, LigW2 was indicated to be a nonoxidative decarboxylase of 5CVA, like LigW. After disruption of ligW2, both the growth rate on DDVA and the 5CVA decarboxylase activity of the mutant were decreased to approximately 30% of the wild-type levels. The ligW ligW2 double mutant lost both the ability to grow on DDVA and the 5CVA decarboxylase activity. These results indicate that both ligW and ligW2 contribute to 5CVA degradation, although ligW2 plays the more important role in the growth of SYK-6 cells on DDVA.


Sandwich enzyme immunoassays for detection of Salmonella typhi.
Enzyme immunoassays were developed using monoclonal antibodies raised against somatic (O), flagellar (H) and capsular (Vi) antigens of Salmonella typhi. The assay based on anti-O monoclonal antibodies could specifically detect S. typhi and soluble lipopolysaccharide (LPS) isolated from S. typhi. Anti-H MoAbs detected motile S. typhi and soluble flagellar antigen. Monoclonal antibodies against capsular polysaccharide could detect Vi-containing S. typhi as well as soluble Vi antigen. The three assays reported here detected S. typhi with 100% sensitivity in blood culture broths obtained from bacteriologically confirmed typhoid patients and were negative with blood specimens containing Salmonella senftenberg, E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis or Streptococcus (alpha-hemolytic) derived from patients with pyrexia. The assays, however, did not demonstrate the presence of soluble antigens in sera and urine samples obtained from typhoid patients.


[Textual research of chu, huo, huo, and hua].
Origin of Chinese Characters (Shuowen Jiezi) records a large number of drug names, providing rich materials for the study of the history of pharmacy. But in the aftertime circulating process, errors were inevitable, making the ancient scholars disagree on the relationship between some drug names and their referents. This paper would give a textual research on medication names about chu, huo, huo, and hua. Relevant content was analyzed by using Shuowen Jiezi, Er Ya,Yu Pian and previous annotations of these exegesis books, as well as herbal literature. The relationship between the names and referents, as well as their lexical meanings were clarified by comparing textual content in specialized book about Chinese exegetics and previous herbal literature. Their medicinal efficacy was explained, and the value of herbalism in these exegesis books was explored.


Atorvastatin activates autophagy and promotes neurological function recovery after spinal cord injury.
Atorvastatin, a lipid-lowering medication, provides neuroprotective effects, although the precise mechanisms of action remain unclear. Our previous studies confirmed activated autophagy following spinal cord injury, which was conducive to recovery of neurological functions. We hypothesized that atorvastatin could also activate autophagy after spinal cord injury, and subsequently improve recovery of neurological functions. A rat model of spinal cord injury was established based on the Allen method. Atorvastatin (5 mg/kg) was intraperitoneally injected at 1 and 2 days after spinal cord injury. At 7 days post-injury, western blot assay, reverse transcription-polymerase chain reaction, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining results showed increased Beclin-1 and light chain 3B gene and protein expressions in the spinal cord injury + atorvastatin group. Additionally, caspase-9 and caspase-3 expression was decreased, and the number of TUNEL-positive cells was reduced. Compared with the spinal cord injury + saline group, Basso, Beattie, and Bresnahan locomotor rating scale scores significantly increased in the spinal cord injury + atorvastatin group at 14-42 days post-injury. These findings suggest that atorvastatin activated autophagy after spinal cord injury, inhibited apoptosis, and promoted recovery of neurological function.


Role of vitamin D in the development of the chick embryo.
Chick embryos of various ages and 1-day-old chicks were injected with different doses of 1,25(OH)2D3 and the concentrations of Ca and Pi in their blood were determined 24 hr after. It was confirmed that the dose required to induce hypercalcemia and hypophosphatemia was much lower in the case of 15-day-old embryos than in younger ones. The age of maximal response corresponds to the period when the chorionic epithelium is fully differentiated. Newly hatched chicks did not respond even with doses 20 times higher than those used in 15-day-old embryos. These findings support the idea that the humoral changes produced by 1,25(OH)2D3 result from increased resorption of calcium from the shell and that the chorionic epithelium is instrumental in this phenomenon. The autoradiographic study of tissues from embryos injected with tritiated 1,25(OH)2D3 showed that the exposure time required to detect nuclear concentration of radioactivity was much shorter in the case of "villus-cavity" cells than in any other tissue (kidney, intestine, bone, parathyroid glands) in which target cells were recognized. The above results are interpreted as indicating that the chorionic epithelium is the main target for 1,25(OH)2D3. The histological study of various organs from embryos injected with large doses of 1,25(OH)2D3 showed generalized infiltration of spleen, liver, and bursa of Fabricius with eosinophilic granulocytes. It has been suggested that 1,25(OH)2D3 influences the proliferation and differentiation of leukocytes; the chick embryo might be a good model for further exploration of this problem.


Global mortality of snakebite envenoming between 1990 and 2019.
Snakebite envenoming is an important cause of preventable death. The World Health Organization (WHO) set a goal to halve snakebite mortality by 2030. We used verbal autopsy and vital registration data to model the proportion of venomous animal deaths due to snakes by location, age, year, and sex, and applied these proportions to venomous animal contact mortality estimates from the Global Burden of Disease 2019 study. In 2019, 63,400 people (95% uncertainty interval 38,900-78,600) died globally from snakebites, which was equal to an age-standardized mortality rate (ASMR) of 0.8 deaths (0.5-1.0) per 100,000 and represents a 36% (2-49) decrease in ASMR since 1990. India had the greatest number of deaths in 2019, equal to an ASMR of 4.0 per 100,000 (2.3-5.0). We forecast mortality will continue to decline, but not sufficiently to meet WHO's goals. Improved data collection should be prioritized to help target interventions, improve burden estimation, and monitor progress.


Adverse effects of antiretroviral treatment.
The introduction of highly active antiretroviral therapy (HAART) has led to significant reduction in acquired immune deficiency syndrome (AIDS)-related morbidity and mortality. Adverse drug reactions (ADRs) to antiretroviral treatment (ART) are however, major obstacles in its success. We sought to study the adverse effects of ART in a resource-restricted setting in India. Hundred patients on ART were studied prospectively over a period of two years. All patients were asked to visit the clinic if they developed any symptoms or on a monthly basis. They were screened clinically and investigated suitably for any ADRs. Out of the 100 patients, ten patients did not come for follow-up; only 90 cases were available for evaluation. ADRs were observed in 64 cases (71.1%) - the maximal frequency of ADRs was seen with zidovudine (AZT) (50%) followed by stavudine (d4T) (47.9%), efavirenz (EFV) (45.4%) and finally, Nevirapine (NVP) (18.4%). Most common ADRs were cutaneous (44.4%) followed by hematological (32.2%), neurological (31.1%), metabolic (22.2%) and gastrointestinal (20%). Most common cutaneous ADRs observed were nail hyperpigmentation (14.4%) and rash (13.3%). Immune reconstitution inflammatory syndrome (IRIS) was observed as a paradoxical reaction to ART in 20 (22.2%) cases. To optimize adherence and thus, efficacy of ART, clinicians must focus on preventing adverse effects whenever possible, and distinguish those that are self-limited from those that are potentially serious.


Cerebral Oxygenation Responses to Standing in Young Patients with Vasovagal Syncope.
Vasovagal syncope (VVS) is common in young adults and is attributed to cerebral hypoperfusion. However, during active stand (AS) testing, only peripheral and not cerebral hemodynamic responses are measured. We sought to determine whether cerebral oxygenation responses to an AS test were altered in young VVS patients when compared to the young healthy controls. A sample of young healthy adults and consecutive VVS patients attending a Falls and Syncope unit was recruited. Continuous beat-to-beat blood pressure (BP), heart rate, near-infrared spectroscopy (NIRS)-derived tissue saturation index (TSI), and changes in concentration of oxygenated/deoxygenated Δ[O2Hb]/Δ[HHb] hemoglobin were measured. BP and NIRS-derived features included nadir, peak, overshoot, trough, recovery rate, normalized recovery rate, and steady-state. Multivariate linear regression was used to adjust for confounders and BP. In total, 13 controls and 27 VVS patients were recruited. While no significant differences were observed in the TSI and Δ[O2Hb], there was a significantly smaller Δ[HHb] peak-to-trough and faster Δ[HHb] recovery rate in VVS patients, independent of BP. A higher BP steady-state was observed in patients but did not remain significant after multiple comparison correction. Young VVS patients demonstrated a similar cerebral circulatory response with signs of altered peripheral circulation with respect to the controls, potentially due to a hyper-reactive autonomic nervous system. This study sets the grounds for future investigations to understand the role of cerebral regulation during standing in VVS.


Optimization of Interphase Intervals to Enhance the Evoked Muscular Responses of Transcutaneous Neuromuscular Electrical Stimulation.
Neuromuscular electrical stimulation (NMES) is a widely used technique for clinical diagnostic, treatment, and research. Normally, it applies charge-balanced biphasic pulses, which several publications have reported to be less efficient than monophasic pulses. A good alternative is the use of interphase intervals (IPI) on biphasic pulses that allows to achieve similar responses than those evoked by monophasic stimulation. This study analyzes the enhancing mechanism of the IPI and provides guidelines on how to optimize the IPI in order to reduce secondary effects such as the electrode corrosion. The tibial nerve was excited by NMES biphasic pulses with different IPI durations and polarities. Then, the elicited responses were recorded on the soleus muscle via electromyography. When cathodic-first pulses were applied, the responses increased proportionally to the IPI until the duration of 250 µs, where the increase saturated at 30% of the original amplitude. The responses evoked during anodic-first were 6% to 30% smaller than those evoked during cathodic-first pulses and continuously increased until the IPI duration of 2500 µs, where the responses reached an increase of around 30%. The results suggest that when a cathodic-first pulse is used, the IPI could be optimized (based on the setup geometry) to allow the action potentials to travel out of the hyperpolarization zone induced by the anodic phase. When anodic-first stimuli are applied, the IPI duration allows the fiber to recover from an apparent insensitive state induced by the anodic phase. The use of IPI is a viable option to improve the efficiency of actual stimulation systems, since only small modifications are required to significantly reduce the electrical charge required and boost the stimulation efficiency.


Blockade of the fractalkine-CX3CR1 axis ameliorates experimental colitis by dislodging venous crawling monocytes.
Chemokine systems modulate inflammatory and immune responses in inflammatory bowel disease (IBD). The colons of IBD patients show increased levels of fractalkine (FKN) and high numbers of FKN receptor-positive (CX3CR1+) cells; however, the FKN-CX3CR1 axis's role in intestinal inflammation, especially in intravascular leukocyte behaviors, still remains unclear. Here, we show that interruption of the FKN-CX3CR1 axis by anti-FKN monoclonal antibody (mAb) ameliorates murine colitis through regulation of intravascular monocyte behaviors in murine colitis models. FKN expression was detectable in vascular endothelium and CX3CR1+ macrophages accumulated in the mucosal lamina propria and submucosa of the inflamed colons. CD115+ monocytes tethered to the venous endothelium and expressed pro-inflammatory mediators. The anti-FKN mAb improved colitis symptoms, markedly reduced pro-inflammatory factors in the colon, maintained blood vessel integrity and reduced tethered monocytes in the inflamed veins. Intravital imaging revealed that CD115+Gr-1low/- monocytes crawled on the apical surfaces of venous endothelium, and anti-FKN mAb rapidly dislodged the crawling monocytes and inhibited their patrolling behavior. These findings suggest that the FKN-CX3CR1 axis triggers the patrolling behavior of crawling monocytes on the venous endothelium of inflamed colons, and accelerates the subsequent leukocyte activation and infiltration by locally producing inflammatory cytokines and chemokines. The mAb also ameliorated symptoms in another IBD model, T-cell-transferred colitis. Blocking the FKN-CX3CR1 axis with an anti-FKN mAb considerably inhibits the colitis-triggered inflammatory cascades, which may be an alternative strategy to treat IBD.


Hydrogen activation by [NiFe]-hydrogenases.
Hydrogenase-1 (Hyd-1) from Escherichia coli is a membrane-bound enzyme that catalyses the reversible oxidation of molecular H2 The active site contains one Fe and one Ni atom and several conserved amino acids including an arginine (Arg(509)), which interacts with two conserved aspartate residues (Asp(118) and Asp(574)) forming an outer shell canopy over the metals. There is also a highly conserved glutamate (Glu(28)) positioned on the opposite side of the active site to the canopy. The mechanism of hydrogen activation has been dissected by site-directed mutagenesis to identify the catalytic base responsible for splitting molecular hydrogen and possible proton transfer pathways to/from the active site. Previous reported attempts to mutate residues in the canopy were unsuccessful, leading to an assumption of a purely structural role. Recent discoveries, however, suggest a catalytic requirement, for example replacing the arginine with lysine (R509K) leaves the structure virtually unchanged, but catalytic activity falls by more than 100-fold. Variants containing amino acid substitutions at either or both, aspartates retain significant activity. We now propose a new mechanism: heterolytic H2 cleavage is via a mechanism akin to that of a frustrated Lewis pair (FLP), where H2 is polarized by simultaneous binding to the metal(s) (the acid) and a nitrogen from Arg(509) (the base).


The use of a selective saturation pulse to suppress t1 noise in two-dimensional (1)H fast magic angle spinning solid-state NMR spectroscopy.
A selective saturation pulse at fast magic angle spinning (MAS) frequencies (60+kHz) suppresses t1 noise in the indirect dimension of two-dimensional (1)H MAS NMR spectra. The method is applied to a synthetic nucleoside with an intense methyl (1)H signal due to triisopropylsilyl (TIPS) protecting groups. Enhanced performance in terms of suppressing the methyl signal while minimising the loss of signal intensity of nearby resonances of interest relies on reducing spin diffusion--this is quantified by comparing two-dimensional (1)H NOESY-like spin diffusion spectra recorded at 30-70 kHz MAS. For a saturation pulse centred at the methyl resonance, the effect of changing the nutation frequency at different MAS frequencies as well as the effect of changing the pulse duration is investigated. By applying a pulse of duration 30 ms and nutation frequency 725 Hz at 70 kHz MAS, a good compromise of significant suppression of the methyl resonance combined with the signal intensity of resonances greater than 5 ppm away from the methyl resonance being largely unaffected is achieved. The effectiveness of using a selective saturation pulse is demonstrated for both homonuclear (1)H-(1)H double quantum (DQ)/single quantum (SQ) MAS and (14)N-(1)H heteronuclear multiple quantum coherence (HMQC) two-dimensional solid-state NMR experiments.


Kinetics of human immune interferon production and blastogenesis.
We studied some of the requirements for production of immune interferon (IFN-gamma) by human peripheral leucocytes following stimulation with concanavalin A (Con A). Synthesis of IFN-gamma commenced 2 hr after the cells were exposed to the lectin and continued for about 20 hr thereafter. IFN-gamma production during the latter period was independent of free Con A in the culture medium but it was sustained by continued Con A binding and required active de novo protein synthesis. Egg lecithin, which inhibits the blastogenic response, did not affect IFN-gamma production.


Hyperuricosuria due to high-dose pancreatic extract therapy in cystic fibrosis.
Dysuria, uric acid crystalluria and hyperuricosuria developed in a child with cystic fibrosis and normal serum uric acid. Hyperuricosuria in this patient and two other children was directly related to ingestion of large amounts of pancreatic extract. In these three children, reducing pancreatic extract dosage by 85 percent lowered their purine intake by 307, 225, and 148 mg, respectively; urinary uric acid excretion decreased by 245, 239, and 158 mg. Overmedication resulted from parents' decisions to increase enzyme dosages. In our cystic fibrosis clinic, 15 of 32 patients screened at random were taking higher than the prescribed dose of pancreatic enzymes, and 14 of these 15 children were hyperuricosuric. On the basis of this information, we suggest that the minimal effective dose of pancreatic extract should be determined and adhered to for each child with cystic fibrosis to avoid potential renal injury from hyperuricosuria.


Risk of Bleeding Associated With Outpatient Use of Rivaroxaban in VTE Management at a National Referral Hospital in Western Kenya.
There is limited data on the bleeding safety profile of direct oral anticoagulants, such as rivaroxaban, in low- and middle-income country settings like Kenya. In this prospective observational study, patients newly started on rivaroxaban or switching to rivaroxaban from warfarin for the management of venous thromboembolism (VTE) within the national referral hospital in western Kenya were assessed to determine the frequency of bleeding during treatment. Bleeding events were assessed at the 1- and 3-month visits, as well as at the end of follow-up. The International Society of Thrombosis and Hemostasis (ISTH) and the Bleeding Academic Research Consortium (BARC) criteria were used to categorize the bleeding events, and descriptive statistics were used to summarize categorical variables. Univariate and multivariate logistic regression model was used to calculate unadjusted and adjusted associations between patient characteristics and bleeding. The frequency of any type of bleeding was 14.4% (95% CI: 9.3%-20.8%) for an incidence rate of 30.9 bleeding events (95% CI: 20.1-45.6) per 100 patient-years of follow-up. The frequency of major bleeding was 1.9% while that of clinically relevant non-major bleeding was 13.8%. In the multivariate logistic regression model, being a beneficiary of the national insurance plan was associated with a lower risk of bleeding, while being unemployed was associated with a higher bleeding risk. The use of rivaroxaban in the management of VTE was associated with a higher frequency of bleeding. These findings warrant confirmation in larger and more targeted investigations in a similar population.


Four-Week Studies of Oral Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor GSK1278863 for Treatment of Anemia.
Hypoxia-inducible factor prolyl hydroxylase inhibitors stabilize levels of hypoxia-inducible factor that upregulate transcription of multiple genes associated with the response to hypoxia, including production of erythropoietin. We conducted two phase 2a studies to explore the relationship between the dose of the hypoxia-inducible factor-prolyl hydroxylase inhibitor GSK1278863 and hemoglobin response in patients with anemia of CKD (baseline hemoglobin 8.5-11.0 g/dl) not undergoing dialysis and not receiving recombinant human erythropoietin (nondialysis study) and in patients with anemia of CKD (baseline hemoglobin 9.5-12.0 g/dl) on hemodialysis and being treated with stable doses of recombinant human erythropoietin (hemodialysis study). Participants were randomized 1:1:1:1 to a once-daily oral dose of GSK1278863 (0.5 mg, 2 mg, or 5 mg) or control (placebo for the nondialysis study; continuing on recombinant human erythropoietin for the hemodialysis study) for 4 weeks, with a 2-week follow-up. In the nondialysis study, GSK1278863 produced dose-dependent effects on hemoglobin, with the highest dose resulting in a mean increase of 1 g/dl at week 4. In the hemodialysis study, treatment with GSK1278863 in the 5-mg arm maintained mean hemoglobin concentrations after the switch from recombinant human erythropoietin, whereas mean hemoglobin decreased in the lower-dose arms. In both studies, the effects on hemoglobin occurred with elevations in endogenous erythropoietin within the range usually observed in the respective populations and markedly lower than those in the recombinant human erythropoietin control arm in the hemodialysis study, and without clinically significant elevations in plasma vascular endothelial growth factor concentrations. GSK1278863 was generally safe and well tolerated at the doses and duration studied. GSK1278863 may prove an effective alternative for managing anemia of CKD.


Distinct clinical phenotypes in paediatric cancer patients with sepsis are associated with different outcomes-an international multicentre retrospective study.
Identifying phenotypes in sepsis patients may enable precision medicine approaches. However, the generalisability of these phenotypes to specific patient populations is unclear. Given that paediatric cancer patients with sepsis have different host response and pathogen profiles and higher mortality rates when compared to non-cancer patients, we determined whether unique, reproducible, and clinically-relevant sepsis phenotypes exist in this specific patient population. We studied patients with underlying malignancies admitted with sepsis to one of 25 paediatric intensive care units (PICUs) participating in two large, multi-centre, observational cohorts from the European SCOTER study (n = 383 patients; study period between January 1, 2018 and January 1, 2020) and the U.S. Novel Data-Driven Sepsis Phenotypes in Children study (n = 1898 patients; study period between January 1, 2012 and January 1, 2018). We independently used latent class analysis (LCA) in both cohorts to identify phenotypes using demographic, clinical, and laboratory data from the first 24 h of PICU admission. We then tested the association of the phenotypes with clinical outcomes in both cohorts. LCA identified two distinct phenotypes that were comparable across both cohorts. Phenotype 1 was characterised by lower serum bicarbonate and albumin, markedly increased lactate and hepatic, renal, and coagulation abnormalities when compared to phenotype 2. Patients with phenotype 1 had a higher 90-day mortality (European cohort 29.2% versus 13.4%, U.S. cohort 27.3% versus 11.4%, p < 0.001) and received more vasopressor and renal replacement therapy than patients with phenotype 2. After adjusting for severity of organ dysfunction, haematological cancer, prior stem cell transplantation and age, phenotype 1 was associated with an adjusted OR of death at 90-day of 1.9 (1.04-3.34) in the European cohort and 1.6 (1.2-2.2) in the U.S. cohort. We identified two clinically-relevant sepsis phenotypes in paediatric cancer patients that are reproducible across two international, multicentre cohorts with prognostic implications. These results may guide further research regarding therapeutic approaches for these specific phenotypes. Part of this study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.


Integration of novel targeted therapies into the systemic treatment of breast cancer--a review.
Over the last few years it has been anticipated that molecularly targeted agents can provide substantial improvement in the treatment of breast cancer. The most illustrative paradigm has been that of trastuzumab (Herceptin), a humanized monoclonal antibody against the HER2 oncoprotein overexpressed in 25% of breast cancers. Trastuzumab when combined with standard cytotoxic chemotherapy improved the outcome and survival in patients with metastatic breast cancer, whereas, over the last 2 years studies incorporating trastuzumab in sequence to or concurrently with taxane-based chemotherapy in the adjuvant setting demonstrated a considerable benefi t in this subset, with the results of longer follow-up regarding long-term outcome and late toxicities expected over the forthcoming years. Moreover, the prognostic and predictive value of topoisomerase IIa (Topo IIa) overexpression in these subgroups with respect to anthracycline treatment has been extensively discussed and analysed. Other inhibitors of both HER1/HER2 have recently been introduced with promising results and results of ongoing studies are awaited with great interest. A recently anticipated target in advanced breast cancer has been the pathway of angiogenesis; first a humanized monoclonal antibody-bevacizumab (Avastin)- has demonstrated encouraging results when combined with chemotherapy in pretreated HER2-negative advanced breast cancer, while combinations with trastuzumab+/-chemotherapy are currently examined in HER2-overexpressing breast cancer. Furthermore, as novel molecular pathways relevant to breast cancer biology are explored, it is expected that a whole array of targeted agents will be tested in combination or in sequence to standard chemotherapy with the aim to improve outcome of high-risk breast cancer patients.


Backcross assisted by microsatellite markers in common bean.
The objectives of the present study were to monitor the effect of backcrossing through microsatellite markers and to compare different marker assisted selection strategies. Four populations were developed using donor parents resistant to the bean golden mosaic virus and, for all crosses, only individuals resistant to the bean golden mosaic virus were backcrossed. For crosses ARC100-4 x DOR303 and ARC100-4 x PHAS8328, assisted selection was carried out in the F(2) and F(2)BC(1) generations, while in the remaining crosses selection was performed only in the F(2)BC(1) generation. For the microsatellite analysis, in each generation, 20 markers were genotyped. The molecular data were analyzed using the NTSys program and the proportion of the recurrent genome introgressed was estimated, based on genotypical configuration of the segregant populations compared to the recurrent parents. The results indicate a higher efficiency in recovering the genotype of the elite genitor through the strategy of backcross assisted selection in the successive generations, and demonstrate a practical and useful application of molecular marker technology associated with bean breeding, to reduce the number of backcrosses and the time to recover the genome of the recurrent genitors.


Low molecular weight polysialic acid prevents lipopolysaccharide-induced inflammatory dopaminergic neurodegeneration in humanized SIGLEC11 transgenic mice.
Parkinson's disease is one of the most common neurodegenerative diseases in the elderly population, with a pathophysiology linked to neuroinflammation, complement activation, and oxidative damage. Soluble polysialic acid with an average degree of polymerization 20 (polySia avDP20) prevents inflammation and oxidative burst in human macrophages via sialic acid-binding immunoglobulin like lectin-11 (SIGLEC11) receptor and interferes with alternative complement activation. Here, we confirmed the anti-inflammatory capacity of polySia avDP20 on cultured murine embryonic stem cell-derived microglia and analyzed the effect of polySia avDP20 in a lipopolysaccharide-triggered animal model of Parkinson's disease. We demonstrated a neuroprotective effect of intraperitoneally applied polySia avDP20 in humanized SIGLEC11 transgenic mice after repeated systemic challenge with lipopolysaccharide. Pathway enrichment analysis of the brain transcriptome on day 19 after disease initiation showed that intraperitoneal application of 10 μg/g body weight polySia avDP20 prevented excessive inflammation. In line with these data, polySia avDP20 attenuated the lipopolysaccharide-triggered increase in mRNA levels of immune-related genes (Il1b, Cd14, Myd88, Fcer1g, Itgam, C4, Cybb, Iba1 and Cd68) and cell death-related genes (Casp8, Ripk1 and Ripk3) in the brains of SIGLEC11 transgenic mice on day 19, but not on day 5. Moreover, immunohistochemistry demonstrated that polySia avDP20 reduced the lipopolysaccharide-induced increase in immunoreactivity of IBA1 and CD68 in the substantia nigra pars reticulata in SIGLEC11 transgenic and wild type mice on day 19. Furthermore, treatment with polySia avDP20 prevented the loss of dopaminergic neurons in the substantia nigra pars compacta induced by lipopolysaccharide challenge in both SIGLEC11 transgenic and wild type mice on day 19. Thus, our data demonstrate that polySia avDP20 ameliorates inflammatory dopaminergic neurodegeneration and therefore is a promising drug candidate to prevent Parkinson's disease-related inflammation and neurodegeneration.


Effectors of Phytophthora pathogens are powerful weapons for manipulating host immunity.
This article provides an overview of the interactions between Phytophthora effectors and plant immune system components, which form a cross-linked complex network that regulates plant pathogen resistance. Pathogens secrete numerous effector proteins into plants to promote infections. Several Phytophthora species (e.g., P. infestans, P. ramorum, P. sojae, P. capsici, P. cinnamomi, and P. parasitica) are notorious pathogens that are extremely damaging to susceptible plants. Analyses of genomic data revealed that Phytophthora species produce a large group of effector proteins, which are critical for pathogenesis. And, the targets and functions of many identified Phytophthora effectors have been investigated. Phytophthora effectors can affect various aspects of plant immune systems, including plant cell proteases, phytohormones, RNAs, the MAPK pathway, catalase, the ubiquitin proteasome pathway, the endoplasmic reticulum, NB-LRR proteins, and the cell membrane. Clarifying the effector-plant interactions is important for unravelling the functions of Phytophthora effectors during pathogenesis. In this article, we review the effectors identified in recent decades and provide an overview of the effector-directed regulatory network in plants following infections by Phytophthora species.


VerSeDa: vertebrate secretome database.
Based on the current tools, de novo secretome (full set of proteins secreted by an organism) prediction is a time consuming bioinformatic task that requires a multifactorial analysis in order to obtain reliable in silico predictions. Hence, to accelerate this process and offer researchers a reliable repository where secretome information can be obtained for vertebrates and model organisms, we have developed VerSeDa (Vertebrate Secretome Database). This freely available database stores information about proteins that are predicted to be secreted through the classical and non-classical mechanisms, for the wide range of vertebrate species deposited at the NCBI, UCSC and ENSEMBL sites. To our knowledge, VerSeDa is the only state-of-the-art database designed to store secretome data from multiple vertebrate genomes, thus, saving an important amount of time spent in the prediction of protein features that can be retrieved from this repository directly. VerSeDa is freely available at http://genomics.cicbiogune.es/VerSeDa/index.php.


Spirulina platensis (Arthrospira platensis) attenuates Cyclophosphamide-induced reproductive toxicity in male Wistar rats: Evidence for sperm apoptosis and p53/Bcl-2 expression.
Cyclophosphamide is an antitumor agent that causes disorders in fertility. This study aimed to evaluate the protective effects of Spirulina platensis against Cyclophosphamide-induced testicular toxicity. 42 male Wistar rats were randomly divided into six groups. Experimental groups included three groups. The first experimental group received Cyclophosphamide at a dose of 5 mg/kg body weight (BW) orally. The second and third experimental groups received 5 mg/kg BW Cyclophosphamide and 500 and 1,000 mg/kg BW S. platensis orally, respectively. The control groups included a control group, and two S. platensis control groups. Following 28 days, two flow cytometry techniques were used to determine sperm apoptosis and testicular protein expression of tumor protein (p53) and B-cell lymphoma 2 (Bcl-2). p53 is a tumor suppressor protein that causes the cell to enter the apoptosis cycle after DNA damage and Bcl-2 is an anti-apoptotic protein that acts through the mitochondrial pathway of apoptosis. FITC-Annexin V assay was used for sperm apoptosis evaluation. For protein expression assay, primary and secondary antibodies staining were performed. The Cyclophosphamide group showed a significant increase in sperm apoptosis compared to the control group. Cyclophosphamide significantly increased p53 and decreased Bcl-2 expression compared to the control group. S. platensis co-treated groups exhibited a significant decrease in sperm apoptosis compared to the Cyclophosphamide group. Moreover, S. platensis co-treated groups displayed a significant decreasing in p53 and increasing in Bcl-2 expression compared to the Cyclophosphamide group. The results of this study indicated that S. platensis protected rats against Cyclophosphamide-induced reproductive toxicity. PRACTICAL APPLICATIONS: Cyclophosphamide is the chemotherapy agent used to treat different cancers. Cyclophosphamide has side effects on the male reproductive system. Spirulina plantesis has a protective effect because of its antioxidant and anti-apoptotic properties. Co-administration of Spirulina plantesis with Cyclophosphamide reduces sperm apoptosis also decreases P53 protein expression and increases Bcl-2 protein expression. This study validated the anti-apoptotic potential of Spirulina plantesis against Cyclophosphamide-induced male reproductive toxicity.


The effects of overloading in density-gradient centrifugation.
The effects of overloading of the sample zone in density gradient centrifugation have been studied by use of a three-component shelf-lavered sample in which the total protein concentration was increased by addition of different amounts of albumin. It is found that overloading of the gradient gives rise to particle movements which are not predictable from the Svedberg equation. The two typical effects of overloading are dislocation of the zone mass centres and changes in the zone shapes. It is found that the magnitude of the calculated sedimentation coefficients increases nearly linearly with increasing sample load. The changes in zone shapes are found to depend on the specific load and two different patterns may be distinguished. The zone of the sample component which causes the overloading is defined as primarily overloaded and the others as secondarily overloaded. In primarily overloaded zones the original Gaussian shape is lost, while in secondarily overloaded zones the Gaussian zone shape is maintained, although a zone broadening is seen. Extreme high loads are found to be able to divide single zones. As a whole these experiments show that evidence for a non-overloaded set of experimental conditions must be provided, when density gradient centrifugation is used for determination of sedimentation coefficients. For preparative gradient centrifugations the power of resolution will decrease with increasing sample load. A simple method to detect overloading in density gradient centrifugations is described.


Nonionic contrast agents and coagulation.
The chemotoxicity of nonionic and ionic contrast media is discussed with reference to chemical structure. Second-generation nonionic contrast media have the lowest chemotoxicity of any agents because of the uniform distribution of hydrophilic groups around the molecule, which mask the hydrophobic iodine atoms. Previous investigations show that second-generation nonionic agents have the same qualitative hematologic effects as other contrast agents. The less marked quantitative hematologic effects of second-generation contrast media compared with conventional agents are consistent with the low toxicity profile of these agents. A study was conducted in which a nonionic and a conventional ionic contrast medium were observed on microscopic slides after small drops of nonanticoagulated blood were added to each. The disordered aggregations of red cells observed were larger in the nonionic agent but easily dispersed with minimal disturbance, suggesting limited clinical significance. A series of coagulation experiments was conducted in which two types of plastic syringes and glass syringes, containing either iohexol or diatrizoate, were contaminated with blood and inspected for blood clots. An ELISA assay for fibrinopeptide A also was performed. Clot formation was uncommon and appeared to be related to syringe material.


Factors Associated with Hospitalization of Chronic Obstructive Pulmonary Disease Patients with Acute Exacerbation in the Emergency Department, Rajavithi Hospital.
Chronic Obstructive Pulmonary Disease with acute exacerbation (AECOPD) is a condition, which frequently results in patients visiting the emergency department (ED). Recently, many studies have reported new factors, which cause AECOPD-patients (AECOPDs) to require urgent hospital admission. To determine the crucial factors of AECOPDs that are associated with patients who visit the ED being admitted to Rajavithi Hospital. This retrospective cross-sectional study was performed from May 1, 2011 to June 30, 2013. Seventy patients were included and their medical records were reviewed. A logistic regression model (SPSSv17) was used to analyze the prognostic factors associated with hospitalization. The study found that patients with a respiratory rate >24 breaths per minute (OR = 3.43; 95% CI = 1.10-10.84; p = 0.040), pulse rate >120 beats per minute (OR = 4.10; 95% CI = 1.31-12.74; p = 0.020), and oxygen saturation <90% (OR = 5.25; 95% CI = 1.20-23.00; p = 0.030), were prone to be admitted to the hospital. Furthermore, such patients more often required hospitalization if they had met any of the following criteria: had respiratory-infection related Global Initiative for Chronic Obstructive Lung Disease standard stages 3-4; were receiving home oxygen therapy; had an annual rate of ED visits of more than 2; had higher leukocytes; classified in the ED emergency triage as emergent; or who received antibiotics at the ED. Respiratory rate, heart rate and oxygen saturation are the crucial symptoms of AECOPDs to which physicians at ED should pay special attention. Such factors are reasonable indicators for hospitalization in order to reduce ED overcrowding. The study also found that patients treated early with antibiotics in the ED may be associated with subsequent hospitalization for ongoing management. However further studies are required for verification.


How Western Australian registrars choose training practices.
While general practice registrars receive advice on how to choose a training practice, little is known about what underlies their decision. A questionnaire was sent to all registrars in Western Australian General Practice Education and Training practices seeking information about the choice of their practice. Most registrars reported that they had chosen their practice. The supervisor was most commonly the person spoken to before the practice was chosen. The supervisor's personality was an important influence on choice and the practice manager was an important contact for registrars who were parents, presumably to arrange a part time attachment. Those who reported speaking to the supervisor also reported that they subsequently received greater remuneration. Registrars from a rural background chose more often to have all their training in a rural area.


Itch in the era of COVID-19 pandemic: An unfolding scenario.
Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome (SARS)-CoV-2, that broke out in December 2019. In just 4 months it has spread to almost every country in the world and up to April 18, 2020, the virus has infected more than two million people. Itch is the most common symptom in dermatology and a frequent one of systemic diseases. The association of itch and viral diseases has been widely documented; however, the actual prevalence of itch in the patients suffering from new the SARS-CoV-2 infection is still unknown. In this paper, we present a review of the available literature on the topic of itch in the affected population. Moreover, we have also analyzed different aspects of itch associated with COVID-19 pandemic, not directly related to the viral infection. Those included use of chemicals, hand sanitizers, common use of personal protective equipment and psychosocial stress.