[Acute and chronic borreliosis transmitted by ticks in Europe].
Ticks are direct pathogenic agents, and also transmit some infectious diseases such as borreliosis. Clinical manifestations of borreliosis are multiple. They most often affect the skin, nervous system, joints and heart. Cutaneous pseudolymphomas, erythema chronicum migrans of Afzelius, acrodermatitis chronica atrophicans of Pick-Herxheimer, meningo-radiculitis and various arthropathies are the most commonly encountered diseases.


A rare unreported bilateral thoracic muscle on the inferior and posteromedial aspect of the rib cage: case report and literature review.
Thoracic wall muscles are essential for respiration. Few anatomical variations in thoracic wall muscles have been reported. Such variants must be considered during surgical procedures that involve the thorax muscles. During routine dissection of a 65-year-old male cadaver as part of a fourth-year clinical anatomy elective, additional muscle strips were found in the inner and inferior aspect of the rib cage closer to the posteromedial body wall. The muscle consisted of two strips of narrow muscle fibres originating from the inferior borders of ribs 11 and 12 that radiated to insert on the transverse processes of the T11 and T12 vertebrae. The case report describes an unusual, novel medial thoracic wall muscle that has not been previously described in the literature. Variations in thoracic muscles can affect respiratory function and surgical interventions like chest tube placement and needle therapy for local anaesthesia, therefore, it is important for clinicians to be aware of such variants.


Ocular delivery of pilocarpine from erodible matrices.
The present study examined the feasibility of sustaining the release of a water-soluble drug, pilocarpine, to the tear film. Both gels and dried films were utilized as drug delivery systems. In vitro studies demonstrated significant prolongation of drug release from these systems as compared with simple aqueous or viscous solutions. The in vitro results were supported by in vivo miosis studies in albino rabbits.


When was secularization? Dating the decline of the British churches and locating its cause.
Dating the decline of Christianity in Britain has a vital bearing on its explanation. Recent work by social historians has challenged the sociological view that secularization is due to long-term diffuse social processes by asserting that the churches remained stable and popular until the late 1950s and that the causes of decline lie in the social and cultural changes associated with the 1960s. We challenge this interpretation of the evidence. We also note that much of the decline of the churches is explained not by adult defection but by a failure to keep children in the faith. Given the importance of parental homogamy for the successful transmission of religious identity, the causes of decline in one generation may well lie in the experiences of the previous generation. We focus on the disruptive effects of the 1939-45 war on family formation and use survey data to argue for a staged model of decline that is compatible with the conventional gradual view of secularization.


Contributions of Conformational Flexibility to High-Affinity Zinc Binding in the Solute Binding Protein AztC.
Bacteria rely on ATP binding cassette (ABC) transporters for the import of various nutrients. Bacterial ABC importers utilize an extracellular solute binding protein (SBP) to bind the substrate with high affinity and specificity and deliver it to the membrane permease for transport. The essential metals iron, manganese, and zinc are bound and transported by the cluster A-I SBPs. Crystal structures exist for the metal-bound and metal-free forms of several cluster A-I SBPs that show relatively subtle conformational changes that accompany metal binding. Recent solution studies and molecular dynamics simulations indicate a more complex conformational landscape for the cluster A-I SBPs, suggesting that changes in protein dynamics upon metal binding may have an important role in recognition by the membrane permease and effective transport. Here, we investigate conformational states and dynamics in the cluster A-I SBP AztC fromParacoccus denitrificans, characterizing its unusual intrinsic fluorescence behavior and thermodynamics of zinc binding. These data suggest a dynamic equilibrium of at least two conformational states in the apo form and compensatory changes in the holo that provide for a significant entropic contribution to zinc binding. Correlation with available crystal structures suggests that the formation of a Trp-Phe π-stacking interaction in the metal-bound form may mediate the observed changes in fluorescence. The conformational dynamics identified here for AztC are likely applicable to other cluster A-I SBPs with relevance to their exploitation as potential antibiotic drug targets.


Overexpression of GATA1 confers resistance to chemotherapy in acute megakaryocytic Leukemia.
It has been previously shown that acute myeloid leukemia (AML) patients with higher levels of GATA1 expression have poorer outcomes. Furthermore, pediatric Down syndrome (DS) patients with acute megakaryocytic leukemia (AMKL), whose blast cells almost universally harbor somatic mutations in exon 2 of the transcription factor gene GATA1, demonstrate increased overall survival relative to non-DS pediatric patients, suggesting a potential role for GATA1 in chemotherapy response. In this study, we confirmed that amongst non-DS patients, GATA1 transcripts were significantly higher in AMKL blasts compared to blasts from other AML subgroups. Further, GATA1 transcript levels significantly correlated with transcript levels for the anti-apoptotic protein Bcl-xL in our patient cohort. ShRNA knockdown of GATA1 in the megakaryocytic cell line Meg-01 resulted in significantly increased cytarabine (ara-C) and daunorubicin anti-proliferative sensitivities and decreased Bcl-xL transcript and protein levels. Chromatin immunoprecipitation (ChIP) and reporter gene assays demonstrated that the Bcl-x gene (which transcribes the Bcl-xL transcripts) is a bona fide GATA1 target gene in AMKL cells. Treatment of the Meg-01 cells with the histone deacetylase inhibitor valproic acid resulted in down-regulation of both GATA1 and Bcl-xL and significantly enhanced ara-C sensitivity. Furthermore, additional GATA1 target genes were identified by oligonucleotide microarray and ChIP-on-Chip analyses. Our findings demonstrate a role for GATA1 in chemotherapy resistance in non-DS AMKL cells, and identified additional GATA1 target genes for future studies.


Skeletal union following long bone reconstruction using vascularised fibula graft.
Thirteen patients had skeletal reconstruction using vascularised fibula graft following resection of the diseased bone. Eleven patients had reconstruction of the lower limbs and two patients of the upper limbs. Clinical and radiographical evidence union were achieved with the average time of 32 weeks (earliest eight weeks). Six out of 11 patients (54%) in lower limb reconstruction started weight bearing at the average of 27 weeks. Bony union in this study is comparable with other studies using vascularised fibula graft.


Homeopathic Treatment of Ramsay Hunt Syndrome: A Case Report.
Ramsay Hunt Syndrome (RHS) is an uncommon neurological complication resulting from the reactivation of latent herpes zoster virus. The condition often presents with facial paralysis, palatal ulcers, dysphagia, and altered taste sensation, leading to reduced quality of life. Standard therapeutic options for RHS have limitations, prompting the exploration of alternative treatments with improved prognostic outcomes. This case report aims to present a noteworthy clinical observation of RHS managed with individualized homeopathic treatment, emphasizing its potential therapeutic efficacy. A 24-year-old female patient exhibited left-sided facial weakness, along with palatal ulcers, dysphagia, and ageusia, prompting the diagnosis of RHS. Following the principles of homeopathy, a personalized therapeutic regimen was formulated, consisting tailored administration of Rhus toxicodendron, Spigelia anthelmia, and Sulphur. The House-Brackmann scale was employed to objectively assess the severity of facial palsy, while photographic documentation tracked the progression of palatal ulcers and facial paralysis. Over a carefully monitored observation period of 14 days, the patient demonstrated notable therapeutic responses. There was a significant reduction in the extent of palatal ulceration, and left-sided facial palsy exhibited marked improvement. Subsequent days witnessed a consistent amelioration of the patient's condition, substantiating the effect of the individualized homeopathic treatment. This case report highlights an exceptional instance of RHS recovery within a relatively short timeframe, achieved through the administration of individualized homeopathic therapy. The favorable outcomes observed in this case underscore the potential of homeopathy as a promising alternative intervention for RHS management. Nevertheless, further systematic investigations are imperative to comprehensively evaluate the scope and applicability of homeopathy in the treatment of RHS.


Teaching individualized antibiotic dosage regimens by means of two computer-assisted learning programs.
We developed two multidisciplinary tutorial programs (TOBRA-DIDACT and VANCO-DIDACT) for teaching the basic principles of antibiotic drug monitoring by simulation of repeated administrations to fictitious patients whose physio-pathologic characteristics were pre-defined in the programs. To illustrate the two types of bactericidal kinetics, we have chosen one time-dependent (vancomycin) and one concentration-dependent (tobramycin) antibiotic. These computer-assisted programs operate on an interactive mode. In each of them, three main steps are connected: (1) Various types of clinical cases are submitted to the student: for each of them, case report includes clinical characteristics, location of infection, bacterial strain and minimal bactericidal concentration. These data must be taken into account during the following steps. (2) The student has to establish the treatment schedule: route of administration, dose for each injection, intervals between injections and duration of infusion. (3) The result of the dosage scheme proposed by the student is represented by a simulation of plotting antibiotic plasma concentrations vs. time during the first 4 days of treatment. These curves are obtained by a monoexponential (TOBRA-DIDACT) or biexponential (VANCO-DIDACT) pharmacokinetic model. Peak and trough concentrations are calculated at steady-state. An expert system provides a commentary with each result to evaluate the efficacy of the treatment and to assist the student in improving his prescription. TOBRA-DIDACT and VANCO-DIDACT illustrate the influence of age, obesity, renal impairment, location of infection and bacterial strain on antibiotic therapy. They also show the role of route of administration, dosing and intervals between injections on therapeutic response.(ABSTRACT TRUNCATED AT 250 WORDS)


Impact of pretransplant renal failure: when is listing for kidney-liver indicated?
Renal and hepatic function are often intertwined both through the existence of associated primary organ diseases and hemodynamic interrelationships. This connection occasionally results in the chronic failure of both organs, necessitating the need for combined kidney-liver transplantation. Since 1990, over 1,790 patients in the United States have received such transplants with a patient survival somewhat less than that for patients receiving either organ alone. Patients with renal failure due to acute injury or to the hepatorenal syndrome have classically not been included as candidates for combined transplantation due to the reversibility of the renal dysfunction following liver transplantation. However, the rate and duration of renal failure prior to liver transplantation continues to be prolonged even with the new allocation scheme prioritizing liver transplants to those with renal failure. Thus the issue of when kidney transplantation should be offered and what evaluation is necessary prior to the decision continues to confront the transplant community.


Synergistic Cu/Pd Catalysis for Enantioselective Allylic Alkylation of Aldimine Esters: Access to α,α-Disubstituted α-Amino Acids.
An unprecedented enantioselective allylic alkylation of readily available aldimine esters has been developed, and is catalyzed by a synergistic Cu/Pd catalyst system. This strategy provides facile access to nonproteinogenic α,α-disubstituted α-amino acids in high yield with excellent enantioselectivity. The more challenging double allylic alkylation of glycinate-derived imine esters was also realized. Furthermore, this methodology was applied for the construction of the key intermediate of PLG peptidomimetics.


Challenges in dyslipidemia.
Dyslipidemia is recognized as a significant risk factor for atherosclerotic disease. There has been a great deal of progress in the detection and management of dyslipidemia, but challenges remain, including whether to treat children, adolescents, and the elderly. Challenges include convincing physicians who tend to manage an outpatient disease with a single therapy that the management of cardiovascular risk and disease often requires multiple therapies, describing how we can combine therapies to provide an additive benefit without adding side effects or increasing morbidity, and determining whether a patient with one or more cardiovascular risk factors but a normal lipid should receive lipid-lowering therapy. Finally, there is the challenge of the Human Genome Project and predictive medicine. How will genetic information be integrated into the practice of medicine for disease prevention and management?


Musk gland seasonal development and musk secretion are regulated by the testis in muskrat (Ondatra zibethicus).
The muskrat is a seasonal breeder. Males secrete musk to attract females during the breeding season. The testosterone binding to the androgen receptor (AR) in musk glands of muskrat may play an important role conducting the musk secretion process. The musk gland, testis and blood samples of musk rats are collected in both breeding and non-breeding seasons. Some part of the samples are kept in liquid nitrogen for transcriptome analysis and Western blotting test. Some part of the samples are kept in 70% alcohol for histology experiment, blood samples are kept at -20 °C for the serum testosterone measurement experiment. This study demonstrates that the quantity of secreted musk, the volume of the musk glands, the diameter of the gland cells and AR expression are all higher during the breeding season than at other times (p < 0.01). StAR, P450scc and 3β-HSD expression in the Leydig cells of the testis were also higher during this season, as was serum testosterone. AR was also observed in the gland cells of two other musk-secreting animals, the musk deer and small Indian civet, in their musk glands. These results suggest that the testes and musk glands co-develop seasonally. The musk glands' seasonal development and musk secretion are regulated by the testes, and testosterone plays an important role in the seasonal development of musk glands.


[Prevalence of cardiovascular risk factors in a cohort of affected by the toxic oil syndrome].
During the first stages of the toxic oil syndrome (TOS), elevations of the blood pressure as well as increases in the cholesterol, glucose and triglycerides levels were reported. Here we analyze these cardiovascular risk factors in the chronic phase of the illness and their distribution according to the severity of the illness. We also compare them with those found in the general population. We studied a sample of 1,862 individuals aged between 35 and 65 years. A medical examination was performed in each and blood pressure, weight, height, tobacco consumption, cholesterol, glucose and triglycerides levels were measured. The prevalence of high blood pressure (>140/90 mmHg) was 46.1% and the prevalence of diabetes mellitus (>126 mg/dl) was 9.1%. The prevalence of obesity (BMI>30) was 24.9%. 11.8% of patients had hypertriglyceridemia (>200 mg/dl) and 19.8% had hypercholesterolemia (>250 mg/dl). 37.9% were smokers. The standardized prevalence rate (SPR) of high blood pressure was 1.35 (95% CI, 1.28-1.44); tobacco consumption SPR=1.27 (95% CI, 1.20-1.36); hypercholesterolemia SPR=1.10 (95% CI, 1.01-1.21). The prevalence of risk factors was higher among the most seriously affected subjects. The chronic phase of TOS is characterized by a high prevalence of cardiovascular risk factors, which was significantly higher than that expected in the general population.


Effect of Tannins in Green Tea on the Urinary Methylguanidine Excretion in Rats Indicating a Possible Radical Scavenging Action.
The hydroxyl radical scavenging action of green tea tannin given orally to rats with experimental renal failure was examined by using the urinary methylguanidine excretion as an index. In rats given 2 mg of a green tea tannin mixture, the urinary methylguanidine excretion was significantly decreased or had a tendency to decrease. (-)-Epigallocatechin 3-O-gallate, the predominant component of the green tea tannin mixture, effected a decrease in the urinary methylguanidine excretion in rats at a dose as low as 0.25 mg, suggesting a hydroxyl radical scavenging action.


Maximal sterile barrier precautions independently contribute to decreased central line-associated bloodstream infection in very low birth weight infants: A prospective multicenter observational study.
The use of peripherally inserted central catheters (PICCs) in neonates differs among various institutions and countries because there are no random controlled trials or large observational studies regarding maximal sterile barrier (MSB) precautions in neonatal intensive care units. Our objective was to investigate the association of MSB implementation with central line-associated bloodstream infection (CLABSI) in very low birth weight infants. This was a prospective multicenter observational study in Japan of infants with birth weight less than 1501 grams and in whom a PICC was placed for the first time between October 2014 and March 2017. Risk factors for CLABSI, both related and unrelated to MSB, were assessed by the mixed-effects Cox proportional hazards model, with the neonatal center variable as the random effect. In total, 33,713 catheter-days among 2383 infants were included. We observed 70 cases of CLABSI. MSB precautions were implemented in 13.9% of insertions and were associated with a lower CLABSI risk (adjusted hazard ratio, 0.20; 95% confidence interval, 0.05-0.84). We found that MSB implementation during PICC insertion in infants with birth weight less than 1501 grams independently contributed to a decrease in CLABSI risk.


Evaluation of a Smartphone-Based Training Strategy Among Health Care Workers Screening for Cervical Cancer in Northern Tanzania: The Kilimanjaro Method.
Almost nine of 10 deaths resulting from cervical cancer occur in low-income countries. Visual inspection under acetic acid (VIA) is an evidence-based, cost-effective approach to cervical cancer screening (CCS), but challenges to effective implementation include health provider training costs, provider turnover, and skills retention. We hypothesized that a smartphone camera and use of cervical image transfer for real-time mentorship by experts located distantly across a closed user group through a commercially available smartphone application would be both feasible and effective in enhancing VIA skills among CCS providers in Tanzania. We trained five nonphysician providers in semirural Tanzania to perform VIA enhanced by smartphone cervicography with real-time trainee support from regional experts. Deidentified images were sent through a free smartphone application on the available mobile telephone networks. Our primary outcomes were feasibility of using a smartphone camera to perform smartphone-enhanced VIA and level of agreement in diagnosis between the trainee and expert reviewer over time. Trainees screened 1,072 eligible women using our methodology. Within 1 month of training, the agreement rate between trainees and expert reviewers was 96.8%. Providers received a response from expert reviewers within 1 to 5 minutes 48.4% of the time, and more than 60% of the time, feedback was provided by regional expert reviewers in less than 10 minutes. Our method was found to be feasible and effective in increasing health care workers' skills and accuracy. This method holds promise for improved quality of VIA-based CCS programs among health care providers in low-income countries.


Selective COX-2 inhibition and cardiovascular effects: a review of the rofecoxib development program.
See related Editorials on pages 561 and 563. Cyclo-oxygenase-2 (COX-2) inhibitors appear to alter the balance of vasoactive eicosanoids (prostacyclin and thromboxane) and to suppress the inflammatory mediators implicated in the progression of atherogenesis and ischemic myocardial injury. Neutral, harmful, and beneficial cardiovascular (CV) effects have all been postulated to result from these changes. Investigations conducted with rofecoxib, a selective COX-2 inhibitor, have substantially contributed to our understanding of this scientific area. Rofecoxib had little or no effect on platelet aggregation or platelet-derived thromboxane synthesis but reduced systemic prostacyclin synthesis by 50% to 60%. These findings prompted extensive analyses of CV thrombotic events within the rofecoxib development program. Among 5435 osteoarthritis trial participants, similar rates of CV thrombotic events were reported with rofecoxib, placebo, and comparator, nonselective NSAIDs (ibuprofen, diclofenac, and nabumetone). In the VIGOR gastrointestinal outcomes trial of >8000 patients, naproxen (an NSAID with aspirin-like sustained antiplatelet effects throughout its dosing interval) was associated with a significantly lower risk of CV events than was rofecoxib. A subsequent pooled analysis from 23 studies (including VIGOR) encompassing multiple disease states and including more than 14,000 patient-years at risk also demonstrated that rofecoxib was not associated with excess CV thrombotic events compared with either placebo or nonnaproxen NSAIDs. Again, naproxen appeared to be the outlier, suggesting a cardioprotective benefit of naproxen. Finally, among the predominantly elderly, male population participating in Alzheimer trials, both rofecoxib- and placebo-treated patients had similar rates of CV thrombotic events. The totality of data is not consistent with an increased CV risk among patients taking rofecoxib.


Ligand-induced structural constraints in human dihydrofolate reductase revealed by peptide-specific antibodies.
Peptides from human dihydrofolate reductase (DHFR) generated by cyanogen bromide cleavage and corresponding to residues 15-52, 53-111, 112-125, and 140-186 (carboxyl terminus) were purified and used to immunize rats. Titration of the immune sera against denatured human DHFR by solid-phase immunoassay showed that peptides 15-52 and 140-186 were relatively highly immunogenic, unlike the native enzyme which is most immunogenic in the sequence 53-111. The antisera were specific for the corresponding peptides used for immunization. Antibodies to peptides 15-52, 53-111, and 140-186 cross-reacted with native human DHFR in solution in competition assays. However, the binding of nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and the inhibitors folate and methotrexate, both in binary and in ternary complexes with the enzyme, caused a striking reduction in binding of antibody. Using a sensitive radioactive assay, it was found that antisera to peptides 15-52 and 140-186, both of which exhibited a high antibody titer, caused significant inhibition of DHFR. Because peptide 140-186 does not include any active-site residues, it is concluded that at least in this case all the antibodies bound to regions outside the active site. Since comparison of the X-ray structures of the chicken liver DHFR holoenzyme with the apoenzyme reveals no changes in secondary structural elements (alpha-helices and beta-sheets), the reduction in antibody binding to DHFR-ligand complexes must not involve epitopes within these structures.(ABSTRACT TRUNCATED AT 250 WORDS)


[INTESTINAL MICROBIOTA: ITS ROLE IN PATHOGENESIS OF ARTERIAL HYPERTENSION].
The review presents data on the relationship of intestinal microbiota and the development of arterial hypertension. Mechanisms through which intestinal dysbiosis may contribute to the development of this disease are reviewed. Results of studies on modulation of intestinal microbiota in patients with arterial hypertension with the use of probiotics and antibiotics are presented. It is concluded that the development of innovative dietary strategies ensuring restoration of the balance in the intestinal microbiota will allow to effectively control and treat arterial hypertension.


Adapting Clinical Guidelines for the Digital Age: Summary of a Holistic and Multidisciplinary Approach.
The Centers for Disease Control and Prevention's Adapting Clinical Guidelines for the Digital Age initiative aims to redesign and improve guideline development, implementation, and standardization. Historically, aspects of guideline development and implementation have been siloed. This leads to long lag times for guidelines to reach patient care, unnecessary redundancy, and potential for misinterpretation, leading to inconsistencies in how the recommendations are applied. A multidisciplinary, multiorganizational holistic approach brought together experts in guideline development, informatics, communication, implementation, and evaluation to understand and identify problems in guideline development and implementation, define an ideal state with no constraints, and then design a future state that advances the process close to the ideal state. The Adapting Clinical Guidelines for the Digital Age workgroups each worked on one focus area and included experts from the other areas to help analyze the current state and develop holistic solutions for the future state. Each workgroup produced interrelated standards, processes, and tools that can be used across the continuum of guideline development and implementation.


Association of Thyroid-Stimulating Hormone Levels with Microvascular Complications in Type 2 Diabetes Patients.
BACKGROUND Subclinical hypothyroidism (SCH) is typically featured by elevated serum concentration of thyroid-stimulating hormone (TSH). This study aimed to determine the relationship between TSH levels and microvascular complications in type 2 diabetes patients. MATERIAL AND METHODS A total of 860 type 2 diabetes patients were enrolled in this cross-sectional study. Subjects were evaluated for anthropometric measurements, thyroid function, diabetic retinopathy, and diabetic kidney disease. TSH was divided into 3 levels: 0.27-2.49 mU/l, 2.5-4.2 mU/l, and >4.2 mU/l. RESULTS Among the participants, 76 subjects (8.8%) were diagnosed with subclinical hypothyroidism (SCH) (male: 6.6% and female: 11.8%). The prevalence of diabetic retinopathy did not differ among the groups (P=0.259). Of the 860 type 2 diabetic subjects, we further excluded invalid or missing data. Therefore, 800 and 860 subjects were included in our study of diabetic retinopathy (DR) and diabetic kidney disease (DKD), respectively. The frequencies of microalbuminuria and macroalbuminuria differed significantly among the different groups. The frequency of DKD was significantly different among the 3 groups (P=0.001) and was higher in subjects with higher TSH levels. After an adjustment for confounding variables, TSH levels were significantly associated with DKD (P<0.001). When compared with subjects with TSH 0.27-2.49 mU/l, the frequency of DKD was higher in subjects with TSH >4.20 mU/l (OR 1.531, 95% CI 1.174-1.997) and with TSH 2.50-4.20 mU/l (OR 1.579, 95% CI 1.098-2.270). However, TSH levels was not significantly correlated with DR (P=0.126). CONCLUSIONS Type 2 diabetic patients with higher TSH values had a higher prevalence of DKD.


Evaluation of the Punch-it™ NA-Sample kit for detecting microbial DNA in blood culture bottles using PCR-reverse blot hybridization assay.
DNA extraction efficiency affects the success of PCR-based method applications. The Punch-it™ NA-Sample kit for extracting DNA by using paper chromatography is technically easy to use and requires just two reagents and only 10min to complete. The Punch-it™ NA-Sample kit could be offered as a rapid, accurate, and convenient method for extracting bacterial and fungal DNA from blood culture bottles. We compared the efficiencies of the commercial kit (Punch-it™ NA-Sample kit) and an in-house conventional boiling method with Chelex-100 resin for DNA extraction from blood culture bottles. The efficiency of the two DNA extraction methods was assessed by PCR-reverse blot hybridization assay (PCR-REBA, REBA Sepsis-ID) for detecting Gram positive (GP) bacteria, Gram negative (GN) bacteria, and Candida species with 196 positive and 200 negative blood culture bottles. The detection limits of the two DNA extraction methods were 10(3)CFU/mL for GP bacteria, 10(3)CFU/mL for GN bacteria, and 10(4)CFU/mL for Candida. The sensitivity and specificity of the Punch-it™ NA-Sample kit by REBA Sepsis-ID were 95.4% (187/196) and 100% (200/200), respectively. The overall agreement of the two DNA extraction methods was 98.9% (392/396). Three of four samples showing discrepant results between the two extraction methods were more accurately matched up with the Punch-it™ NA-Sample kit based on conventional culture methods. The results indicated that the Punch-it™ NA-Sample kit extracted bacterial and fungal DNA in blood culture bottles and allowed extracted DNA to be used in molecular assay.


Plasma antiphospholipid antibody levels in age-related macular degeneration.
To investigate the association of age-related macular degeneration (AMD) with plasma antiphospholipid antibody levels. This prospective study included 19 patients diagnosed as having dry-type AMD, 23 patients with exudative-type AMD, and 25 control subjects. Venous blood samples of the participants were obtained. Anticardiolipin antibodies (aCL) isotypes IgG and IgM were measured by means of an enzyme-linked immunosorbent assay. Lupus anticoagulant (LA) antibodies were measured by the dilute Russell viper venom time screen test. The mean aCL IgG concentration in patients with exudative-type AMD was significantly higher than in patients with dry-type AMD and control subjects. The mean ± SE of aCL IgG levels in patients with exudative-type AMD and dry-type AMD and control subjects was 5.46 ± 1.26; 2.55 ± 0.78; and 0.32 ± 0.1, respectively. The mean aCL IgM levels and LA levels in the 3 groups were not statistically different. Our findings suggest that elevated levels of serum aCL, a risk factor for cardiovascular and cerebrovascular diseases, may be associated with exudative-type AMD.


N-peptide of vMIP-Ⅱ reverses paclitaxel-resistance by regulating miRNA-335 in breast cancer.
Acquisition of resistance to paclitaxel is one of the most important problems in treatment of breast cancer patients, but the molecular mechanisms underlying sensitivity to paclitaxel remains elusive. Emerging evidence has demonstrated that microRNAs (miRNAs) play important roles in regulation of cell growth, migration and invasion through inhibiting the expression of its target genes. In our previous studies, we have shown that microRNA-335 (miR‑335) decreased obviously between paclitaxel-resistant (PR) and parental breast cancer cells through miRNA microarray. However, the roles of miR‑335 in breast cancer progression and metastasis are still largely unknown. NT21MP was designed and synthesized as an antagonist with CXCR4 to inhibit cellular proliferation and induce apoptosis. Therefore, the aim of this study was to explore the underlying mechanism of miR‑335 and NT21MP in reverse PR in breast cancer cells. In this study, we found that miR‑335 expression is significantly lower in PR MCF‑7 and SKBR-3 cells (MCF‑7/PR and SKBR-3/PR) compared with their parental MCF‑7 and SKBR-3 cells. Functional experiments showed that overexpression of miR‑335 and NT21MP increased the number of apoptosis cells, arrested cells in G0/G1 phase transition, and suppressed cell migration and invasion in vitro. Dual luciferase assays revealed that SETD8 is a direct target gene of miR‑335. Furthermore, miR‑335 markedly inhibited expression of SETD8 via Wnt/β‑catenin signaling and subsequently inhibited the expression of its downstream genes cyclin D1, and c‑Myc. Additionally, ectopic expression of miR‑335 or depletion of its target gene SETD8 could enhance the sensitivity of PR cells to paclitaxel. Taken together, these date elucidated that NT21MP and miR‑335 mediated PR of breast cancer cells partly through regulation of Wnt/β‑catenin signaling pathway. Activation of miR‑335 or inactivation of SETD8 could be a novel approach for the treatment of breast cancer.


Colonic polyps and adenocarcinoma complicating ureterosigmoidostomy: report of a case.
A case of bilateral juvenile polyps and unilateral adenocarcinoma at the ureterocolic junctions occurring 40 years after ureterosigmoidostomy for exstrophy of the bladder is reported. Although adenocarcinoma of colon at the anastomotic site represents an uncommon late complication of ureterosigmoidostomy, patients undergoing this form of urinary diversion have a risk of developing colonic carcinoma that is 100 to 550 times greater than the normal population. Moreover this complication is being reported with increasing frequency in the literature. Different pathogenetic factors may play a role in carcinogenesis, but none has been satisfactorily proven. We suggest the possibility that polyps developing at the site of a ureterocolic junction may represent precancerous lesions.


Hidradenitis Suppurativa is Associated with Higher Heart Rate but Not Atrial Fibrillation: A Comparative Cross-sectional Study of 462 Individuals with Hidradenitis Suppurativa in Denmark.
Hidradenitis suppurativa (HS) is a chronic inflammatory dermatological disease with inflammatory mechanisms overlapping those of psoriasis, and both diseases have been associated with cardiovascular risk factors i.e. smoking and metabolic syndrome. Two studies have recently linked psoriasis with Atrial Fibrillation (AF). AF is the most frequently occurring cardiac arrhythmia in the general population and is typically accompanied by increased heart rate. Both AF and heart rate are linked with inflammation. The aim of the study was to investigate a potential association between HS and increased heart rate as well as AF. We performed a comparative cross-sectional study using digital measurements of heart rate and resting 12-lead electrocardiography (ECG) in combination with self-reported information when diagnosing AF. Our study comprised 32 individuals with HS from the hospital (the hospital HS group), 430 from the general population HS group (the population HS group), and 20,780 controls. Age and sex adjusted analysis demonstrated a significantly higher heart rate in the HS groups vs. controls (15% (range: 8-23%) higher for the hospital HS group and 4% (2-5%) higher for the population HS group). We found no association between HS and AF (P=0.1670).


Primary progressive multiple sclerosis: clinical and paraclinical characteristics with application of the new diagnostic criteria.
The aim of our study was to analyse clinical and paraclinical characteristics of patients with multiple sclerosis (MS) with previous diagnosis of primary-progressive (PP) MS according to the Poser's criteria and further investigate if they fulfil the McDonald's diagnostic criteria for this disorder. A total of 561 MS patients were registered in the database at the Institute of Neurology, Belgrade, from 1 January 1997 to 31 December 2000 and 63 of them (11.2%) with previous diagnosis of PPMS were analysed retrospectively. Male/female ratio was 1.3:1 and mean age at onset 33.2 years. Most frequent at onset were pyramidal (in 73% of patients) and sensory symptoms (in 41% of patients); 74.6% of patients had greater than or equal to nine brain magnetic resonance imaging (MRI) lesions. Intrathecal oligoclonal immunoglobulin G (IgG) was detected in 96.7% and prolonged visual evoked potentials (VEP) P100 latency in 82.4% of patients. Of the total study group of 561 patients, 10.2% fulfilled the recently recommended McDonald's diagnostic criteria for the diagnosis of PPMS. Our findings further support the significance of the brain/spinal cord MRI, cerebrospinal fluid and VEP findings for precise diagnostic assessment in patients with suspected PP form of MS.


Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease.
Pain is prevalent among patients with diabetes and chronic kidney disease (CKD). The management of chronic pain in these patients is limited by nephrotoxicity of commonly used drugs including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Since previous studies implicated endothelin-1 in pain nociception, our post hoc analysis of the SONAR trial assessed the association between the endothelin receptor antagonist atrasentan and pain and prescription of analgesics. SONAR was a randomized, double-blind, placebo-controlled clinical trial that recruited participants with type 2 diabetes and CKD (estimated glomerular filtration rate 25-75 ml/min/1.73 m2; urinary albumin-to-creatinine ratio 300-5000 mg/g). Participants were randomized to receive atrasentan or placebo (1834 each arm). The main outcome was pain-related adverse events (AEs) reported by investigators. We applied Cox regression to assess the effect of atrasentan compared to placebo on the risk of the first reported pain-related AE and, secondly, first prescription of analgesics. We used the Anderson-Gill method to assess effects on all (first and subsequent) pain-related AEs. During 2.2-year median follow-up, 1183 pain-related AEs occurred. Rates for the first pain-related event were 138.2 and 170.2 per 1000 person-years in the atrasentan and placebo group respectively (hazard ratio 0.82 [95% confidence interval 0.72-0.93]). Atrasentan also reduced the rate of all (first and subsequent) pain-related AEs (rate ratio 0.80 [0.70-0.91]). These findings were similar after accounting for competing risk of death (sub-hazard ratio 0.81 [0.71-0.92]). Patients treated with atrasentan initiated fewer analgesics including NSAIDs and opioids compared to placebo during follow-up (hazard ratio = 0.72 [0.60-0.88]). Thus, atrasentan was associated with reduced pain-related events and pain-related use of analgesics in carefully selected patients with type 2 diabetes and CKD.


The rheumatoid cervical spine: signs of instability on plain cervical radiographs.
The cervical spine is a common focus of destruction from rheumatoid arthritis, second only to the metacarpophalangeal joints. Joint, bone and ligament damage in the cervical spine leads to subluxations which can cause cervical cord compression resulting in paralysis and even sudden death. Because many patients with significant subluxations are asymptomatic, the radiologist plays a key role in recognizing the clinically important clues to instability on plain radiographs of the cervical spine-often difficult in rheumatoid arthritis when the bony landmarks are osteoporotic or eroded. This review focuses on the signs of instability on plain radiographs of the cervical spine, using diagrams and clinical examples to illustrate methods of identifying significant subluxations in rheumatoid arthritis.


Integrative review: Persistent vocalizations among nursing home residents with dementia.
ABSTRACTBackground:Nursing home (NH) residents with dementia commonly exhibit persistent vocalizations (PVs), otherwise known in the literature as disruptive or problematic vocalizations. Having a better understanding of PVs and the research completed to date on this phenomenon is important to guide further research and clinical practice in NHs. This integrative review examines the current literature on the phenomenon of PVs among NH residents with dementia. We conducted a search in the PubMed, Scopus, Ovid Medline, and CINAHL databases for articles published in English. Articles were included if the focus was specifically on research involving vocal behaviors of older adults with dementia residing in NHs. Our literature search revealed eight research articles that met the inclusion criteria. These studies were published in 2011 or earlier and involved small sample sizes. Seven of these studies were descriptive and the eighth was a non-pharmacological intervention study for PVs exhibited by NH residents with dementia. These studies were vastly different in their labeling, definitions, and categorization of the PVs as well as methods of measuring PVs. The heterogeneity of the evidence limits the ability to make recommendations for practice. Given the paucity of research on this phenomenon; recommendations for additional research are given.


Risk Factors of Acute Kidney Injury in Critically Ill Children.
Acute kidney injury may be promoted by critical illness, preexisting medical conditions, and treatments received both before and during ICU admission. We aimed to estimate the frequency of acute kidney injury during ICU treatment and to determine factors, occurring both before and during the ICU stay, associated with the development of acute kidney injury. Cohort study of critically ill children. University-affiliated PICU. Eligible patients were admitted to the ICU between January 2006 and June 2009. We excluded those admitted with known primary renal failure, chronic renal failure or postrenal transplant, conditions with known renal complications, or metabolic conditions treated with dialysis. Patients were also excluded if they had a short ICU stay (< 6 hr) and those who had no creatinine or urine output measurements during their ICU stay. None. Of the 3,865 pediatric patients who met the inclusion criteria, 915 (23.7%) developed acute kidney injury, as classified by the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease criteria, during their ICU stay. Patients at high risk for development of acute kidney injury included those urgently admitted to the ICU (adjusted odds ratio, 1.88), those who developed respiratory dysfunction during their ICU care (adjusted odds ratio, 2.90), and those who treated with extracorporeal membrane oxygenation (adjusted odds ratio, 2.72). The single greatest risk factor for acute kidney injury was the administration of nephrotoxic medications during ICU admission (adjusted odds ratio, 3.37). This study, the largest evaluating the incidence of RIFLE-defined acute kidney injury in critically ill children, found that one-quarter of patients admitted to the ICU developed acute kidney injury. We identified a number of potentially modifiable risk factors, the largest of which was the administration of nephrotoxic medication. The results of this study may be used to inform targeted interventions to reduce acute kidney injury and improve the outcomes of critically ill children.


Genomic relations among 31 species of Mammillaria haworth (Cactaceae) using random amplified polymorphic DNA.
Thirty-one species of Mammillaria were selected to study the molecular phylogeny using random amplified polymorphic DNA (RAPD) markers. High amount of mucilage (gelling polysaccharides) present in Mammillaria was a major obstacle in isolating good quality genomic DNA. The CTAB (cetyl trimethyl ammonium bromide) method was modified to obtain good quality genomic DNA. Twenty-two random decamer primers resulted in 621 bands, all of which were polymorphic. The similarity matrix value varied from 0.109 to 0.622 indicating wide variability among the studied species. The dendrogram obtained from the unweighted pair group method using arithmetic averages (UPGMA) analysis revealed that some of the species did not follow the conventional classification. The present work shows the usefulness of RAPD markers for genetic characterization to establish phylogenetic relations among Mammillaria species.


[Molecular study on minute alterations of the p53 and the N-ras genes in hematologic malignancies].
Minute alterations of the p53 tumor suppressor gene and N-ras oncogene were investigated in 106 samples for the p53 gene and 23 samples for the N-ras gene obtained from patients with various types of hematologic malignancies using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and direct nucleotide sequencing. Mobility shifts suggesting sequence alteration were observed in 9 cases (8.5%) in exons 5 through 8 containing evolutionarily highly conserved regions of the p53 gene by PCR-SSCP; missense point mutations in 3 cases (1 acute myelogenous leukemia (AML), 1 chronic myelogenous leukemia (CML) in the accelerated phase, and 1 CML in the blast crisis), silent point mutation in 1 case (malignant lymphoma), and frame shift mutations due to insertions and deletions causing stop codons in 3 cases (1 AML, 1 CML in the chronic phase and 1 acute lymphoblastic leukemia (ALL)). p53 gene alterations did not always cluster within evolutionarily highly conserved regions, and there were various base change forms in cases with p53 point mutations. p53 mutations were detected in 2 cases out of 4 cases with 17 monosomy. There was no case with p53 gene alteration in myelodysplastic syndrome (MDS) cases. Mobility shifts suggesting sequence alteration were observed in 5 cases (22%) in exon 1 and 2 of the N-ras gene by PCR-SSCP. 3 cases (1 MDS, 1 MDS overt AML and 1 ALL) were detected to contain missense point mutations. However, simultaneous mutations in both the genes were detected in only 2 cases out of 23, thereby indicating infrequent occurrence of concomitant mutation of both the genes in hematologic malignancies. Alterations of the p53 and the N-ras genes are involved in the tumorigenesis, progression and prognosis of at least some cases of hematologic malignancies, in spite that they are relatively infrequent.


Do patients with localized prostate cancer treatment really want more aggressive treatment?
Examine whether patients with prostate cancer choose the more aggressive of two radiotherapeutic options, whether this choice is reasoned, and what the determinants of the choice are. One hundred fifty patients with primary prostate cancer (T(1-3)N(0)M(0)) were informed by means of a decision aid of two treatment options: radiotherapy with 70 Gy versus 74 Gy. The latter treatment is associated with more cure and more toxicity. The patients were asked whether they wanted to choose, and if so which treatment they preferred. They also assigned importance weights to the probability of various outcomes, such as survival, cure and adverse effects. Patients who wanted to choose their own treatment (n = 119) are described here. The majority of these patients (75%) chose the lower radiation dose. Their choice was highly consistent (P < or = .001), with the importance weights assigned to the probability of survival, cure (odds ratio [OR] = 6.7 and 6.9) and late GI and genitourinary adverse effects (OR = 0.1 and 0.2). The lower dose was chosen more often by the older patients, low-risk patients, patients without hormone treatment, and patients with a low anxiety or depression score. Most patients with localized prostate cancer prefer the lower radiation dose. Our findings indicate that many patients attach more weight to specific quality-of-life aspects (eg, GI toxicity) than to improving survival. Treatment preferences of patients with localized prostate cancer can and should be involved in radiotherapy decision making.


Increased sensitization prevalence to common inhalant and food allergens in young adult Polish males.
Numerous epidemiological studies concluded recently have suggested that the prevalence of allergic diseases has increased, which mainly results from an increase in the prevalence of atopic diseases. The problem is even more difficult because the number of people sensitized, who are prone to fall ill, exceeds the number of people presently ill. The prevalence of sensitization to atopic allergens and its time dynamic is still unknown. The aim of the study was to determine the prevalence of atopic sensitization in the population of young Polish males and to compare these findings with those obtained 16 years before. The present study was performed on a group of 156 randomized healthy men, voluntary blood donors, aged 18-27 years. Having filled out a questionnaire, they underwent skin prick tests (SPTs) to common inhalant allergens. They also had a blood sample taken to have serum total IgE concentration and allergen-specific IgE (asIgE) determined to inhalant and food allergens. Positive SPT findings to at least one allergen were found in 50 (32%) subjects, and in equivocal 12 (8%). In 54 (35%) subjects asIgE to inhalant allergens was found, including 11 (7%) who had been tested for food allergens. The most common sensitizing allergen was house dust mite (20%), followed by grass/rye pollen (17%), while mould spore was the least common (4%). In town dwellers, positive SPTs were found in 41%, and were positive in 19% of people living in rural areas. While comparing the present findings with those of a similar study carried out in 1986, we found that in the last 16 years there had been a 52% increase in the prevalence of asIgE to atopic allergens. This means that the percentage of sensitized people can be estimated to have increased at a rate of approximately 3.25%/year.


US suicide rates by age group, 1970-2002: an examination of recent trends.
US suicide rates have declined in recent years, reversing earlier trends. We examined suicide rates among 4 age groups from 1970 to 2002 and the factors that may have contributed to the decline. We paid particular attention to newer anti-depressants because of recent concerns and controversy about a possible association with suicidal behaviors. These trends warrant more extensive analysis of suicide rates among specific subgroups, including consideration of additional variables that may influence rates differentially. The relative contributions of depression diagnosis and treatment, postsuicide attempt care, and other contextual factors (e.g., overall economic conditions) also deserve attention. If the decline is associated with contextual factors, clarifying these associations will better inform public policy decisions and contribute to more effective interventions for preventing suicide.


Congenital lobar emphysema: long-term evaluation of surgically and conservatively treated children.
The clinical conditions, roentgenographic findings, and pulmonary function tests of 6 children (mean age, 10.9 years) with surgically treated congenital lobar emphysema (group 1) were compared with those of 5 children (mean age, 10.3 years) with congenital lobar emphysema who had been treated conservatively, i.e., nonsurgically (group 2). At the time of this study, patients in both groups were asymptomatic. Patients in group 1 were surgically treated because of severe respiratory distress in the newborn period, with the exception of one patient, who was eupneic as a newborn and was not operated on until the age of 9 years. Patients in group 2 were eupneic or mildly distressed in the neonatal period and received only conservative treatment. Two patients in group 1 had occasional wheezing and labored breathing, but no patient in group 2 had recurrent respiratory distress. Roentgenographically, at the time of the study, patients in group 1 had generalized overinflation, whereas those in group 2 had only localized overinflation of the involved lobe and minimal compression of remaining lung tissue. Pulmonary function studies in both groups were not significantly different (P greater than 0.05). Both groups had reduced forced vital capacities, large trapped gas volumes, and reduced forced expiratory flows at low lung volumes. Reductions in forced vital capacity were proportional to the unventilated volumes of lung either excised because of congenital lobar emphysema (group 1) or chronically obstructed by congenital lobar emphysema (group 2). These studies suggest that lung growth was not different in these 2 groups and that asymptomatic or midly symptomatic patients do not benefit from surgical treatment.


Peroxisomal localization of hypoxia-inducible factors and hypoxia-inducible factor regulatory hydroxylases in primary rat hepatocytes exposed to hypoxia-reoxygenation.
Many signals involved in pathophysiology are controlled by hypoxia-inducible factors (HIFs), transcription factors that induce expression of hypoxia-responsive genes. HIFs are post-translationally regulated by a family of O2-dependent HIF hydroxylases: four prolyl 4-hydroxylases and an asparaginyl hydroxylase. Most of these enzymes are abundant in resting liver, which is itself unique because of its physiological O2 gradient, and they can exist in both nuclear and cytoplasmic pools. In this study, we analyzed the cellular localization of endogenous HIFs and their regulatory hydroxylases in primary rat hepatocytes cultured under hypoxia-reoxygenation conditions. In hepatocytes, hypoxia targeted HIF-1alpha to the peroxisome, rather than the nucleus, where it co-localized with von Hippel-Lindau tumor suppressor protein and the HIF hydroxylases. Confocal immunofluorescence microscopy demonstrated that the HIF hydroxylases translocated from the nucleus to the cytoplasm in response to hypoxia, with increased accumulation in peroxisomes on reoxygenation. These results were confirmed via immunotransmission electron microscopy and Western blotting. Surprisingly, in resting liver tissue, perivenous localization of the HIF hydroxylases was observed, consistent with areas of low pO2. In conclusion, these studies establish the peroxisome as a highly relevant site of subcellular localization and function for the endogenous HIF pathway in hepatocytes.


The global burden of alcoholic liver disease: a systematic analysis of the global burden of disease study 2019.
Alcohol use is a major risk factor for the burden of mortality and morbidity. Alcoholic cirrhosis (AC) and alcoholic liver cancer (ALC) are most important and severe liver disease outcomes caused by alcohol use. The objectives of the current study were to investigate the global prevalence and burden of disease in disability-adjusted life years (DALYs) for AC and ALC, based on data from the Global Burden of Disease (GBD). Incidence, prevalence, death, and DALYs for GBDs in different locations, years, sex, and age groups were estimated using DisMod-MR 2.1 and a generic Cause of Death Ensemble Modeling approach. The correlations between the age-standardized incidence rate or age-standardized death rate and gender, sociodemographic index (SDI), and alcohol usage were conducted by Generalized Linear Models. Globally, the changes of age-standardized rates of indicators were not much significant over the 30-year period. However, the changes varied widely across regions. Central Asia and East Europe contributed the highest age-standardized incidence, prevalence, death, and DALYs and increased sharply by past 30 years. Generalized Linear Models (GLMs) showed male gender as a risk factor of AC, with the relative risk of incidence of 1.521 and relative risk of death of 1.503. Globally, there were improvements in overall health with regard to GBDs over the 30 years. However, the prevention of AC and ALC should be promoted in middle and middle-high SDI regions, especially Central Asia and East Europe, whereas more medical resources should be provided to improve treatment levels in low SDI region.


Chelation versus Non-Chelation Control in the Stereoselective Alkenyl sp2 C-H Bond Functionalization Reaction.
A hydroxy group chelation-assisted stereospecific oxidative cross-coupling reaction between alkenes was developed under mild reaction conditions. In the presence of palladium catalyst, the alkenes tethered with hydroxy functionality can couple efficiently with electron-deficient alkenes to form the corresponding multi-substituted olefin products. The hydroxy group on the substrate could play dual roles in reaction, acting as the directing group for alkenyl C-H bond activation and controlling the stereoselectivity of the products.


Single-dose versus multiple instillations of epirubicin as prophylaxis for recurrence after transurethral resection of pTa and pT1 transitional-cell bladder tumours: a prospective, randomized controlled study.
To compare single-dose and multiple instillations of epirubicin in the chemoprophylaxis of superficial bladder tumours. In a prospective randomized and controlled study, 168 evaluable patients were assigned to three groups after transurethral resection of bladder tumour (TURBT) and histological confirmation of its superficial nature (pTa and pT1). The groups were comparable for tumour stage, grade and other tumour characteristics. In group 1, patients received a single dose of 50 mg epirubicin in 50 mL normal saline immediately after TURBT; group 2 received 50 mg epirubicin in 50 mL normal saline 1-2 weeks after TURBT and the instillations were repeated for 8 weeks and thereafter monthly to complete one year of treatment: group 3 (control group) received no adjuvant therapy after TURBT. The patients were assessed by cysto-urethroscopy, urine cytology and DNA flow cytometry 8 weeks after resection and then every 3 months during the first 2 years and 6 monthly thereafter during the next 2 years. Intravenous urography was performed annually and when otherwise indicated. The recurrence rate was significantly lower in the patients treated with epirubicin than in the control group (24, 25 and 52%, respectively; P < 0.001). In those receiving epirubicin, the rates of recurrence were statistically comparable (P = 0.9). Patients who had a large tumour burden showed slightly lower recurrence rates with single-dose epirubicin than with delayed maintenance therapy but the difference was statistically insignificant. Patients with a history of bladder tumours before treatment had lower recurrence rates with maintenance treatment than with a single dose (34.6 and 22.6% in groups 1 and 2, respectively); again this difference was statistically insignificant. Patients with grade 3 tumours showed a marginal difference in favour of maintenance therapy. The rates of progression amongst the three groups were 5.5, 3.4 and 9.3%, respectively, with no significant differences. The overall toxicity rates were comparable in the two treated groups (22 and 25%). With the possible exception of grade 3 tumours, single-dose immediate epirubicin is as effective as delayed maintenance therapy, with the advantage of being more cost-effective.


Number of germ cells and somatic cells in human fetal ovaries during the first weeks after sex differentiation.
This study presents the number of germ cells and somatic cells in human fetal ovaries during week 6 to week 9 post conception, i.e. the first weeks following sex differentiation of the gonads. One ovary with attached mesonephros from each of 11 individual legal abortions was used for estimation of cell numbers. After recovery of the fetus, the ovary-mesonephric complexes were immediately isolated, fixed and processed for histology. A stereological method was utilized to estimate the total number of oogonia in all ovaries and somatic cells in seven of them. The number of oogonia per ovary increased from approximately 26,000 in week 6 to approximately 250,000 in week 9 and somatic cells from approximately 240,000 to approximately 1.4 x 10(6). The ratio of oogonia to somatic cells tended to increase throughout the period. The concentration of oogonia was similar in the cranial (mesonephric connected) part and the caudal part of the ovaries. This is the first stereological estimation of the number of oogonia and somatic cells in human fetal ovaries, and the first estimation of germ cells and somatic cells in ovaries aged <9 weeks. The number of oogonia in week 9 is comparable to the numbers previously published based on non-stereological estimations. We found early stages of meiosis in fetal ovaries from week 9.


Molecular biological aspects on canine and human mammary tumors.
The high incidence of mammary tumor disease reported in certain canine breeds suggests a significant genetic component, as has already been described in human familial breast cancer-in BRCA1- and BRCA2-associated breast cancer in particular. The identification of genetic risk factors is critical to improvements in the prevention, diagnosis, and treatment of these tumors. In recent years, there has been significant progress in developing the tools and reagents necessary to analyze the canine genome. This work has culminated in a high-quality draft genome sequence, as well as a single-nucleotide polymorphism map and single-nucleotide polymorphism arrays for genomewide association analysis. These tools provide an unprecedented opportunity to characterize the genetic influences in canine diseases such as cancer, eventually allowing for exploration of more effective therapies. Given the high homology between the canine genome sequence and its human counterpart--as well as the many similarities regarding the morphology, biological behavior, and clinical course of mammary tumors in both species--the dog has proven to be an excellent comparative model. This review highlights the comparative aspects regarding certain areas within molecular biology, and it discusses future perspectives. The findings in larger genomewide association analyses and cDNA expression arrays are described, and the BRCA1/BRCA2 complex is compared in detail between the 2 species.


Normalizing Anxiety on Social Media Increases Self-Diagnosis of Anxiety: The Mediating Effect of Identification (But Not Stigma).
Normalizing mental health disorders in media communication can have a positive impact on the public by improving awareness. However, normalizing issues like anxiety could lead people to categorize normal anxiety as a disorder. In Study One, viewing social media posts that normalized anxiety resulted in a greater likelihood of self-diagnosis of anxiety disorder compared to social media posts that did not normalize it. This effect was through identification with and liking of the person featured in the social media post. In Study Two, those results were replicated. Additionally, we expected, but did not find, that normalizing anxiety had an impact on perceived stigma of anxiety disorders. Thus, at least in this case, normalization influenced self-diagnosis primarily through increasing identification with another person with anxiety, rather than decreasing stigma. Efforts to maximize positive impacts of normalizing disorders should examine unintended, potentially negative, consequences.


Skin surface proteolytic activity. Partial characterization and identification.
Skin surface proteolytic activity in the living animal was determined by a sensitive, non-invasive methodology developed in our laboratory. A non-leaky well was constructed on the shaved back of an anesthetized guinea pig. The well contained the reaction mixture including the substrate 125I-S-carboxymethylated insulin B-chain (ICMI). The proteolytic activity was shown to be time-dependent. The activity was strongly inhibited by pepstatin A, indicating the involvement of aspartic proteinase(s) such as cathepsin D and/or E. Pretreatment of the skin with propylene glycol blocked the proteolytic activity. The present study demonstrates the presence of proteolytic activity located on skin surface using a unique, non-invasive method for in situ proteinase determination in the living animal.


Proteomics-based analysis of novel genes involved in response toward soybean mosaic virus infection.
Soybean mosaic virus (SMV) is one of the most serious virus diseases of soybean. However, little is known about the molecular basis of the soybean defense mechanism against this pathogen. We identified differentially expressed proteins in soybean leaves infected with SMV by proteomic approaches. Twenty-eight protein spots that showed ≥2-fold difference in intensity were identified between mock-inoculated and SMV-infected samples. Among them, 16 spots were upregulated and 12 spots were downregulated in the SMV-infected samples. We recovered 25 of the 28 differentially expressed proteins from two-dimensional electrophoresis (2-DE) gels. These spots were identified as 16 different proteins by Matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) and tandem TOF/TOF MS, and were potentially involved in protein degradation, defense signal transfer, reactive oxygen, cell wall reinforcement, and energy and metabolism regulation. Gene expression analysis of 13 genes by quantitative real time polymerase chain reaction (qRT-PCR) showed that metabolism genes and photosynthesis genes were downregulated at all time points. One energy gene was downregulated, whereas another energy gene was upregulated at five of the six time points. The other interesting genes that were altered by SMV infection showed changes in transcription over time. This is the first extensive application of proteomics to the SMV-soybean interaction. These results contribute to a better understanding of the molecular basis of soybean's responses to SMV.


SN003, a CRF1 receptor antagonist, attenuates depressive-like behavior and detrusor overactivity symptoms induced by 13-cis-retinoic acid in rats.
Overactive bladder (OAB) often co-exists with depression in women. The corticotropin-releasing factor (CRF) system participates in the pathophysiology of both disorders. Therefore, we tested the effects of acute treatment with a reversible CRF receptor type-1 (CRF1) antagonist, SN003 (1mg/kg, i.v.), representatives of first (solifenacin, 0.03mg/kg, i.v.) and second (mirabegron, 1mg/kg, i.v.) line treatments for OAB as well as an antidepressant imipramine (30mg/kg, i.p.) on changes in depressive-like behavior and detrusor overactivity (DO) symptoms induced by a 6-week administration of 13-cis-retinoic acid (13-cis-RA, 1mg/kg/day, i.p.) in female Wistar rats, using in vivo cystometric investigations, forced swim test (FST) and spontaneous locomotor activity test. Following cystometric and behavioral studies, tissue was harvested and CRF level was assessed in the hypothalamus, amygdala and plasma. 13-cis-RA-induced depressive-like behavior and DO symptoms were associated with increased CRF levels in the hypothalamus, amygdala and plasma. Solifenacin and mirabegron attenuated DO symptoms induced by 13-cis-RA, did not display antidepressant-like activity and did not influence CRF levels in brain tissues or plasma. Imipramine and SN003 displayed antidepressant-like activity and lowered increased levels of CRF in brain tissues and plasma. Imipramine attenuated changes in some of the cystometric parameters, which are associated with OAB dry (without urge incontinence), whereas SN003 attenuated changes in almost all cystometric parameters that were induced by 13-cis-RA. CRF1 antagonist may be beneficial in case of OAB wet (with urge incontinence) or dry co-existing with depression. The possible mechanism may be related to the effects on central/peripheral CRF system.


Clinical assessment of early morning blood pressure in patients with hypertension.
In most individuals with hypertension, blood pressure (BP) shows a moderate to marked increase around the time of awakening, which has been linked to increases in cardiovascular complications occurring at this time of day. Many antihypertensive agents do not adequately control early morning BP, particularly when administered once daily in the morning. Points to consider in selecting an effective antihypertensive drug include pharmacokinetics and formulation of the agent and timing of administration. Agents with long pharmacologic half-lives, such as the angiotensin II receptor blocker telmisartan, the calcium antagonist amlodipine, and the beta-blocker bisoprolol, are examples of antihypertensive drugs with demonstrated efficacy in controlling early morning BP. Bedtime administration of chronotherapeutic preparations is also effective for controlling early morning BP. Given the association between early morning BP and cardiovascular risk, future clinical trials should focus on the efficacy of antihypertensive drugs during this important period of risk.


In vitro characterization of physico-chemical properties, cytotoxicity, bioactivity of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate nasal powder formulation.
An innovative lyophilized dry powder formulation consisting of urea-crosslinked hyaluronic acid (HA-CL) and sodium ascorbyl phosphate (SAP) - LYO HA-CL - SAP- was prepared and characterized in vitro for physico-chemical and biological properties. The aim was to understand if LYO HA-CL - SAP could be used as adjuvant treatment for nasal inflammatory diseases. LYO HA-CL - SAP was suitable for nasal delivery and showed to be not toxic on human nasal septum carcinoma-derived cells (RPMI 2650 cells) at the investigated concentrations. It displayed porous, polygonal particles with unimodal, narrow size distribution, mean geometric diameter of 328.3 ± 27.5 µm, that is appropriate for nasal deposition with no respirable fraction and 88.7% of particles with aerodynamic diameter >14.1 µm. Additionally, the formulation showed wound healing ability on RPMI 2650 cells, and reduced interleukin-8 (IL-8) level in primary nasal epithelial cells pre-induced with lipopolysaccharide (LPS). Transport study across RPMI 2650 cells showed that HA-CL could act not only as carrier for SAP and active ingredient itself, but potentially also as mucoadhesive agent. In conclusion, these results suggest that HA-CL and SAP had anti-inflammatory activity and acted in combination to accelerate wound healing. Therefore, LYO HA-CL - SAP could be a potential adjuvant in nasal anti-inflammatory formulations.


Aerobic fitness evaluation during walking tests identifies the maximal lactate steady state.
The aim of this study was to verify the possibility of lactate minimum (LM) determination during a walking test and the validity of such LM protocol on predicting the maximal lactate steady-state (MLSS) intensity. Eleven healthy subjects (24.2 ± 4.5 yr; 74.3 ± 7.7 kg; 176.9 ± 4.1 cm) performed LM tests on a treadmill, consisting of walking at 5.5 km · h⁻¹ and with 20-22% of inclination until voluntary exhaustion to induce metabolic acidosis. After 7 minutes of recovery the participants performed an incremental test starting at 7% incline with increments of 2% at each 3 minutes until exhaustion. A polynomial modeling approach (LMp) and a visual inspection (LMv) were used to identify the LM as the exercise intensity associated to the lowest [bLac] during the test. Participants also underwent to 2-4 constant intensity tests of 30 minutes to determine the MLSS intensity. There were no differences among LMv (12.6 ± 1.7%), LMp (13.1 ± 1.5%), and MLSS (13.6 ± 2.1%) and the Bland and Altman plots evidenced acceptable agreement between them. It was possible to identify the LM during walking tests with intensity imposed by treadmill inclination, and it seemed to be valid on identifying the exercise intensity associated to the MLSS.


The POK/AtVPS52 protein localizes to several distinct post-Golgi compartments in sporophytic and gametophytic cells.
The organization and dynamics of the plant endomembrane system require both universal and plant-specific molecules and compartments. The latter, despite the growing wealth of information, remains poorly understood. From the study of an Arabidopsis thaliana male gametophytic mutant, it was possible to isolate a gene named POKY POLLEN TUBE (POK) essential for pollen tube tip growth. The similarity between the predicted POK protein sequence and yeast Vps52p, a subunit from the GARP/VFT complex which is involved in the docking of vesicles from the prevacuolar compartment to the Golgi apparatus, suggested that the POK protein plays a role in plant membrane trafficking. Genetic analysis of Arabidopsis mutants affecting AtVPS53 or AtVPS54 genes which encode putative POK partners shows a transmission defect through the male gametophyte for all lines, which is similar to the pok mutant. Using a combination of biochemical approaches and specific antiserum it has been demonstrated that the POK protein is present in phylogenetically divergent plant species, associated with membranes and belongs to a high molecular weight complex. Combination of immunolocalization studies and pharmacological approaches in different plant cells revealed that the POK protein associates with Golgi and post-Golgi compartments. The role of POK in post-Golgi endomembrane trafficking and as a member of a putative plant GARP/VFT complex is discussed.


State of the Art in Degenerative Cervical Myelopathy: An Update on Current Clinical Evidence.
Degenerative cervical myelopathy (DCM) is a common cause of spinal cord dysfunction that confronts clinicians on a daily basis. Research performed over the past few decades has provided improved insight into the diagnosis, evaluation, and treatment of this disorder. We aim to provide clinicians with an update regarding the state of the art in DCM, focusing on more recent research pertaining to pathophysiology, natural history, treatment, consideration of the minimally symptomatic patient, surgical outcome prediction, and outcome measurement. Current concepts of pathophysiology focus on the combination of static and dynamic elements leading to breakdown of the blood-spinal cord barrier at the site of compression resulting in local inflammation, cellular dysfunction, and apoptosis. With respect to treatment, although there is a dearth of high-quality studies comparing surgical to nonoperative treatment, several large prospective studies have recently associated surgical management with clinically and statistically significant improvement in functional, disability, and quality of life outcome at long-term follow-up. When selecting the specific surgical intervention for a patient with DCM, anterior (discectomy, corpectomy, hybrid discectomy/corpectomy), posterior (laminectomy and fusion, laminoplasty), and combined approaches may be considered as options depending on the specifics of the patient in question; evidence supporting each of these approaches is reviewed in detail. Recently developed clinical prediction models allow for accurate forecasting of postoperative outcomes, permitting enhanced communication and management of patient expectations in the preoperative setting. Finally, an overview of outcome measures recommended for use in the assessment of DCM patients is provided.


Evaluation of the effects of silk and polyethylene terephthalate sutures on postoperative complications in impacted lower third molar surgery.
The aim of this study was to compare the efficacy of silk and Polyethylene Terephthalate (PET) sutures on postoperative complications in impacted lower third molar surgery. This prospective, randomized, split-mouth, double-blind clinical study was performed between January 2021 and June 2022 at the Faculty of Dentistry, Department of Oral and Maxillofacial Surgery, Van Yüzüncü Yıl University. The patients were categorized into two groups in terms of using suture material. PET suture was used in Group 1, and the silk suture in Group 2 for wound closure following impacted lower third molar surgery. The statistical significance level was accepted as p < 0.05 in the study. Forty patients (21 women, 19 men; mean age: 26.1 ± 7.25 years) were included in the study. When values for swelling and trismus evaluation were analyzed, there was no significant intergroup difference (p > 0.05). However, the VAS values of the silk group patients were higher at the 12th and 24th hours (p < 0.05). In addition, the plaque accumulation value in the silk group was higher than that in the PET group on the second postoperative day (p < 0.05). The results indicated that the plaque accumulation in the PET suture was less on the second postoperative day. Also, PET suture group patients felt less pain during the 12th and 24th hours. These results support to use PET sutures in impacted lower third molar surgery.


Cigarette smoking and the disenfranchisement of adolescent girls: a discourse of resistance?
The consequences of smoking for women are of particular concern in light of recent observations that more adolescent females than males are taking up smoking. To date, few studies have explored gender differences in depth, but we do know that males and females smoke for different reasons and that current smoking prevention programs may be differentially effective depending on gender. Recent evidence suggests that the school environment may have an important influence on smoking. The purpose of this study, therefore, was to explore gender differences in the relationships between cigarette smoking and adolescents' experiences of school climate and their relationships with the school and significant adults in their lives. A secondary data analysis was done using a data set derived from a student survey conducted in 20 secondary schools in British Columbia (BC), Canada, which included 8,179 students in grades 8 to 12. Analyses were primarily descriptive. The results demonstrated that adolescent girls who smoke are more likely than either males or nonsmoking females to experience powerlessness in their school environment and to feel considerably less attachment to the school. Female smokers are more likely than males or female nonsmokers to be engaged in oppositional, distanced, and unsatisfactory relationships with important adults in their lives, particularly those who are in positions of relative power and authority. These findings are discussed in relation to critical and feminist perspectives that suggest smoking is part of a larger discourse of resistance within schools. The implications for health practitioners are discussed.


Size-dependent transitions in grafted polymer brushes.
The partition function of a grafted polymer brush was calculated as a sum over all possible configurations, each of them being an ensemble of n1, n2, ...n(i), ... loops having 2, 4, ..., 2i, ... segments. A system of equations for the most likely configuration has been obtained, and it was concluded that no solution exists for an infinite chain, with nonvanishing interactions between segments and surface. This implies that an infinite chain is either collapsed on the surface (for attractive interactions) or is forming a stretched brush (for repulsive interactions). However, for finite chains, a solution could be found. When the attractive segment-surface interaction becomes sufficiently strong, the brush collapses on the surface (the "loops" to "trains" transition). When the interaction is repulsive and sufficiently strong, the brush becomes stretched, with most segments belonging to open loops which do not return to the surface (the "loops" to "tails" transition). The critical values of the segment-surface interaction, for which the above transitions occur, depend on the length of the polymer chain as well as on other physical properties of the brush, such as the segment-segment and segment-solvent interactions and the grafting density.


Behavioral and neural auditory thresholds in a frog.
Vocalizations play a critical role in mate recognition and mate choice in a number of taxa, especially, but not limited to, orthopterans, frogs, and birds. But receivers can only recognize and prefer sounds that they can hear. Thus a fundamental question linking neurobiology and sexual selection asks-what is the threshold for detecting acoustic sexual displays? In this study, we use 3 methods to assess such thresholds in túngara frogs: behavioral responses, auditory brainstem responses, and multiunit electrophysiological recordings from the midbrain. We show that thresholds are lowest for multiunit recordings (ca. 45 dB SPL), and then for behavioral responses (ca. 61 dB SPL), with auditory brainstem responses exhibiting the highest thresholds (ca. 71 dB SPL). We discuss why these estimates differ and why, as with other studies, it is unlikely that they should be the same. Although all of these studies estimate thresholds they are not measuring the same thresholds; behavioral thresholds are based on signal salience whereas the 2 neural assays estimate physiological thresholds. All 3 estimates, however, make it clear that to have an appreciation for detection and salience of acoustic signals we must listen to those signals through the ears of the receivers.


[Testosterone deficiency, metabolic syndrome and diabetes mellitus].
Testosterone deficiency in adult age is associated with a decrease in libido, energy, hematocrit, muscle mass and bone mineral density, as well as with depression. More recently, testosterone deficiency has also been associated with various components of the metabolic syndrome, which in turn is associated with a five-fold increase in the risk of cardiovascular disease. Low testosterone levels are associated with increased insulin resistance, increase in fat mass, low HDL cholesterol, higher triglyceride levels and hypertension. Testosterone replacement therapy in patients with testosterone deficiency and type 2 diabetes mellitus and/or metabolic syndrome has shown reductions in insulin resistance, total cholesterol, LDL cholesterol and triglycerides and improvement in glycemic control and anthropometric parameters.


PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and immunosuppression in breast cancer.
Proteasome activator subunit 3 (PSME3) plays a key role in breast cancer by regulating the cell cycle. However, its role in other pathogenesis-related features of breast cancer is unclear. In this study, we found that overexpression of PSME3 induced the epithelial-mesenchymal transition and contributed to induce the expression of cancer stem cell markers of the MDA-MB-231 cell line, thus increasing the migration, and invasion of the cells. Moreover, overexpression of PSME3 reduced the chemotaxis of CD8+ T cells and induced the apoptosis of T cells in vitro. Furthermore, PSME3 knockdown increased the number of CD8+ T cells in vivo and reduced the subcutaneous tumor growth rate. These findings revealed that PSME3 induces epithelial-mesenchymal transition with inducing the expression of CSC markers and influencing the tumor immune microenvironment in breast cancer.


[Application of next generation sequencing in microRNA detection].
MicroRNAs (miRNAs) are a class of ~22nt long non-coding RNAs. They are evolutionarily conserved and play essential roles in the regulation of post-transcriptional gene expression. The rapidly developing next generation sequencing (NGS) has important applications in miRNA detection. This review is focused on the mechanism of three NGS platforms and their applications in miRNA detection. In contrast to traditional methods, NGS has major advantages: high throughput, precise, accurate, and repeatable. Its application includes new miRNAs exploration, detection of miRNA*, miRNA editing, and isomiR and target mRNA detection. As NGS develops, the cost of sequencing is declining which makes it possible for NGS to be widely used in the coming years. Next generation sequencing will greatly promote researches of miRNAs.


Cannabidiol attenuates methamphetamine-induced cardiac inflammatory response through the PKA/CREB pathway in rats.
Methamphetamine (MA) abuse is a major global public health problem. However, it is not yet known whether cannabidiol (CBD) has protective effects on MA-induced cardiotoxicity. The present study investigated whether CBD has protective effects on MA-induced cardiac damage in rats via the protein kinase A/cyclic adenosine monophosphate (cAMP)-response element-binding protein (PKA/CREB) pathway. A total of 30 rats were randomly divided into 5 groups. The rats were administered MA (10 mg/kg) by intraperitoneal (IP) injection once a day for 4 weeks, and with CBD (40 or 80 mg/kg, IP) treatment 1 h before the MA injections. Morphological changes were determined using hematoxylin and eosin and Masson's trichrome staining. The serum levels of interleukin (IL)-6 and IL-10 were detected using enzyme-linked immunoassay kits. The protein expression levels of cardiac troponin I (cTnI), PKA, phospho-PKA (p-PKA), CREB, and phospho-CREB (p-CREB) in the myocardium were detected by Western blot analysis. There was no significant difference in body weight among the groups. Heart weight and the heart-to-body weight ratio were higher in the MA group than the control group, while CBD (80 mg/kg) pretreatment (CBD80 + MA group) reduced the heart weight and the heart-to-body weight ratio compared to the MA group. The chronic administration of MA resulted in a cardiac inflammatory response, the progressive development of fibrosis, and necrosis, while CBD treatment attenuated these lesions. The protein expression levels of PKA, p-PKA, CREB, and p-CREB increased following MA administration, but significantly decreased with CBD treatment. These results indicate that chronic MA administration leads to cardiotoxicity, but these effects can be attenuated by CBD pretreatment. This study was the first to examine the protective effects of CBD on cardiotoxicity elicited by chronic MA exposure in rats. Our research suggests that CBD attenuates the cardiac inflammatory response induced by MA through the PKA/CREB pathway, and CBD may have potential clinical application in the treatment of MA-induced cardiotoxicity.


Conformational ensembles explain NMR spectra of frozen intrinsically disordered proteins.
Protein regions which are intrinsically disordered, exist as an ensemble of rapidly interconverting structures. Cooling proteins to cryogenic temperatures for dynamic nuclear polarization (DNP) magic angle spinning (MAS) NMR studies suspends most of the motions, resulting in peaks that are broad but not featureless. To demonstrate that detailed conformational restraints can be retrieved from the peak shapes of frozen proteins alone, we developed and used a simulation framework to assign peak features to conformers in the ensemble. We validated our simulations by comparing them to spectra of α-synuclein acquired under different experimental conditions. Our assignments of peaks to discrete dihedral angle populations suggest that structural constraints are attainable under cryogenic conditions. The ability to infer ensemble populations from peak shapes has important implications for DNP MAS NMR studies of proteins with regions of disorder in living cells because chemical shifts are the most accessible measured parameter.


Absence of an angiogenic factor in large systemic arteriovenous malformations.
Large symptomatic arteriovenous malformations (AVMs) are currently managed by a combination of surgery, embolization, and supportive measures. If patients with such lesions should have a circulating factor responsible for their growth and development, the evolution of a more rational therapy might be possible. To explore this possibility, sera from 14 patients with high-flow systemic AVMs, widely distributed anatomically, were tested for the presence of a circulating growth factor using an assay already successfully used to isolate such a factor in diabetics with proliferative retinopathy. None of the patients tested positive for such a factor. This result, although negative, contributes to our knowledge of the biology of these uncommon but important lesions and leads us to conclude that, for the foreseeable future, embolization is likely to remain the most effective form of treatment for high-flow AVMs.


Prostacyclin, thromboxane A2 and calcium antagonists: effects on atherosclerotic characteristics of vascular cells.
We investigated the effects of stable analogues of prostacyclin (carbacyclin) and thromboxane A2 (U46619) and various calcium antagonists on atherosclerotic cellular indices, intracellular cholesterol content and [3H]thymidine incorporation. Primary culture of human subendothelial cells derived from atherosclerotic plaques of aorta was used. Carbacyclin reduced cholesterol accumulation and cell proliferation. U46619 in opposite to carbacyclin stimulated this processes. In general, carbacyclin exerted a direct antiatherosclerotic and U46619 - atherogenic action in culture. Calcium antagonists: dihydropyridines, verapamil derivatives and diltiazem demonstrated antiatherosclerotic properties themselves and potentiated carbacyclin effect but restricted atherogenicity of U46619.


GLP-1 Receptor Agonists and Coronary Arteries: From Mechanisms to Events.
Objective: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) lower plasma glucose through effects on insulin and glucagon secretion and by decelerating gastric emptying. GLP-1 RAs have many beneficial effects beyond glycemic control, including a protective role on the cardiovascular system. However, underlying mechanisms linking GLP-1 RAs with coronary artery disease are complex and not fully elucidated. In this mini-review, we discuss these mechanisms and subsequent clinical events. Data Sources: We searched PubMed and Google Scholar for evidence on GLP-1 RAs and coronary events. We did not apply restrictions on article type. We reviewed publications for clinical relevance. Synopsis of Content: In the first part, we review the current evidence concerning the role of GLP-1 RAs on potential mechanisms underlying the development of coronary events. Specifically, we discuss the role of GLP-1 RAs on atherosclerosis and vasospasms of epicardial coronary arteries, as well as structural/functional changes of coronary microvasculature. In the second part, we summarize the clinical evidence on the impact of GLP-1 RAs in the prevention of acute and chronic coronary syndromes and coronary revascularization. We conclude by discussing existing gaps in the literature and proposing directions for future research.


Aliskiren enhances protective effects of valsartan against type 2 diabetic nephropathy in mice.
Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy. db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group. Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy. Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.


The effect of different antioxidants on nitric oxide production in hypertensive rats.
The imbalance between nitric oxide (NO) and reactive oxygen species (ROS) production appears to be a common feature of experimental and human hypertension. Previously, different antioxidants and/or scavengers of oxygen free radicals were shown to activate nitric oxide synthase (NO synthase, NOS) and to increase the expression of both endothelial and neuronal NO synthase isoforms leading to blood pressure reduction. On the other hand, various antihypertensive drugs have been documented to possess antioxidant properties, which may contribute to their beneficial effect on blood pressure. This review is focused on the effects of antioxidant treatment in different models of experimental hypertension with a special attention to the prevention of oxidative damage and the augmentation of NO synthase activity and expression of NOS isoforms.


Metastatic rectal cancer to the breast.
Rectal cancer metastatic to the breast is an exceedingly rare event with around 15 cases reported in the literature. A metastatic breast deposit from the rectum signifies diffuse disseminated disease or a highly aggressive tumor such that surgical intervention other than palliation has a limited role. In the present report, we discuss a patient who presented with rectal cancer and developed a breast metastatic deposit. She soon developed progressive metastatic involvement of the lungs and the soft tissues and succumbed to the malignant course of this disease 12 months after the diagnosis of the primary rectal tumor.


The effect of mushroom and pokeweed extract on salmonella, egg production, and weight loss in molting hens.
An experiment was conducted to evaluate the effects of mushroom and pokeweed extract alone or in combination with alfalfa meal on Salmonella spp. population, egg production, and weight loss in laying hens during a 10-d molting period. The trial used 54 active laying hens approximately 77 wk of age that were naturally infected with Salmonella spp. The layers were subjected to 1 of 9 treatment groups, replicated 3 times with 2 hens per replicate cage. The treatment conditions were as follows: 1) full-fed + H(2)0 (FFW), 2) full-fed + mushroom (FFM), 3) full-fed + pokeweed (FFP), 4) nonfed + H(2)0 (NFW), 5) nonfed + mushroom (NFM), 6) nonfed + pokeweed (NFP), 7) full-fed alfalfa meal + H(2)0 (FFAW), 8) full-fed alfalfa meal + mushroom (FFAM), and 9) full-fed alfalfa meal + poke-weed (FFAP). The results showed that the base-10 logarithm values of Salmonella from the ceca significantly increased (P <or= 0.05) in treatment NFW (3.48), NFM (3.22), and FFAW (3.33), whereas the greatest reduction was observed in treatment FFAM (2.72). The number of Salmonella bacteria recovered from the crop was significantly greater in the NFW treatment (3.43) and lowest in treatment FFAM (2.62). Treatment FFAM (30.0%) had the lowest BW loss and differed significantly from treatment NFW (42.3%), NFM (39.7%), and NFP (41.5%) but not from FFAW (38.0%) and FFAP (34.0%). Ovary weights for treatments NFW, NFP, FFAM, and FFAP did not differ significantly from each other but did so for NFM and FFAW (38.0%), which had the lowest weight. Return to egg production at 2 mo lagged behind in treatments FFAM, NFP, and FFM more than in any other treatments. At 3 mo, treatments FFAAM and NFW differed from the other treatments. Findings indicate that a greater decrease in the natural Salmonella population in the ceca and crop can be obtained with the combination of full-fed alfalfa plus mushroom extract in molting hens and induce a comparable molt with feed withdrawal.


The tail of Tyrannosaurus: reassessing the size and locomotive importance of the M. caudofemoralis in non-avian theropods.
Unlike extant birds and mammals, most non-avian theropods had large muscular tails, with muscle arrangements similar to those of modern reptiles. Examination of ornithomimid and tyrannosaurid tails revealed sequential diagonal scarring on the lateral faces of four or more hemal spines that consistently correlates with the zone of the tail just anterior to the disappearance of the vertebral transverse processes. This sequential scarring is interpreted as the tapering boundary between the insertions of the M. caudofemoralis and the M. ilioischiocaudalis. Digital muscle reconstructions based on measurements of fossil specimens and dissections of modern reptiles showed that the M. caudofemoralis of many non-avian theropods was exceptionally large. These high caudofemoral mass estimates are consistent with the elevation of the transverse processes of the caudal vertebra above the centrum, which creates an enlarged hypaxial region. Dorsally elevated transverse processes are characteristic of even primitive theropods and suggest that a large M. caudofemoralis is a basal characteristic of the group. In the genus Tyrannosaurus, the mass of the M. caudofemoralis was further increased by dorsoventrally lengthening the hemal arches. The expanded M. caudofemoralis of Tyrannosaurus may have evolved as compensation for the animal's immense size. Because the M. caudofemoralis is the primary hind limb retractor, large M. caudofemoralis masses and the resulting contractile force and torque estimates presented here indicate a sizable investment in locomotive muscle among theropods with a range of body sizes and give new evidence in favor of greater athleticism, in terms of overall cursoriality, balance, and turning agility.


Disorders of serum omega-3 fatty acid composition in dialyzed patients, and their associations with fat mass.
Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular mortality. Lipid disorders, a constant feature of CKD, might contribute to this state. The aim of this study was to evaluate n-3 polyunsaturated fatty acids (PUFA) composition in CKD patients treated with dialysis, in comparison to the general population and to assess possible associations between the n-3 PUFA profile and anthropometric variables. Thirty-three prevalent dialysis patients were studied and compared with an age- and sex-adjusted control group of 22 patients. Fatty acid composition in serum was analyzed by gas chromatography with a mass spectrometer detector (GC-MS) and anthropometric measures were assessed by bioimpedance spectroscopy. The fatty acid profile of dialyzed patients was characterized by a significantly lower percentage content of n-3 PUFA. For α-linolenic acid (ALA), it was 0.21 ± 0.09% in dialysis patients versus 0.33 ± 0.11% in the control group (p < .001). For eicosapentanoic acid (EPA), 0.59 ± 0.23% versus 1.15 ± 0.87% (p < .001), and for docosahexaenoic acid (DHA) 1.11 ± 0.50% versus 1.75 ± 0.87% (p < .001), respectively. The amount of n-3 PUFA decreased with time on dialysis and it correlated positively with body fat mass. For DHA, this correlation was r = .48 (p < .01) and for EPA r = .40 (p < .05). Patients with CKD have a relatively low content of n-3 PUFA which may contribute to their high cardiovascular risk. Patients with a higher content of body fat are characterized by a favorable fatty acid composition.