In-vitro anti-inflammatory and immunomodulatory effects of grepafloxacin in zymogen A- or Staphylococcus aureus -stimulated human THP-1 monocytes

 The effects of grepafloxacin on the release of cytokines, chemical mediators, hydrolytic enzyme activities, and lipoxygenation in zymogen A- or Staphylococcus aureus-stimulated human THP-1 monocytes were evaluated. Initially, consistent with stimulation of phagocytic mechanisms of the monocytes, increases in cyclic adenosine monophosphate (cAMP) release, nitric oxide [NO] release, and hydrogen peroxide [H₂O₂] release, with a small decrease in cellular pH, occurred within 2 h. Enzymatic activities associated with oxygen burst of phagocytic cells (e.g., protein kinase C and nicotinamide adenine dinucleotide phosphate, reduced (NADPH) oxidase) were elevated, suggesting that monocytes attempted to destroy the invading organism through an innate phagocytic cidal immunologic mechanism. After 1–2 h of exposure to grepafloxacin, the oxygen burst and the release of proinflammatory cytokines and chemical mediators were suppressed. After 4 h, suppression of n-acetyl glucosaminidase (NAG) and cathepsin D activities and lipid peroxidation occurred, suppressing the pathogen-induced spread of infection and inflammation. Release of tumor necrosis factor (TNFα), interleukin (IL)-1, IL-6, and IL-8 was inhibited by grepafloxacin in a concentration-dependent manner, suggesting a reduction in the acute-phase inflammatory responses initiated by cytokine release from monocytes. Later, S. aureus were killed through inhibition of DNA synthesis, consistent with a bacteriostatic effect. Drug action against invading organisms appears to occur through multiple processes. Modulation of the innate immune system occurs within the first hour, causing the activation of cytokines, chemical mediators, and hydrolytic enzymes. A second phase between 2–4 h appears to involve the suppression of cellular components involved in inflammation and the spread of the infection. The third response, an apparent bacteriostatic inhibition of DNA synthesis, causes bacterial death. Received: August 22, 2002 / Accepted: January 13, 2003 Acknowledgments We would like to thank Otsuka Pharmaceuticals for the donation of active drug powder.     

Complex cancer gene therapy in mice melanoma

OBJECTIVE: We investigated the effects of continuous cancer gene therapy, including APC engineering and local stimulation of the immune system in a mice melanoma model. MATERIALS AND METHODS: B16 melanoma cells were injected into C57/Bl6 mice intradermally. The overlying dermis or the tumor were shot with different plasmids using a gene gun every 4th day starting 8 days after tumor implantation. Control groups were mice without any therapy or gene therapy as described above with the empty plasmid. Therapy was: group I, IL-12 and IL-2; group II, IFN-gamma/B7.1; group III, IFN-gamma/B7.1, IL-12, and IL-2. RESULTS: The median survival time of all therapy groups was significantly enhanced. The longest median survival was in the IL-12/IL-2 group. Tumor growth was reduced in all therapy groups. Control groups suffered a higher rate of metastasis and had fewer inflammatory cells at the tumor site. CONCLUSIONS: Continuous therapy with the gene gun is easy to handle and shows good results. Therapy with genes for IL-12 and IL-2 was superior to that with additional IFN-gamma/B7.1 or IFN-gamma/B7.1 alone. APC engineering is clearly less sufficient in the case of the B16 melanoma.     

Metatarsalgia in hallux valgus deformity: a pedographic analysis.

The purpose of this study was to analyze the plantar loading patterns in patients with hallux valgus (HV) with and without symptoms of metatarsalgia in order to find predictive pressure variabilities which are likely to result in metatarsalgia. Two groups of subjects (100 feet) volunteered for this study. Both groups provided the diagnosis of HV deformity. Group A (50 feet) exhibited a metatarsalgia symptomatology, whereas group B was asymptomatic. Plantar loading patterns were assessed using the two-step method and data were collected by the use of a capacitive pressure measurement platform. For each patient, 10 acceptable trials were collected. For the analysis, the foot was divided into six plantar regions: heel, midfoot, medial forefoot, lateral forefoot, medial toe, and lateral toe. Maximal peak pressure (PP, N/cm2), pressure-time integral (P/T integral, N/cm2*s), and force-time integral (%) were calculated. In group A, loading patterns (PP, P/T integral) of the lateral forefoot were significantly higher than in group B. The mediolateral pressure transfer from the big toe to the lateral metatarsal region was significantly greater in group A compared to group B. Regarding the lateral forefoot, a pressure time integral < 10 N/cm2*s was indicative of asymptomatic HV feet, whereas in symptomatic HV feet, a pressure time integral >28 N/cm2*s was observed. These results were statistically significant at the p < .01 level.     

Genetic analysis of Rhipicephalus sanguineus sensu lato ticks,parasites of dogs in the Canary Islands,Cyprus, and Croatia,based on mitochondrial 16S rRNA gene sequences

Parasitology Research - The aim of this work was to perform an analysis based on mtDNA sequences of the 16S rRNA gene in order to determine the phylogenetic position of ticks belonging to the...     

Subjective cognitive-affective status following thalamic stroke

Previous patient studies suggest that thalamic stroke may yield persistent deficits in several cognitive domains. At present, the subjective dimension and everyday relevance of these impairments is unclear, since many patients with thalamic stroke only show minor changes on physical examination. Here, we have studied subjective consequences of focal thalamic lesions. A sample of 68 patients with a history of ischemic thalamic stroke was examined by using established clinical self-report questionnaires assessing memory, attention, executive functions, emotional status and health-related quality of life. In order to control for general factors related to cerebrovascular disease, self-reports were compared to an age-matched group of 34 patients with a history of transient ischemic attack. Thalamic lesions were co-registered to an atlas of the human thalamus. Lesion overlap and subtraction analyses were used for lesion-to-symptom mapping. When both patient groups were compared, no significant differences were found for either questionnaire. However, when subgroups were compared, patients with infarctions involving the posterior thalamus showed significant emotional disturbances and elevated anxiety levels compared to patients with more anterior lesions. Our findings thus point to the existence of a persistent affective impairment associated with chronic lesions of the posterior thalamus. This syndrome may result from damage to connections between medial pulvinar and extra-thalamic regions involved in affective processing. Our findings suggest that the posterior thalamus may contribute significantly to the regulation of mood.     

How Many Sonograms Are Needed to Reliably Predict the Absence of Fetal Overgrowth in Gestational Diabetes Mellitus Pregnancies?

OBJECTIVE

Serial measurements of the fetal abdominal circumference have been used to guide metabolic management of pregnancies complicated by gestational diabetes mellitus (GDM). A reduction in the number of repeat ultrasound examinations would save resources. Our purpose was to determine the number of serial abdominal circumference measurements per patient necessary to reliably predict the absence of fetal overgrowth.

RESEARCH DESIGN AND METHODS

Women who had GDM were asked to return for repeat ultrasound at 3- to 4-week intervals starting at initiation of care (mean 26.9 ± 5.7 weeks). Maternal risk factors associated with fetal overgrowth were determined.

RESULTS

A total of 4,478 ultrasound examinations were performed on 1,914 subjects (2.3 ± 1.2 per pregnancy). Of the 518 women with fetal abdominal circumference >90th percentile, it was diagnosed in 73.9% with the first ultrasound examination at entry and in 13.1% with the second ultrasound examination. Of the fetuses, 85.9 and 86.9% of the fetuses were born non-large for gestational age (LGA) when abdominal circumference was <90th percentile at 24–27 weeks and 28–32 weeks, respectively, and 88.0% were born non-LGA when both scans showed normal growth. For those women who had no risk factors for fetal overgrowth (risk factors: BMI >30 kg/m², history of macrosomia, and fasting glucose > 100 mg/dl), the accuracy of prediction of a non-LGA neonate was 90.0, 89.5, and 95.2%. The predictive ability did not increase with more than two normal scans.

CONCLUSIONS

The yield of sonographic diagnosis of a large fetus drops markedly after the finding of a fetal abdominal circumference <90th percentile on two sonograms, which excludes with high reliability the risk of a LGA newborn. The ability was enhanced in women who had no risk factors for neonatal macrosomia.The recommendations for diagnosis and treatment of gestational diabetes mellitus (GDM) of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus (1) suggest consideration of fetal growth patterns to guide metabolic management of pregnant women with GDM. Estimation of fetal weight, particularly at term and in fetuses with high neonatal weight, is not as precise as is desirable (2). However, enlarged size (3–6) and accelerated growth velocity of the fetal abdominal circumference in the third trimester is known to predict large-for-gestational-age (LGA) birth weight (7). Previous randomized studies have demonstrated that measurement of the fetal abdominal circumference throughout pregnancy in women who have GDM is useful to identify pregnancies at high risk for fetal overgrowth and therefore in need of intensified intervention (8–11). On the other side, relaxed glycemic goals had been allowed in women with sonographic evidence of normal fetal growth. Besides saving insulin therapy, this approach reduced the rate of fetal growth restriction in the fetuses of those women. Published protocols for fetal growth–based management require sonographic determination of fetal abdominal circumference at the time of diagnosis of GDM (8–11) followed by repeat examinations at 2 (11)- to 4-week intervals (9,10). Serial sonographic examinations are costly and require the time and expertise of experienced ultrasonographers and/or physicians.The purpose of our study was to determine the number of sequential ultrasound examinations necessary not to miss development of an enlarged abdominal circumference during pregnancy and to assure a low risk for a LGA neonate with a great degree of certainty when the scans suggest normal fetal growth. In addition, we wished to evaluate whether the absence of maternal risk factors for neonatal macrosomia would enhance the accuracy of the ultrasound examination predicting a non-LGA neonate.     

Neuroanatomical profiles of alexithymia dimensions and subtypes

Alexithymia, a major risk factor for a range of psychiatric and neurological disorders, has been recognized to comprise two dimensions, a cognitive dimension (difficulties identifying, analyzing, and verbalizing feelings) and an affective one (difficulties emotionalizing and fantasizing). Based on these dimensions, the existence of four distinct alexithymia subtypes has been proposed, but never empirically tested. In this study, 125 participants were assigned to four groups corresponding to the proposed alexithymia subtypes: Type I (impairment on both dimensions), Type II (impairment on the cognitive, but not the affective dimension), Type III (impairment on the affective, but not the cognitive dimension), and Lexithymics (no impairment on either dimension). By means of voxel‐based morphometry, associations of the alexithymia dimensions and subtypes with gray and white matter volumes were analyzed. Type I and Type II alexithymia were characterized by gray matter volume reductions in the left amygdala and the thalamus. The cognitive dimension was further linked to volume reductions in the right amygdala, left posterior insula, precuneus, caudate, hippocampus, and parahippocampus. Type III alexithymia was marked by volume reduction in the MCC only, and the affective dimension was further characterized by larger sgACC volume. Moreover, individuals with the intermediate alexithymia Types II and III showed gray matter volume reductions in distinct regions, and had larger corpus callosum volumes compared to Lexithymics. These results substantiate the notion of a differential impact of the cognitive and affective alexithymia dimensions on brain morphology and provide evidence for separable neuroanatomical representations of the different alexithymia subtypes. Hum Brain Mapp 36:3805–3818, 2015. © 2015 Wiley Periodicals, Inc.     

Impaired Cognition after Stimulation of P2Y1 Receptors in the Rat Medial Prefrontal Cortex

We hypothesize that cortical ATP and ADP accumulating in the extracellular space, eg during prolonged network activity, contribute to a decline in cognitive performance in particular via stimulation of the G protein-coupled P2Y₁ receptor (P2Y₁R) subtype. Here, we report first evidence on P2Y₁R-mediated control of cognitive functioning in rats using bilateral microinfusions of the selective agonist MRS2365 into medial prefrontal cortex (mPFC). MRS2365 attenuated prepulse inhibition of the acoustic startle reflex while having no impact on startle amplitude. Stimulation of P2Y₁Rs deteriorated performance accuracy in the delayed non-matching to position task in a delay dependent manner and increased the rate of magazine entries consistent with both working memory disturbances and impaired impulse control. Further, MRS2365 significantly impaired performance in the reversal learning task. These effects might be related to MRS2365-evoked increase of dopamine observed by microdialysis to be short-lasting in mPFC and long-lasting in the nucleus accumbens. P2Y₁Rs were identified on pyramidal cells and parvalbumin-positive interneurons, but not on tyrosine hydroxylase-positive fibers, which argues for an indirect activation of dopaminergic afferents in the cortex by MRS2365. Collectively, these results suggest that activation of P2Y₁Rs in the mPFC impairs inhibitory control and behavioral flexibility mediated by increased mesocorticolimbic activity and local disinhibition.