Antiviral and antioxidant activity of flavonoids and proanthocyanidins from Crataegus sinaica

The antiviral and antioxidant activity of some fractions and of a series of flavonoids and proanthocyanidins obtained from Crataegus sinaica (Rosaceae) was evaluated. The O-glycosidic flavonoids and the oligomeric proanthocyanidins exhibited significant inhibitory activity against herpes simplex virus type 1 (HSV-1), which was shown to be due to an extracellular mechanism for procyanidin C-1. Procyanidin C-1 also had the highest antioxidant activity in both the microsomal lipid peroxidation and the hydroxyl radical scavenging assay. In addition to the previously reported phenolic compounds, the pentacyclic triterpenoid ursolic acid (1) and a tetrameric (2) and pentameric procyanidin (3) are reported for the first time.     

Synthesis and antibacterial activity of fused 1, 2, 4-triazolo[4, 3-a]quinoxaline and oxopyrimido[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-a]quinoxaline derivatives

A new series of potential antibacterial agents having tricyclic 1, 2, 4-triazolo-[4, 3-a] quinoxaline fused with one or more heterocyclic rings was synthesized via several routes. The tricyclic 1-amino-4-chloro-1, 2, 4-triazolo[4, 3-a] quinoxaline (2 ) and tetracyclic 1, 6-diamino-bis-1, 2, 4-triazolo[4, 3-a:3, 4-c] quinoxaline (3) were synthesized from 2, 3-dichloroquinoxaline (1) with two or four equivalents of thiosemicarbazide, respectively. Compound 2 was allowed to react with different aldehydes, alkoxides, cyclic amines, phenyl isothiocyanate, and t-butyl isocyanate to afford the corresponding quinoxaline derivatives. Moreover, compound 2 reactedwithhydrazine hydrate to give compound 4 which was cyclized by carbondisulfide inalcoholic potassium hydroxide to give the tetracyclic compound 5. Compound 2 was subjected to another cyclocondensation reaction using diethyl ethoxymethylene malonate (DEMM), dimethyl acetylenedicarboxylate (DMAD), and ethyl cyanoacetate to give the tetracyclic compounds 18, 20, and 21, respectively. All the synthesized compounds were evaluated in vitro for antibacterial activity; compounds 18 and 20 were found to display the greatest antibacterial activities. Structural identification was provided by elemental analyses, IR, and (1)H-NMR spectroscopy.     

Different mechanism of LPS-induced vasodilation in resistance and conductance arteries from SHR and normotensive rats

1. The direct and endothelium-dependent effects of lipopolysaccharide (LPS) were investigated on resistance and conductance arteries from normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats. 2. In both NWR and SHR, LPS induced dose-dependent relaxations of the mesenteric vascular bed, which were inhibited by L-NNA in SHR but not in NWR. Iberiotoxin (IBTX) inhibited the responses to LPS in both groups, indicating the participation of high conductance Ca(2+)-dependent K(+) channels. 3. In mesenteric artery rings, the resting membrane potentials and the hyperpolarizing responses of NWR to LPS did not differ in endothelized and denuded preparations but L-NNA inhibited the responses only in endothelized rings. These responses were reduced by bosentan, suggesting that endothelin release may mask a possible hyperpolarizing response to LPS. The hyperpolarizing responses to LPS were blocked by IBTX in both endothelized and de-endothelized NWR rings. In the SHR only intact rings showed hyperpolarization to LPS, which was inhibited by IBTX and byL-NNA. 4. In SHR aortic endothelized or denuded rings, LPS induced hyperpolarizing responses which, in endothelized rings, were partially blocked by L-NNA, by IBTX or by glibenclamide, but totally abolished by IBTX plus glibenclamide. No response to LPS was observed in NWR aortic rings. 5. Our results indicate that LPS activates large conductance Ca(2+)-sensitive K(+) channels located in the smooth muscle cell membrane both directly and indirectly, through NO release from the endothelium in NWR, whereas NO is the major mediator of the LPS responses in SHR resistance vessels.     

A novel mutation in the PSEN2 gene (T430M) associated with variable expression in a family with early-onset Alzheimer disease

BACKGROUND: Autosomal dominant early-onset Alzheimer disease is a heterogeneous condition that has been associated with mutations in 3 different genes: the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes. Most cases are due to mutations in the PSEN1 gene, whereas mutations in the APP and PSEN2 genes are rare. OBJECTIVE: To describe a novel mutation in the PSEN2 gene associated with early-onset autosomal dominant Alzheimer disease. PATIENTS AND METHODS: The proband was a 49-year-old individual who displayed progressive dementia beginning at age 45 years. One of the parents and one of the grandparents had developed dementia at ages 64 years and 60 years, respectively, and 1 sibling had mild cognitive impairment. Some family members also had Tourette syndrome. Mutation analysis of the APP, PSEN1, PSEN2, and tau (TAU) genes was performed. Apolipoprotein E (APOE) was also genotyped. RESULTS: We found a missense mutation at codon 430 of the PSEN2 gene that predicts a threonine-to-methionine substitution. This mutation was detected in the affected individuals and in 1 cognitively healthy sibling. The mutation was absent in 260 control chromosomes. The normal amino acid was conserved in the human and mouse PSEN1 and mouse PSEN2 homologues. No influence of the APOE genotype was observed. CONCLUSIONS: We have found a novel mutation in the PSEN2 gene in a family with early-onset Alzheimer disease. The variation in the age at onset confirms that PSEN2 mutations are associated with variable clinical expression.     

Comparison of electrodiagnostic abnormalities and criteria in a cohort of patients with chronic inflammatory demyelinating polyneuropathy

BACKGROUND: Current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) are research oriented favoring specificity over sensitivity. Application of such criteria in clinical practice may miss the diagnosis in potentially treatable patients. OBJECTIVES: To analyze the electrophysiologic abnormalities in a cohort of patients with clinically defined CIDP, to compare these data with published electrodiagnostic criteria, and to identify a set of abnormalities that is shared by all patients with CIDP. DESIGN: Retrospective medical record review. SETTING: Academically based neuromuscular clinic.Patients Fifteen patients with clinically diagnosed relapsing sensorimotor CIDP. INTERVENTIONS: Administration of intravenous immunoglobulin or prednisone. MAIN OUTCOME MEASURES: Electrodiagnostic studies. RESULTS: All patients had electrodiagnostic abnormalities in at least 3 nerves with possible partial conduction block or demyelinating range abnormalities in at least 1 nerve. The diagnostic sensitivities of 5 published CIDP criteria were as follows: the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (40%), Saperstein et al (47%), Nicolas et al (53%), Hughes et al for the Inflammatory Neuropathy Cause and Treatment Group (60%), and Thaisetthawatkul et al (70%). CONCLUSIONS: Current electrodiagnostic criteria for CIDP are insensitive and may fail to diagnose the condition in a substantial number of patients. More inclusive criteria that allow identification of patients in routine clinical practice are needed.     

Analgesia and c-Fos expression in the periaqueductal gray induced by electroacupuncture at the Zusanli point in rats

The need to use anaesthetised or restrained animals in acupuncture research in laboratory animals may represent a confounding variable, since both anaesthesia and stress alter the pain threshold and the activity of pain-related brain areas. In the current study we assessed the participation of the periaqueductal gray (PAG) in electroacupuncture's (EA) analgesic effects applied to the Zusanli point (36S) under carefully controlled stress conditions. Repeated immobilisation protocols (6 days, 1 h/day and 13 days, 2 h/day) were used to diminish the influence of acute immobilisation stress on c-Fos expression and analgesia (tail-flick test) induced by electroacupuncture on the 36S point (EA36S). Animals submitted to immobilisation alone (IMMO) or to electroacupuncture (100 Hz, 2-4 V, faradic wave) on a non-point region (EANP) were compared with animals submitted to electroacupuncture on the 36S point. In animals not previously submitted to repeated immobilisation, electroacupuncture on the 36S point induced analgesia and c-Fos expression in the PAG was not different from that induced by electroacupuncture at a non-acupuncture point. In animals submitted to repeated immobilisation (repeated immobilisation for 6 days or repeated immobilisation for 13 days), however, electroacupuncture on point 36S led to higher levels of analgesia and c-Fos expression, specifically in the ventrolateral PAG (vlPAG), as compared with animal groups subjected only to immobilisation or to electroacupuncture on a non-point. Our findings endorse previous results, and point to a specific part of the PAG involved in the effects of electroacupuncture at the Zusanli point.     

The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans

Sex specificity of neural mechanisms modulating nociceptive information has been demonstrated in rodents, and these qualitative sex differences appear to be relevant to analgesia from kappa-opioid receptor agonists, a drug class reported to be clinically effective only in women. Via quantitative trait locus mapping followed by a candidate gene strategy using both mutant mice and pharmacological tools, we now demonstrate that the melanocortin-1 receptor (Mc1r) gene mediates kappa-opioid analgesia in female mice only. This finding suggested that individuals with variants of the human MC1R gene, associated in our species with red hair and fair skin, might also display altered kappa-opioid analgesia. We found that women with two variant MC1R alleles displayed significantly greater analgesia from the kappa-opioid, pentazocine, than all other groups. This study demonstrates an unexpected role for the MC1R gene, verifies that pain modulation in the two sexes involves neurochemically distinct substrates, and represents an example of a direct translation of a pharmacogenetic finding from mouse to human.     

Etiopathogenesis of autoimmune thyroiditis

Human autoimmune thyroid diseases include both autoimmune hypothyroidism (thyroiditis) and autoimmune hyperthyroidism (Graves' disease). Either of the two feature profuse thyroidal infiltrates of CD4+ and CD8+ T-cells and a biased intrathyroidal T-cell-receptor repertoire. Despite strong epidemiologic evidence in favor of a genetic component in the etiology of autoimmune thyroiditis, few hereditary risk factors have been consistently identified, which include a well-characterized series of HLA genes. These may account for the progression from a harmless autoimmune response characterized solely by production of autoantibodies to thyroglobulin to pathogenic autoimmunity where injury occurs to the thyroid cells. We hereafter summarize the role of inherited risk factors along with that of environmental risk factors. It was suggested that iodine increase the autoantigenic potency of thyroglobulin, a major pathogenic antigen in the induction of autoimmune thyroiditis. The clinical entities included together as autoimmune thyroiditis is shortly reviewed, along with the presentation of the common pathogenetic pathways. Unique features of each member of the group are further emphasized.     

Quality monitoring of composting processes of wastewater sludge in Alexandria

There are two wastewater primary treatment plants in Alexandria (west and east). The produced primary sludge is mechanically dewatered and transported to sludge disposal site 9N where composting is carried out. However, prior to 1970, composting played a very minor role in sludge or solid wastes treatment because of greatly unfavorable balance between its economics and those of the principal competing option, namely landfill disposal. This study aims at monitoring and evaluating the composting process of demitted sludge produced from Alexandria wastewater treatment plants. Ten batches of sludge were composted. During the composting process the batches were been investigated and followed up to 3 months. Representative samples (10 for each batch) were taken from these batches at the start of windrowing and after each turning (4-15 days) and were analyzed for physical; chemical; bacteriological; and parasitological characteristics, heavy metals, and plant nutrients. Results revealed that C/N ratio of the final compost product comply with the decree of the Minister of Agriculture No. 100 11967, while moisture, C%, and TKN did not. Heavy metals, faecal coliforms, and helminthes complied with the decree No. 222/2002 for the Minister of Housing, Utilities, and Urban Communities. Moisture had positive correlation with both C and VS and negative correlation with pH. Temperature had negative correlation with TKN. Both total and faecal coliforms had negative correlation with temperature and positive correlation with C, N, and VS. It is recommended to optimize the quality of the produced sludge compost by use bulking agent rich in carbon and nitrogen as Hay or Rice straw, instead of the matured sludge compost.