Use of 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus

A novel anti-hepatitis B virus (anti-HBV) agent, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.     

Interferon-gamma activation of a mitogen-activated protein kinase, KFR1, in the bloodstream form of Trypanosoma brucei

KFR1, a mitogen-activated protein (MAP) kinase identified in the African trypanosome, Trypanosoma brucei, is a serine protein kinase capable of phosphorylating the serine residues in histone H-1, myelin basic protein, and beta-casein. It phosphorylates four proteins with estimated molecular masses of 22, 34, 46, and 90 kDa from the T. brucei bloodstream-form lysate in vitro. KFR1 bears significant sequence similarity to the yeast MAP kinases KSS1 and FUS3 but cannot functionally complement the kss1/fus3 yeast mutant. It is encoded by a single-copy gene in the diploid T. brucei, and only one of the two alleles can be successfully disrupted, suggesting an essential function of KFR1 in T. brucei. KFR1 activity is present at a much enhanced level in the bloodstream form of T. brucei when compared with that in the insect (procyclic) form. This enhanced activity can be eliminated in vitro by the treatment with protein phosphatase HVH2 known to act specifically on MAP kinases. It can also be decreased in the bloodstream form of T. brucei by serum starvation but induced specifically by interferon-gamma. The production of interferon-gamma in the mammalian host is known to be triggered by T. brucei infection, and this cytokine, as has been reported, promotes the proliferation of T. brucei in the mammalian blood. Since none of these phenomena can be observed in the procyclic form of T. brucei, activation of KFR1 is most likely involved in mediating the interferon-gamma-induced proliferation of T. brucei in the mammalian host.     

Neutrophil accumulation is reduced during partial liquid ventilation

OBJECTIVE: This study evaluates the ability of perflubron to inhibit pulmonary neutrophil accumulation during partial liquid ventilation (PLV) in the setting of acute lung injury. DESIGN: Randomized, controlled, nonblinded study. SETTING: Research laboratory at a university. SUBJECTS: Male, Sprague-Dawley rats (n = 120, 506 +/- 42 g). INTERVENTIONS: Animals were divided into eight groups (n = 15 in each group, of which n = 12 for myeloperoxidase content and n = 3 for histologic neutrophil counting): a) GV-CVF group, animals received gas ventilation (GV) with the induction of lung injury using cobra venom factor (CVF); b) PLV-CVF group, animals received partial liquid ventilation before the induction of lung injury; c) PEEP-CVF group, animals received positive end-expiratory pressure (PEEP) before the administration of cobra venom factor; d) CVF-PLV group, animals received partial liquid ventilation after cobra venom factor; e) CVF-PEEP group, animals received PEEP after cobra venom factor; f) PLV only group, animals received partial liquid ventilation only; g) GV only group, animals received gas ventilation only; and h) NVSBA group, nonventilated spontaneous breathing animals. MEASUREMENTS AND MAIN RESULTS: After the experimental period, total lung myeloperoxidase content was significantly decreased in the PLV-CVF (0.29 +/- 0.08, p = .02) and PEEP-CVF (0.34 +/- 0.04, p = .01) groups when compared with the GV-CVF group (0.62 +/- 0.07). When compared with the GV-CVF group, a trend toward a reduction in myeloperoxidase was observed in the CVF-PLV (0.42 +/- 0.05, p = .07) and the CVF-PEEP (0.39 +/- 0.06, p = .07) groups. When compared with the cobra venom factor only group (GV-CVF 47 +/- 2 neutrophils/high-power field), reductions in neutrophil count were observed in all groups (neutrophils/high-power field): PLV-CVF (20 +/- 2, p = .009); PEEP-CVF (24 +/- 1, p = .01); CVF-PLV (30 +/- 2, p = .03); and CVF-PEEP (37 +/- 1, p = .04). CONCLUSION: These data suggest that both partial liquid ventilation and PEEP result in a reduction in neutrophil accumulation in the setting of acute lung injury.     

Dental practice patterns. II: Treatment related to oral health status

We report and describe the clinical findings of three patients who developed atonic pupil after uncomplicated extracapsular cataract extraction with posterior chamber intraocular lens implantation. All patients had normally reactive pupils one day postoperatively, but after two weeks, the pupils were dilated and nonreactive to light, accommodation, and miotics. To estimate the incidence of atonic pupil after cataract surgery, we sent a survey on the frequency, clinical features, and possible etiologies of this syndrome to members of the American Society of Cataract and Refractive Surgery. Of the 567 respondents, 60% had seen at least one case of atonic pupil in the past five years; they reported a total of 1543 cases during that time. This is probably a conservative figure since many cases undoubtedly go unnoticed because of a lack of visual disturbance. We believe this condition occurs more frequently than previously reported. The atonic pupil should be recognized as a possible complication of cataract surgery that should be included in the preoperative consent form.     

G protein-coupled receptor kinase specificity for phosphorylation and desensitization of alpha2-adrenergic receptor subtypes

The alpha2-adrenergic receptor (alpha2AR) subtype alpha2C10 undergoes rapid agonist-promoted desensitization which is due to phosphorylation of the receptor. One kinase that has been shown to phosphorylate alpha2C10 in an agonist-dependent manner is the betaAR kinase (betaARK), a member of the family of G protein-coupled receptor kinases (GRKs). In contrast, the alpha2C4 subtype has not been observed to undergo agonist-promoted desensitization or phosphorylation by betaARK. However, the substrate specificities of the GRKs for phosphorylating alpha2AR subtypes are not known. We considered that differential capacities of various GRKs to phosphorylate alpha2C10 and alpha2C4 might be a key factor in dictating in a given cell the presence or extent of agonist-promoted desensitization of these receptors. COS-7 cells were co-transfected with alpha2C10 or alpha2C4 without or with the following GRKs: betaARK, betaARK2, GRK5, or GRK6. Intact cell phosphorylation studies were carried out by labeling cells with 32Pi, exposing some to agonist, and purifying the alpha2AR by immunoprecipitation and SDS-polyacrylamide gel electrophoresis. BetaARK and betaARK2 were both found to phosphorylate alpha2C10 to equal extents (>2-fold over that of the endogenous kinases). On the other hand, GRK5 and GRK6 did not phosphorylate alpha2C10. In contrast to the findings with alpha2C10, alpha2C4 was not phosphorylated by any of these kinases. Functional studies carried out in transfected HEK293 cells expressing alpha2C10 or alpha2C4 and selected GRKs were consistent with these phosphorylation results. With the marked expression of these receptors, no agonist-promoted desensitization was observed in the absence of GRK co-expression. However, desensitization was imparted to alpha2C10 by co-expression of betaARK but not GRK6, while alpha2C4 failed to desensitize with co-expression of betaARK. These results indicate that short term agonist-promoted desensitization of alpha2ARs by phosphorylation is dependent on both the receptor subtype and the expressed GRK isoform.     

Identification of a novel endogenous memory facilitating cyclic dipeptide cyclo-prolylglycine in rat brain

Using high-performance liquid chromatography, gas-chromatography and chromato-mass spectrometry methods a novel endogenous cyclic dipeptide cyclo-prolylglycine was identified in rat brain. Its content according to gas chromatography is 2.8 +/- 0.3 nmol/g wet brain. Synthetic cyclo-prolylglycine has demonstrated antiamnesic activity in the passive avoidance test in rats at a dose of 0.1 mg/kg i.p. Cyclic dipeptide cyclo-prolylglycine seems to be a memory facilitating substance and its presence in rat brain suggests the existence of a new mechanism of memory regulation.     

The clinico-neuropsychological manifestations of arteriovenous malformations of the thalamus

A comprehensive clinical and neuropsychological study was made of 34 patients with thalamic arteriovenous malformations. In the thalamus. Memory disorders were a common abnormality (in 31 of 34 patients). They were modally nonspecific and depended on the site of arteriovenous malformations. With the prevalent ventricular pattern of hemorrhages, memory disorders were accompanied by disorientation and emotional and volitional impairments. Arteriovenous malformation was removed in 12 patients (on the left side in 7 patients and on the right in 5). After surgery there was virtually progression of memory defects in all patients. Speech disorders combining the specific features of lesions in various cortical regions were detected in 5 of 7 patients with left thalamic arteriovenous malformations.     

Production and perception of final consonant voicing in speech produced by inexperienced signers during simultaneous communication

Simultaneous communications combines both spoken and manual modes to produce each word of an utterance. This study investigated the potential influence of alterations in the temporal structure of speech produced by inexperienced signers during simultaneous communication on the perception of final consonant voicing. Inexperienced signers recorded words that differed only in the voicing characteristic of the final consonant under two conditions: (1) speech alone and (2) simultaneous communication. The words were subsequently digitally edited to remove the final consonant and played to 20 listeners who, in a forced-choice paradigm, circled the word they thought they heard. Results indicated that accurate perception of final consonant voicing was not impaired by changes in the temporal structure of speech that accompanied the inexperienced signers' simultaneous communication.