Enthalpy of the Cerium (Ce) Chemi-Ionization Reaction and CeO+, CeC+, and CeCO+ Bond Energies Determined by Energy-Resolved Guided Ion Beam Mass Spectrometry Experiments.

Cerium (Ce) oxide, carbide, and carbonyl cation bond energies and the exothermicity of the Ce chemi-ionization (CI) reaction with atomic oxygen were investigated using guided-ion beam tandem mass spectrometry (GIBMS). The kinetic energy dependent product cross sections for reactions of Ce+ with O2, CO, and CO2 and CeO+ with O2, CO, Xe, and Ar were measured using GIBMS. For the reactions of Ce+ with O2 and CO2, CeO+ is formed through an exothermic reaction, whereas CeO+ formation is endothermic in the reaction with CO. This reaction also forms CeC+ and CeCO+ is formed in the reaction of Ce+ with CO2, both in endothermic processes. Reactions of CeO+ with all four gases led to endothermic collision-induced dissociation as well as exchange reactions to form CeO2+ for the O2 and CO reactants. Bond dissociation energies (BDEs) at 0 K were determined through analyses of the kinetic energy dependent cross sections for all endothermic reactions. We determined that the BDEs of CeO+, CeC+, and CeCO+ are 8.46 ± 0.15, 3.93 ± 0.16, and ≥0.25 ± 0.07 eV, respectively, where the CeO+ BDE is a weighted average of 6 independent 0 K threshold measurements. The CeO+ BDE is combined with the ionization energy (IE) of Ce to determine an exothermicity of 2.91 ± 0.15 eV for the Ce + O → CeO+ + e- chemi-ionization reaction. Combined with neutral BDEs from the literature, the thermochemistry determined here also provides IE(CeO) = 5.03 ± 0.12 eV and IE(CeC) = 6.50 ± 0.16 eV. Theoretical calculations for ground and some excited states were performed for CeO+, CeC+, and CeCO+ to provide insight into the bonding and a comparison with the experimentally determined BDEs for each molecule.

Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA.

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.

Allelic modifications of the cg2 and cg1 genes do not alter the chloroquine response of drug-resistant Plasmodium falciparum.

The determinant of chloroquine resistance (CQR) in a Plasmodium falciparum cross was previously mapped by linkage analysis to a 36 kb segment of chromosome 7. Candidate genes within this segment have been previously shown to include two genes, cg2 and cg1, that have complex polymorphisms linked to the CQR phenotype. Using DNA transfection and allelic exchange, we have replaced these polymorphisms in CQR parasites with cg2 and cg1 sequences from chloroquine sensitive parasites. Drug assays of the allelically-modified lines show no change in the degree of CQR, providing evidence against the hypothesis that these polymorphisms are important to the CQR phenotype. Similarly, no change was found in the degree to which verapamil or other chloroquine sensitizers reverse CQR in the transformants. These results and the high though not complete degree of association of CQR with cg2 and cg1 polymorphisms in field isolates suggest involvement of another nearby gene in the P. falciparum CQR mechanism.

The role of vitrectomy in the treatment of postoperative bacterial endophthalmitis. An experimental study.

While the diagnostic value of vitreous culture in the management of bacterial endophthalmitis is well established, the therapeutic value of vitrectomy in this condition is debated. The present experimental study uses an aphakic model of Staphylococcus aureus endophthalmitis in the rabbit. Animals were treated with the following: (1) intravitreal antibiotics alone; (2) intravitreal antibiotics with vitrectomy; (3) vitrectomy alone; and (4) no treatment. Eyes treated with antibiotics and vitrectomy displayed significantly clearer media at 14 days after therapy compared with eyes treated with antibiotics alone. There was also a greater tendency for eyes treated with antibiotics and vitrectomy to have negative cultures at 14 days, although this difference was not statistically significant. These findings are consistent with beneficial effects of therapeutic vitrectomy as an adjunct to intravitreal antibiotic therapy in an animal model of aphakic bacterial endophthalmitis.

The use of polymerase chain reaction for the detection of chlamydial keratoconjunctivitis.

Ocular swabs from 30 consecutive patients with follicular conjunctivitis were screened for Chlamydia trachomatis, herpes simplex virus, and adenovirus by a variety of laboratory techniques. For the detection of C. trachomatis, we compared two polymerase chain reaction methods, McCoy cell culture isolation, and the direct fluorescein-conjugated monoclonal antibody test. Four of 30 patients tested positive for C. trachomatis by using both conventional and biotinylated polymerase chain reaction methods. Two of the four patients were also McCoy cell culture-positive for C. trachomatis and one of four patients tested positive by using a fluorescein-conjugated chlamydial monoclonal antibody test. All four patients responded to oral antibiotic treatment. On follow-up testing, all four patients were polymerase chain reaction-negative, McCoy cell culture-negative, and fluorescein-conjugated antibody test-negative for C. trachomatis. The polymerase chain reaction appears to be an equally specific and more sensitive method than McCoy cell culture or fluorescein-conjugated antibody testing for the detection of C. trachomatis from ocular specimens.

Comparative diagnosis of neonatal chlamydial conjunctivitis by polymerase chain reaction and McCoy cell culture.

Cervical and ocular swabs from 100 mother/newborn pairs delivering on the clinic service were assayed for Chlamydia trachomatis with standard McCoy cell culture and with standard and biotinylated polymerase chain reaction techniques, using primers directed against the major outer membrane protein gene and C. trachomatis-specific cryptic plasmid, respectively. Using the polymerase chain reaction, 20 (20%) mothers and seven (7%) neonates were positive for Chlamydia. All neonates positive by polymerase chain reaction were from mothers positive by polymerase chain reaction, yielding a 35% transmission rate. Only five of 20 (25%) mothers and two of seven (28%) neonates positive by polymerase chain reaction were positive by cell culture. All cell culture samples were positive by polymerase chain reaction testing. Culture and polymerase chain reaction analysis two weeks after treatment with oral erythromycin were negative. The polymerase chain reaction assay appears to be equally specific and more sensitive than McCoy cell culture for the detection of C. trachomatis from ocular specimens.

Results one year after using the 193-nm excimer laser for photorefractive keratectomy in mild to moderate myopia.

As part of a clinical trial, photorefractive keratectomy using the VISX 2015 193-nm excimer laser was performed on 91 healthy eyes of 91 patients. Preoperative refractive errors (spherical equivalent) ranged from -1.00 to -7.50 diopters (mean, -4.16 +/- 1.41 diopters). No patient had more than 1 diopter of refractive astigmatism. Six months postoperatively, the average residual refractive error was +0.09 +/- 0.63 diopters (range, -2.13 to +1.63 diopters). Correction within 1 diopter of that attempted was attained in 85 eyes (93%). Uncorrected visual acuity of 20/40 or better was attained in 86 eyes (95%) and was 20/25 or better in 67 eyes (74%). At one year, follow-up information was available on 85 eyes of 85 patients. The average residual refractive error was -0.15 +/- 0.65 diopters (range, -2.50 to +1.63 diopters). Correction within 1 diopter of that attempted was attained in 85 eyes (93%). Uncorrected visual acuity was 20/40 or better in 83 eyes (98%) and was 20/25 or better in 68 eyes (80%). One patient lost three lines of best-corrected visual acuity because of corneal haze, dropping from 20/15 to 20/30, whereas all other patients returned to best-corrected visual acuity within one line of their preoperative best-corrected visual acuity. Photorefractive keratectomy with the 193-nm excimer laser appears to be a useful treatment modality for the reduction of mild to moderate myopia.

Delayed onset keratectasia following laser in situ keratomileusis.

We present a case of unilateral iatrogenic keratectasia developing 10 months after bilateral laser in situ keratomileusis (LASIK) involving enhancement surgery using a broad-beam excimer laser (Summit Apex) to treat 6.6 diopters (D) of myopia. The ectasia progressed rapidly over the subsequent 12 months. The surgeon did not measure preoperative pachymetry, but preoperative topography and corneal measurements did not reveal underlying keratoconus or forme fruste keratoconus. Corneal transplantation was required for final visual rehabilitation. Light microscopy of the button revealed no underlying inflammation, which suggests biomechanical corneal weakening as the cause of the ectasia. Scanning electron microscopy showed the dramatic thinning seen clinically. latrogenic keratectasia appears to be a possible complication of LASIK.

Use of the 193 nm excimer laser for photorefractive keratectomy in low to moderate myopia.

As part of a Phase III clinical trial, photorefractive keratectomy using the VISX 2015 193 nm excimer laser was performed on 91 sighted eyes of 91 patients. Preoperative refractive errors (spherical equivalent) ranged from -1.00 diopters (D) to -7.50 D (mean -4.11 D +/- 1.43 D). At six months, average residual refractive error was 0.02 D +/- 0.64 D (range -2.21 D to +1.38 D). Ninety-three percent of eyes were within 1.00 D of attempted correction, 93% had uncorrected visual acuity of 20/40 or better, and 72% achieved uncorrected visual acuity of 20/25 or better. All patients returned to their best corrected visual acuity within one line of their preoperative best corrected visual acuity. Photorefractive keratectomy with the 193 nm excimer laser appears to be useful in reducing low to moderate myopia.

Epilepsy and neurocysticercosis in a village in Huaraz, Peru.

Sixteen individuals presenting with seizures in a rural village of Peru were screened for antibodies to Taenia solium, and those willing to attend were offered a complete neurological work-up including EEG and cerebral CT scan in a reference center. Seroprevalence using immunoblot was 35% (5/16). Eight individuals came for examination. CT scans were abnormal in all four seropositive cases (an enhancing lesion in one case, multiple live cysts and calcifications in one case, and multiple calcifications in two cases), and normal in the four seronegative individuals. Electroencephalographic tracings were normal in six cases, and abnormal in one seronegative and in one seropositive individual. Neurocysticercosis (NCC) is frequently found in epileptic individuals in most developing countries, and is probably the major cause of seizures in this zone.

Effect of anterior chamber paracentesis on decreased retinal circulation due to retrobulbar hematoma in dogs.

An experimental canine model for blindness following blepharoplasty was developed to demonstrate occlusion of retinal circulation resulting from simulated retrobulbar hematoma. Seven mongrel dogs were studied, monitoring retinal vascular patterns by funduscopic examination and intraocular pressure by pneumotonometry. Anterior chamber paracentesis was performed in five dogs 10 minutes after injecting blood retrobulbarly, with an immediate decrease in pressure and return of retinal blood flow. In two dogs without paracentesis, increased pressure and blindness persisted. Anterior chamber paracentesis has been shown to reduce intraocular pressure from hematoma of the retro-orbital area in dogs. Although controversial, anterior chamber paracentesis may represent a useful temporizing adjunct in the treatment of increased intraocular pressure and impaired vision from hematoma following blepharoplasty.

The relationship of retrobulbar hematomas to vision in cynomolgus monkeys.

An experimental model has been developed to measure the effect of retrobulbar hematomas on functional vision in cynomolgus monkeys. In this model, functional vision was quantitated using flashed evoked visual potentials in five monkeys following creation of retrobulbar hematomas. In one monkey used as a control, functional vision remained impaired for 180 minutes following induction of retinal ischemia by increased intraorbital pressure. In two monkeys in which increased intraorbital pressure was relieved by anterior chamber paracentesis following 15 minutes of retinal ischemia, flashed evoked visual potential promptly returned to baseline level. In two additional monkeys in which increased intraorbital pressure was relieved following 30 minutes of retinal ischemia, flashed evoked visual potentials improved but never returned to baseline levels. This study demonstrates the usefulness of flashed evoked visual potentials in measuring functional vision in cynomolgus monkeys. This experimental model should prove useful in evaluating the effects of increased intraorbital pressure on functional vision and the effect of intervention on impaired vision due to retrobulbar hematomas. Further studies with larger numbers of animals are needed to clarify these preliminary studies and document longer-term effects of retinal ischemia secondary to retrobulbar hematomas.

Reducing antibiotic prescribing for children with respiratory tract infections in primary care: a systematic review.

BACKGROUND: Respiratory tract infections (RTIs) in children are common and often result in antibiotic prescription despite their typically self-limiting course. AIM: To assess the effectiveness of primary care based interventions to reduce antibiotic prescribing for children with RTIs. DESIGN AND SETTING: Systematic review. METHOD: MEDLINE(®), Embase, CINAHL(®), PsycINFO, and the Cochrane library were searched for randomised, cluster randomised, and non-randomised studies testing educational and/or behavioural interventions to change antibiotic prescribing for children (<18 years) with RTIs. Main outcomes included change in proportion of total antibiotic prescribing or change in 'appropriate' prescribing for RTIs. Narrative analysis of included studies was used to identify components of effective interventions. RESULTS: Of 6301 references identified through database searching, 17 studies were included. Interventions that combined parent education with clinician behaviour change decreased antibiotic prescribing rates by between 6-21%; structuring the parent-clinician interaction during the consultation may further increase the effectiveness of these interventions. Automatic computerised prescribing prompts increased prescribing appropriateness, while passive information, in the form of waiting room educational materials, yielded no benefit. CONCLUSION: Conflicting evidence from the included studies found that interventions directed towards parents and/or clinicians can reduce rates of antibiotic prescribing. The most effective interventions target both parents and clinicians during consultations, provide automatic prescribing prompts, and promote clinician leadership in the intervention design.

Duration of symptoms of respiratory tract infections in children: systematic review.

OBJECTIVE: To determine the expected duration of symptoms of common respiratory tract infections in children in primary and emergency care. DESIGN: Systematic review of existing literature to determine durations of symptoms of earache, sore throat, cough (including acute cough, bronchiolitis, and croup), and common cold in children. DATA SOURCES: PubMed, DARE, and CINAHL (all to July 2012). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials or observational studies of children with acute respiratory tract infections in primary care or emergency settings in high income countries who received either a control treatment or a placebo or over-the-counter treatment. Study quality was assessed with the Cochrane risk of bias framework for randomised controlled trials, and the critical appraisal skills programme framework for observational studies. MAIN OUTCOME MEASURES: Individual study data and, when possible, pooled daily mean proportions and 95% confidence intervals for symptom duration. Symptom duration (in days) at which each symptom had resolved in 50% and 90% of children. RESULTS: Of 22,182 identified references, 23 trials and 25 observational studies met inclusion criteria. Study populations varied in age and duration of symptoms before study onset. In 90% of children, earache was resolved by seven to eight days, sore throat between two and seven days, croup by two days, bronchiolitis by 21 days, acute cough by 25 days, common cold by 15 days, and non-specific respiratory tract infections symptoms by 16 days. CONCLUSIONS: The durations of earache and common colds are considerably longer than current guidance given to parents in the United Kingdom and the United States; for other symptoms such as sore throat, acute cough, bronchiolitis, and croup the current guidance is consistent with our findings. Updating current guidelines with new evidence will help support parents and clinicians in evidence based decision making for children with respiratory tract infections.

Serious complications of topical mitomycin-C after pterygium surgery.

BACKGROUND: The use of topical mitomycin (mitomycin-C) as a medical adjunct to pterygium and glaucoma surgery is increasing. METHODS: The authors report on a series of 10 patients who experienced serious, vision-threatening complications associated with the use of this drug after pterygium surgery. RESULTS: Complications included severe secondary glaucoma (4 patients), corneal edema (3 patients), corneal perforation (1 patient), corectopia (2 patients), iritis (8 patients), sudden onset mature cataract (2 patients), scleral calcification (1 patient) and incapacitating photophobia and pain (8 patients). Two patients required penetrating keratoplasties and a third required three lamellar keratoplasties. Another patient underwent four additional surgeries including a conjunctival Z-plasty, scleral patch grafting, and conjunctival autografting before his intractable pain and photophobia resolved 15 months after the original surgery. Because of these complications, 6 patients required a total of 20 return visits to the operating room after their original pterygium surgery. In 5 eyes, visual acuity remained at 20/200 or less. Three of the six patients with the most severe complications had concomitant chronic external diseases (rosacea [3 patients], ichthyosis [1 patient], keratitis sicca [1 patient]). CONCLUSION: The authors urge extreme caution in the use of mitomycin. If mitomycin is used, the lowest possible concentration should be applied for the shortest time period in an effort to avoid these complications. A prospective multicenter study of the ophthalmic use of this medication is needed.

Topical diclofenac in the treatment of ocular pain after excimer photorefractive keratectomy.

BACKGROUND: Following excimer laser photorefractive keratectomy, patients experience significant ocular pain until corneal reepithelialization. Despite the use of cold compresses, bandage soft contact lenses, cycloplegics, narcotics, and topical corticosteroids, the pain has not been adequately controlled in many patients. METHODS: A randomized, double-masked, parallel-group study of diclofenac sodium 0.1% ophthalmic solution and its placebo vehicle was evaluated. Patients undergoing excimer myopic photorefractive keratectomy on their second eye were admitted overnight. Postoperative procedures included two drops of diclofenac or placebo immediately after surgery and then qid until reepithelialization, topical tobramycin (qid), 0.1% fluorometholone (q2h), cycloplegics, and a disposable soft contact lens. Thirty-two patients (diclofenac = 16, placebo = 16) were evaluated from +30 minutes to +96 hours by several types of questionnaires. RESULTS: Most patients who received placebo experienced pain, starting within 1 hour, peaking at 4 to 6 hours and lasting 36 to 48 hours. The diclofenac-treated patients rarely experienced the early peak in pain, had less pain overall until 72 hours postoperatively, and experienced significantly less photophobia and burning/stinging. Significantly fewer patients on diclofenac required oral narcotics. Three patients (diclofenac = 2, placebo = 1) developed corneal infiltrates, the etiology of which is not known. In a separate study we conducted, there was no difference in epithelial healing times between the diclofenac-treated eyes and those not receiving the drug. CONCLUSIONS: Diclofenac appears to significantly reduce the ocular pain following excimer photorefractive keratectomy.

Differentiating Taenia solium and Taenia saginata infections by simple hematoxylin-eosin staining and PCR-restriction enzyme analysis.

Species-specific identification of human tapeworm infections is important for public health purposes, because prompt identification of Taenia solium carriers may prevent further human cysticercosis infections (a major cause of acquired epilepsy). Two practical methods for the differentiation of cestode proglottids, (i) routine embedding, sectioning, and hematoxylin-eosin (HE) staining and (ii) PCR with restriction enzyme analysis (PCR-REA), were tested on samples from 40 individuals infected with T. solium (n = 34) or Taenia saginata (n = 6). Microscopic examination of HE staining of sections from 24 cases, in which conserved proglottids were recovered, clearly revealed differences in the number of uterine branches. Distinct restriction patterns for T. solium and T. saginata were observed when the PCR products containing the ribosomal 5.8S gene plus internal transcribed spacer regions were digested with either AluI, DdeI, or MboI. Both HE histology and PCR-REA are useful techniques for differentiating T. solium from T. saginata. Importantly, both techniques can be used in zones of endemicity. HE histology is inexpensive and is currently available in most regions of endemicity, and PCR-REA can be performed in most hospital centers already performing PCR without additional equipment or the use of radioactive material.

Tegument-specific, virus-reactive CD4 T cells localize to the cornea in herpes simplex virus interstitial keratitis in humans.

Herpes stromal keratitis (HSK) is a prevalent and frequently vision-threatening disease associated with herpes simplex virus type 1 (HSV-1) infection. In mice, HSK progression occurs after viral clearance and requires T cells and neutrophils. One model implicates Th1-like CD4 T cells with cross-reactivity between the HSV-1 protein UL6 and a corneal autoantigen. HSK can be prevented by establishing specific immunological tolerance. However, HSK can also occur in T-cell receptor-transgenic X SCID mice lacking HSV-specific T cells. To study the pathogenesis of HSK in the natural host species, we measured local HSV-specific T-cell responses in HSK corneas removed at transplant surgery (n = 5) or control corneas (n = 2). HSV-1 DNA was detected by PCR in two specimens. HSV-specific CD4 T cells were enriched in three of the five HSK specimens and were not detectable in the control specimens. Reactivity with peptide epitopes within the tegument proteins UL21 and UL49 was documented. Responses to HSV-1 UL6 were not detected. Diverse HLA DR and DP alleles restricted these local responses. Most clones secreted gamma interferon, but not interleukin-5, in response to antigen. HSV-specific CD8 cells were also recovered. Some clones had cytotoxic-T-lymphocyte activity. The diverse specificities and HLA-restricting alleles of local virus-specific T cells in HSK are consistent with their contribution to HSK by a proinflammatory effect.

Mutations in the P. falciparum digestive vacuole transmembrane protein PfCRT and evidence for their role in chloroquine resistance.

The determinant of verapamil-reversible chloroquine resistance (CQR) in a Plasmodium falciparum genetic cross maps to a 36 kb segment of chromosome 7. This segment harbors a 13-exon gene, pfcrt, having point mutations that associate completely with CQR in parasite lines from Asia, Africa, and South America. These data, transfection results, and selection of a CQR line harboring a novel K761 mutation point to a central role for the PfCRT protein in CQR. This transmembrane protein localizes to the parasite digestive vacuole (DV), the site of CQ action, where increased compartment acidification associates with PfCRT point mutations. Mutations in PfCRT may result in altered chloroquine flux or reduced drug binding to hematin through an effect on DV pH.