Comparing the direct normal form and multiple scales methods through frequency detuning.

Approximate analytical methods, such as the multiple scales (MS) and direct normal form (DNF) techniques, have been used extensively for investigating nonlinear mechanical structures, due to their ability to offer insight into the system dynamics. A comparison of their accuracy has not previously been undertaken, so is addressed in this paper. This is achieved by computing the backbone curves of two systems: the single-degree-of-freedom Duffing oscillator and a non-symmetric, two-degree-of-freedom oscillator. The DNF method includes an inherent detuning, which can be physically interpreted as a series expansion about the natural frequencies of the underlying linear system and has previously been shown to increase its accuracy. In contrast, there is no such inbuilt detuning for MS, although one may be, and usually is, included. This paper investigates the use of the DNF detuning as the chosen detuning in the MS method as a way of equating the two techniques, demonstrating that the two can be made to give identical results up to ε 2 order. For the examples considered here, the resulting predictions are more accurate than those provided by the standard MS technique. Wolfram Mathematica scripts implementing these methods have been provided to be used in conjunction with this paper to illustrate their practicality.

Fibroblast growth factor-2 drives and maintains progressive corneal neovascularization following HSV-1 infection.

Herpes simplex virus type 1 (HSV-1) infection of the cornea induces vascular endothelial growth factor A (VEGF-A)-dependent lymphangiogenesis that continues to develop well beyond the resolution of infection. Inflammatory leukocytes infiltrate the cornea and have been implicated to be essential for corneal neovascularization, an important clinically relevant manifestation of stromal keratitis. Here we report that cornea infiltrating leukocytes including neutrophils and T cells do not have a significant role in corneal neovascularization past virus clearance. Antibody-mediated depletion of these cells did not impact lymphatic or blood vessel genesis. Multiple pro-angiogenic factors including IL-6, angiopoietin-2, hepatocyte growth factor, fibroblast growth factor-2 (FGF-2), VEGF-A, and matrix metalloproteinase-9 were expressed within the cornea following virus clearance. A single bolus of dexamethasone at day 10 post infection (pi) resulted in suppression of blood vessel genesis and regression of lymphatic vessels at day 21 pi compared to control-treated mice. Whereas IL-6 neutralization had a modest impact on hemangiogenesis (days 14-21 pi) and lymphangiogenesis (day 21 pi) in a time-dependent fashion, neutralization of FGF-2 had a more pronounced effect on the suppression of neovascularization (blood and lymphatic vessels) in a time-dependent, leukocyte-independent manner. Furthermore, FGF-2 neutralization suppressed the expression of all pro-angiogenic factors measured and preserved visual acuity.

Cataract surgery for junior ophthalmologists: are there enough cases?

AIM: To evaluate those cases that are suitable for operation by the junior ophthalmic trainee. METHODS: A prospective survey of 96 consecutive cases from five consultant lists for phacoemulsification over a 1 month period were preoperatively assessed for their suitability for the ophthalmic trainee using set criteria. A checklist was designed for all patients and criteria were marked with reference to suitability by a single examiner. The criteria chosen were arbitrary and had no bearing on a consultant's final decision to allow the junior to operate. RESULTS: Twenty-two out of 96 cases (22.9%) were deemed to be suitable for operation by a junior ophthalmologist (ie 4.4 cases per consultant list). The three main reasons for exclusion were first eye case, eye for operation with visual acuity 6/12 or better, and mature cataract. DISCUSSION: Using our results, if 4.4 cases were suitable for a junior ophthalmologist per month, this would allow for adequate exposure during the early stages of training. However, if the number of relatively straightforward cases on training lists were to be reduced owing to unavailability on hospital waiting lists, this could potentially compromise ophthalmic training in the future.

A particle-tracking method for simulating the dispersion of non-conservative radionuclides in coastal waters.

A particle-tracking method has been used to simulate the dispersion of non-conservative radionuclides in the sea. Three dimensional turbulent diffusion and the interactions between water, suspended matter and bottom sediments are simulated using a stochastic method. Kinetic transfer coefficients, as in finite difference models, are used to describe the transfers between the liquid and solid phases. Deposition of suspended matter and erosion of sediment are also included in the model. The method has been applied to simulate the dispersion of 137Cs and (239,240)Pu in the English Channel and the results have been compared with those of a finite difference model. The results from both techniques are, in general, in good agreement.

Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity.

The design and synthesis of novel, orally active, potent, and selective inhibitors of influenza neuraminidase differing structurally from existing neuraminidase inhibitors are described. X-ray crystal structures of complexes of neuraminidase with known five- and six-membered ring inhibitors revealed that potent inhibition of the enzyme is determined by the relative positions of the interacting inhibitor substituents (carboxylate, glycerol, acetamido, hydroxyl) rather than by the absolute position of the central ring. This led us to design potential neuraminidase inhibitors in which the cyclopentane ring served as a scaffold for substituents (carboxylate, guanidino, acetamido, alkyl) that would interact with the four binding pockets of the neuraminidase active site at least as effectively as those of the established six-membered ring inhibitors such as DANA (2), zanamivir (3), and oseltamivir (4). A mixture of the isomers was prepared initially. Protein crystallography of inhibitor-enzyme complexes was used to screen mixtures of isomers in order to identify the most active stereoisomer. A synthetic route to the identified candidate 50 was developed, which featured (3 + 2) cycloaddition of 2-ethylbutyronitrile oxide to methyl (1S,4R)-4[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (43). Structures of the synthetic compounds were verified by NMR spectroscopy using nuclear Overhauser effect methodology. Two new neuraminidase inhibitors discovered in this work, 50 and 54, have IC(50) values vs neuraminidase from influenza A and B of <1 and <10 nM, respectively. These IC(50) values are comparable or superior to those for zanamivir and oseltamivir, agents recently approved by the FDA for treatment of influenza. The synthetic route used to prepare 50 and 54 was refined so that synthesis of pure active isomer 54, which has five chiral centers, required only seven steps from readily available intermediates. Further manipulation was required to prepare deoxy derivative 50. Because the activities of the two compounds are comparable and 54 [RWJ-270201 (BCX-1812)] is the easier to synthesize, it was selected for further clinical evaluation.

On the disposal of contaminated milk in coastal waters.

Estimates have been made of the reduction in dissolved oxygen levels in coastal waters that would result from the disposal of contaminated milk following a radiological accident. Two contrasting sites were chosen: the Bristol Channel near Hinkley Point and the coast of Cumbria near Sellafield. The results suggest that the dilution would be sufficiently strong near Hinkley Point, due to vigorous tidal mixing, that the impact on the DO levels of the coastal waters would be negligible. However, at both Sellafield and Heysham the disposal of milk could result in a reduction of the DO by 1-2 mg l(-1). In contrast to shallow estuarine waters, the recovery of oxygen levels due to the effects of re-aeration through surface gas exchange is unlikely to be significant due to the depth of the coastal waters. However, the recovery of the dissolved oxygen levels to ambient conditions following the completion of the discharge would occur on a time scale of about 17 days due to mixing of the DO deficit plume into the surrounding waters.

Antidepressant efficacy in HIV-seropositive outpatients with major depressive disorder: an open trial of nefazodone.

BACKGROUND: Treatment studies of major depression in patients who are seropositive for the human immunodeficiency virus (HIV) have shown comparable efficacy for both tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Nefazodone appears to be more tolerable than TCAs and similar to SSRIs. This study examined the efficacy and tolerability of nefazodone in an open 12-week trial of HIV-seropositive outpatients with major depressive disorder. METHOD: Fifteen HIV-seropositive patients with DSM-IV major depressive disorder and a 21-item Hamilton Rating Scale for Depression (HAM-D) score of > or =18 were treated with open-label nefazodone for 12 weeks. Hamilton Rating Scale for Anxiety, HAM-D, Clinical Global Impressions scale, and Systematic Assessment for Treatment Emergent Events general inquiry (for safety and tolerability) scores were obtained at weeks 2, 4, 6, 8, and 12. RESULTS: Of 15 patients receiving nefazodone, 4 discontinued treatment (1 for adverse effects). Of 11 patients who completed the trial, 8 (73%) were classified as full responders with a 50% reduction in HAM-D scores and final CGI score of 1 or 2, and 10 (91%) were classified as partial responders (only 50% reduction in HAM-D scores). Nefazodone-treated subjects experienced few total adverse effects (mean = 1.5), no sexual side effects, and low rates of adverse-effect-related dropout (1 subject, 7%). CONCLUSION: Depressed HIV-seropositive outpatients respond to nefazodone comparably to other outpatient populations and have few adverse effects, suggesting that nefazodone may have a role in the treatment of depression in HIV-seropositive patients. Potential drug interactions with protease inhibitors indicate that it is essential to evaluate for appropriate dosing to avoid adverse effects and increase overall antidepressant efficacy.

Analysis of a petrol plume over England: 18-19 January 1997.

OBJECTIVES: About 7000 tonnes of unleaded petrol were discharged into the English Channel after a tanker collision off Ostend on Saturday 18 January 1997. The petrol evaporated and the vapour plume was carried across the central part of England to Wales, resulting in reports of unidentified odours, and irritation of the eyes, skin, and upper respiratory tract. This work uses this incident to show how marine and atmospheric dispersion modelling together with routine air quality monitoring can assist in identifying hazards to the population at risk from chemical incidents. METHODS: Public health surveillance and results from environmental sampling were compared with the behaviour of the plume as predicted by computer modelling. RESULTS: The predicted plume path and dispersion were shown to correlate well with the results from surveillance and environmental analysis. CONCLUSIONS: There is a need for public health professionals to interact with medical toxicologists, atmospheric and marine scientists and engineers, and other environmental experts in managing events of this nature.

Simplified habit reversal treatment for chronic hair pulling in three adolescents: a clinical replication with direct observation.

Three developmentally normal adolescents with chronic hair pulling were treated with a simplified habit reversal procedure consisting of awareness training, competing response training, and social support. Treatment resulted in an immediate reduction to near-zero levels of hair pulling, with one to three booster sessions required to maintain these levels. The results were maintained from 18 to 27 weeks posttreatment, although 1 participant reported difficulty at follow-up. The effectiveness of simplified habit reversal and suggestions for future research are discussed.

Randomized, placebo-controlled trial of paroxetine versus imipramine in depressed HIV-positive outpatients.

OBJECTIVE: This study examined whether a selective serotonin reuptake inhibitor (paroxetine) had comparable efficacy but greater tolerability than a tricyclic antidepressant (imipramine) in depressed patients with HIV infection. METHOD: Seventy-five HIV-positive patients (45% of whom had AIDS) were blindly and randomly assigned to receive paroxetine (N = 25), imipramine (N = 25), or placebo (N = 25) in a 12-week trial. The Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, the Clinical Global Impression scale, and the SAFETEE general inquiry (for safety and tolerability) were administered at weeks 2, 4, 6, 8, and 12. RESULTS: Fifty-six (75%) of the 75 patients completed 6 weeks and 34 (45%) completed 12 weeks of the trial. The mean daily doses of both paroxetine (33.9 mg) and imipramine (162.5 mg) were significantly more effective than placebo; they were comparably effective at weeks 6, 8, and 12 according to the intent-to-treat analysis and at week 8 according to the analysis for the subjects who completed the trial (for them, only imipramine was superior to placebo at week 12). There were significantly more dropouts due to side effects from imipramine (48%) than from both paroxetine (20%) and placebo (24%). CONCLUSIONS: Depressed patients with HIV infection responded to imipramine or paroxetine at a higher rate than to placebo irrespective of severity of immunosuppression. Because paroxetine was much better tolerated than imipramine, its overall effectiveness may be greater. However, because of the small study group and the high attrition rate, these findings cannot be generalized and may need replication in a larger study group.

Brief application of simplified habit reversal to treat stuttering in children.

We evaluated a brief therapy protocol involving the simplified regulated breathing method as a treatment for stuttering in children. The simplified treatment included awareness training, competing response training, and social support. Treatment was implemented in a multiple baseline across subjects design for 5 boys between the ages of 5 and 11. Each child received a 1 h treatment session, and 1/2 h booster sessions as needed. Four of the 5 children reduced their stuttering to less than 3% stuttered words (the criterion for successful treatment) after one 1 h treatment session. These results were maintained for 3 of the subjects from 6 to 9 months posttreatment. Social validity measures revealed significant differences between ratings on baseline and posttreatment speech samples. Treatment acceptability and credibility measures indicated that the subjects' guardians found the simplified regulated breathing method a reasonable treatment for stuttering in children.

Cognitive functions and complaints in HIV-1 individuals treated for depression.

Progressive neuropsychological dysfunction and complaints of cognitive difficulty frequently accompany HIV-1 infection. Providing appropriate treatment to HIV-1 patients requires determination of the extent to which the presentation of cognitive complaints reflects HIV-1-associated neuropsychological abnormalities or represents expression of depressive symptomatology. We prospectively treated 75 HIV-1 patients who were not demented but met criteria for major mood disorder with antidepressants for 12 weeks and compared pretreatment and posttreatment measures of depression, cognitive complaints, and neuropsychological performance. Complaints of difficulty with memory and attention were found to be independent of neuropsychological impairment, whereas memory complaints were highly correlated with severity of depression. Cognitive complaints declined significantly across the course of treatment for those patients who responded to antidepressant treatment. All patients, regardless of antidepressant treatment response, exhibited parallel improvement on 12-week follow- up neuropsychological examination. These findings suggest that treatment of depression affects cognitive complaints in HIV-1 individuals and that cognitive complaints of patients in asymptomatic or early symptomatic stages of HIV-1 infection may signal the need for evaluation of depression. In patients with more advanced HIV-1 infection, investigation into the basis of cognitive complaints may require a dual assessment of mood disturbance and neuropsychological status.

A profile of medically serious suicide attempts.

BACKGROUND: This study identified factors associated with medically serious suicide attempts (requiring medical hospitalization). METHOD: Demographic information, current psychiatric mental state, suicide attempt and psychiatric history characteristics, and DSM-IV diagnoses were compared between 65 patients hospitalized for a medically serious suicide attempt (MSSA) and 32 patients seen in the emergency room for suicide attempt but not medically hospitalized (NMSSA). RESULTS: Those with MSSAs had a higher rate of substance-induced mood disorder (but not substance abuse or dependence), while those with NMSSA had more attempts, more years since first attempt, and a higher rate of sexual and physical abuse, traumatic life events, borderline personality disorder, and bipolar disorder. CONCLUSION: Substance-induced mood disorder is an important diagnosis in the evaluation of suicidal patients. The vulnerability of mood effects caused by substance abuse may lead to a more serious suicide attempt despite less extensive psychiatric problems. The most important early psychiatric intervention may be the immediate recognition and aggressive treatment of an individual's affective and substance use disorders.

Maternal acceptance of voluntary human immunodeficiency virus antibody testing during the newborn period with the Guthrie card.

In order to provide the opportunity for women delivering newborns to have human immunodeficiency virus (HIV) testing we piloted a hospital-based voluntary HIV testing program during the newborn period using the Guthrie card. During the study period 789 women were offered newborn HIV antibody testing. Test acceptance during the newborn period (61.0%) was comparable to that reported for the prenatal period (60.6%). Overall 77.4% of women were tested in the newborn period or reported being tested in the prenatal period. Prenatal test acceptance best predicted newborn HIV test acceptance (odds ratio, 3.37; 95% confidence interval, 2.40 to 4.74). When compared to HIV testing during the newborn period prenatal HIV testing is preferable because it enables the recognition of HIV infection early during pregnancy and allows the mother the option to elect zidovudine therapy and potentially prevent infection in her newborn. However, when prenatal HIV testing is not routinely made available or cannot be assured, women should be offered the opportunity to be tested during the newborn period.