Risk of neurosyphilis in HIV-infected persons with syphilis lacking signs or symptoms of central nervous system infection.

OBJECTIVES: People living with HIV (PLWH) are at increased risk of asymptomatic neurosyphilis; thus, it has been common practice to perform a lumbar puncture (LP) in all PLWH presenting with syphilis regardless of stage, signs or symptoms. However, this practice varies widely among clinicians. Our objective was to elucidate the number of LPs required to diagnose a single case of asymptomatic neurosyphilis. METHODS: We performed an electronic health record (EHR) review of PLWH who were diagnosed with syphilis of any stage over a 10-year period. EHRs were reviewed to determine the number of subjects who had an LP performed, what proportion had neurological signs or symptoms, and whether a diagnosis of neurosyphilis was made at presentation or follow-up. RESULTS: In 261 separate episodes of syphilis in 230 subjects, we found the major risk factors for asymptomatic neurosyphilis to be low CD4 T-cell count (P = 0.0007), high rapid plasma reagin (RPR) titre (P = 0.019) and lack of HIV virological suppression (P = 0.003). The majority of our subjects (78%) with neurosyphilis presented with central nervous system (CNS) symptoms. We estimate, if standard practice is to perform LP in all patients, that the number needed to test (NNTT) = 38. CONCLUSIONS: This large number of potentially unnecessary LPs, along with heterogeneity of presentation, and the never-nil risk of asymptomatic neurosyphilis should be incorporated into clinical decision-making. The majority of PLWH presenting with a serological diagnosis of syphilis, but no neurological signs or symptoms, do not necessarily require an LP for an evaluation of asymptomatic neurosyphilis.

Therapeutic drug monitoring and TB treatment outcomes in patients with diabetes mellitus.

BACKGROUND: Diabetes mellitus (DM) increases the risk of TB disease and poor treatment outcomes such as delayed sputum culture conversion due to inadequate drug exposure. Therapeutic drug monitoring (TDM) has improved these outcomes in some settings.METHODS: To compare treatment outcomes in programs with routine TDM vs. programs that did not use TDM, we conducted a retrospective study among people with DM and TB at health departments in four US states.RESULTS: A total of 170 patients were enrolled (73 patients in the non-TDM group and 97 patients in the TDM group). Days to sputum culture conversion and total treatment duration were significantly shorter in the TDM group vs. the non-TDM group. In adjusted analyses, patients who underwent TDM were significantly more likely to achieve sputum culture conversion at 2 months (P = 0.007).CONCLUSION: TDM hastened microbiological cure from TB among people with DM and a high risk for poor treatment outcomes in the programmatic setting.

Perceived visual motion as effective stimulus to pursuit eye movement system.

Human eye tracking of a foveal afterimage during angular head oscillation in the dark produced smooth eye movements exceeding those for normal vestibular nystagmus, and a reduction in the frequency of the fast phase component of nystagmus eye movements. These results may support a closed loop extension of the corollary discharge theory, with oculomotor commands based on perceived object velocity.

Moving visual scenes influence the apparent direction of gravity.

When an observer views a wide-angled display rotating around his line of sight, he both feels his body tilted and sees a vertical straight edge tilted opposite to the moving stimulus. Displacement of the perceived vertical increases with stimulus speed to reach a maximum (averaging 15 degrees) at 30 degrees per second.

Spatial orientation in weightlessness and readaptation to earth's gravity.

Unusual vestibular responses to head movements in weightlessness may produce spatial orientation illusions and symptoms of space motion sickness. An integrated set of experiments was performed during Spacelab 1, as well as before and after the flight, to evaluate responses mediated by the otolith organs and semicircular canals. A variety of measurements were used, including eye movements, postural control, perception of orientation, and susceptibility to space sickness.

Incidence of Clostridium difficile infection in patients receiving high-risk antibiotics with or without a proton pump inhibitor.

BACKGROUND: Considering the incidence and severity of Clostridium difficile infection (CDI), risk reduction strategies are crucial. Prior studies suggest that proton pump inhibitor (PPI) use can increase the risk of CDI over antibiotics alone; however, data and guidelines have been conflicting. AIM: The aim was to compare CDI incidence in patients receiving high-risk antibiotics, comparing rates in those prescribed a PPI versus those without overlapping PPI exposure. METHODS: This retrospective cohort study assessed the incidence of CDI in veterans receiving high-risk antibiotics over an approximately three-year period. High-risk antibiotics were defined as: ciprofloxacin, levofloxacin, moxifloxacin, clindamycin, ceftriaxone, cefotaxime, ceftazidime, or cefixime. FINDINGS: We identified subjects who were prescribed any high-risk antibiotic, finding 3513 on a concomitant PPI and 6149 not taking a PPI. Of these subjects, 111 were diagnosed with CDI and met inclusion criteria. Baseline characteristics, CDI severity, length of hospitalization and antibiotic therapy prior to infection were similar in both groups. The incidence of CDI was significantly higher in patients prescribed a PPI (odds ratio: 2.2; 95% confidence interval: 1.52-3.23; P=0.0001). A strong association was found between concurrent PPI use with fluoroquinolones (P=0.005) and clindamycin (P=0.045). CONCLUSION: The use of PPIs together with high-risk antibiotics was associated with a significantly higher incidence of CDI. Our study provides further support for the CDI prevention strategy of judicious PPI use, especially in patients receiving high-risk antibiotics. Prudent avoidance of PPIs may reduce the incidence of CDI, a major cause of morbidity and mortality worldwide.

A common mechanism for recombinant human NGF, BDNF, NT-3, and murine NGF slow unfolding.

The recombinant human nerve growth factor (hNGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin 4/5 (NT4/5), and murine NGF (mNGF) dimers all undergo rapid unfolding and dissociation to monomer in GdnHCl. Fluorescence spectroscopy, reversed-phase high-performance liquid chromatography, and size-exclusion chromatography were used to show that this monomer M1 converts slowly to a more fully unfolded monomer, M2, by a first order process with half-lives of 22, 2.5, 1.6, and 0.73 h for hNGF, mNGF, NT-3, and BDNF, respectively, at 25 degrees C. Linear Arrhenius plots for the conversion of M1 to M2 yielded activation energies of 27, 22, 24, and 24 kcal/mol for hNGF, mNGF, NT-3, and BDNF, respectively. The refolding of these neurotrophins from 5 M GdnHCl was also first order with NT-3 the slowest to refold and BDNF the fastest. Threading of the N-terminus out through the cystine-knot loop present in each of these proteins is proposed as the slow step in unfolding. The number of amino acids in the cystine-knot loop (14 for hNGF, mNGF, NT-3, and BDNF; 21 for NT4/5), and the number and position of the proline residues in this loop (2 for hNGF; 1 for mNGF, NT-3, BDNF, and NT4/5) correlate with the relative rates of unfolding. The smaller the loop and the greater the number of prolines, the more hindered and slower the unfolding.

RhNGF slow unfolding is not due to proline isomerization: possibility of a cystine knot loop-threading mechanism.

The unfolding of recombinant human beta-NGF (NGF) in guanidine hydrochloride (GdnHCl) was found to be time dependent with the denaturation midpoint moving to lower GdnHCl concentration over time. Dissociation and extensive unfolding of the NGF dimer occurred rapidly in 5 M GdnHCl, but further unfolding of the molecule occurred over many days at 25 degrees C. Fluorescence spectroscopy, size-exclusion and reversed-phase HPLC, ultra-centrifugation, and proton NMR spectroscopy were used to ascertain that the slow unfolding step was between two denatured monomeric states of NGF (M1 and M2). Proton NMR showed the monomer formed at early times in GdnHCl (M1) had little beta-sheet structure, but retained residual structure in the tryptophan indole and high-field methyl regions of the spectrum. This residual structure was lost after prolonged incubation in GdnHCl giving a more fully unfolded monomer, M2. From kinetic unfolding experiments in 5 M GdnHCl it was determined that the conversion of M1 to M2 had an activation energy of 26.5 kcal/mol, a half-life of 23 h at 25 degrees C, and the rate of formation of M2 was dependent on the GdnHCl concentration between 5 and 7.1 M GdnHCl. These properties of the slow unfolding step are inconsistent with a proline isomerization mechanism. The rate of formation of the slow folding monomer M2 increases with truncation of five and nine amino acids from the NGF N-terminus. A model for the slow unfolding reaction is proposed where the N-terminus threads through the cystine knot to form M2, a loop-threading reaction, increasing the conformational freedom of the denatured state.

Current and future management of serious skin and skin-structure infections.

The purpose of this study was to compare in a randomized, open-label clinical study, the efficacy and safety of cefepime (1 g every 12 hours) with that of ceftazidime (1 g every 8 hours) in patients with serious skin and skin-structure infections. Of 298 patients enrolled in the study, 130 with serious skin and skin-structure infections were evaluable. Demographics and underlying medical conditions were comparable in both groups. The most common infections were cellulitis, abscesses, ulcers, and postoperative wound infections. The most common pathogens isolated were Staphylococcus aureus, group A streptococci, Enterobacteriaceae, and Pseudomonas aeruginosa. Duration of therapy in the 93 patients treated with cefepime was 3-18 days and in the 37 ceftazidime-treated patients was 4-16 days. Pathogen bacteriologic response rates were high: 92% (124 of 135) of pathogens were eradicated by cefepime and 95% (55 of 58) by ceftazidime. Clinical response rates were satisfactory in 88% (82 of 93) of cefepime-treated patients and in 89% (33 of 37) of ceftazidime-treated patients. Adverse events occurred with similar frequency in both groups. Events probably related to study drugs affected 3% (6 of 198) of patients treated with cefepime and 4% (4 of 100) of ceftazidime-treated patients. Cefepime, a new parenteral cephalosporin administered every 12 hours, is an extremely well tolerated and effective alternative to ceftazidime given every 8 hours for the treatment of serious skin and skin-structure infections.

Portion sizes in dietary assessment: issues and policy implications.

Accurate estimates of energy and nutrient intake of individuals and populations are contingent on the reliability of information obtained about food intake, food composition, and portion size. This article reviews issues related to the definition, determination, and use of portion sizes in dietary assessment and public education.

Artificial gravity considerations for a mars exploration mission.

Artificial gravity (AG), as a means of preventing physiological deconditioning of astronauts during long-duration space flights, presents certain special challenges to the otolith organs and the adaptive capabilities of the CNS. The key issues regarding the choice of AG acceleration, radius, and rotation rate are reviewed from the viewpoints of physiological requirements and human factors disturbances. Head movements and resultant Coriolis forces on the rotating platform may limit the usefulness of economical short centrifuges for other than brief periods of intermittent stimulation.

Optimal estimator model for human spatial orientation.

A model is presented to predict human dynamic spatial orientation in response to multisensory stimuli. Motion stimuli are first processed by dynamic models of the visual, vestibular, tactile, and proprioceptive sensors. Central nervous system function is modeled as a steady state Kalman filter that optimally blends information from the various sensors to form an estimate of spatial orientation. Where necessary, nonlinear elements preprocess inputs to the linear central estimator in order to reflect more accurately some nonlinear human response characteristics. Computer implementation of the model has shown agreement with several important qualitative characteristics of human spatial orientation.

Ocular torsion on earth and in weightlessness.

Ocular torsion (OT) was measured in human subjects during horizontal linear acceleration on a sled in the laboratory and when emerging from weightlessness during parabolic flights in NASA's KC-135 aircraft. Analysis of the frequency response of OT to sinusoidal horizontal oscillation on earth shows results consistent with constant tilt rate studies and with earlier models based on perception of acceleration. Step responses of OT to lateral acceleration are compared to similar profiles from aircraft tests with no preexisting gravitoinertial force on the otoliths. The sensitivity of OT to rotating wide fields producing vection and to tactile cues is compared for earth and weightlessness. A new instrument for high bandwidth video measurement of OT using a soft-contact-lens target is described.

Tactile influences on astronaut visual spatial orientation: human neurovestibular studies on SLS-2.

Human spatial orientation in spaceflight is initially disturbed by the absence of usable graviceptor information from the otolithic organs. Experiments measuring astronaut visually induced motion (vection) strength on various flight days during the first 10 days of the Spacelab Life Sciences-2 mission demonstrated two new phenomena in addition to confirming the initial increased weighting of visual and localized tactile cues. The reliance on tactile and visual noninertial cues apparently declined after a week in space, as the crew became able to utilize their internal reference frame. Subjects also showed that even nondirectional tactile cues served as a direction anchor and inhibited visually induced roll sensation relative to a new loosely tethered test condition. Individual perceptual styles were again revealed among the four astronauts tested. The readaptation to 1 G similarly shows a period of reinterpretation of inertial and visual cues to spatial orientation. The results are discussed in terms of an internal-model representation of body orientation, with time-varying weights applied to extrinsic and intrinsic signals.

Quality of pharmacotherapy consultations provided by drug information centers in the United States.

We evaluated the performance of 116 U.S. drug information centers in responding to specific questions about drugs. The primary measures were correctness of responses and extent of probing for patient data. Questions addressed the effect of ranitidine on blood alcohol concentrations, the potential interaction between didanosine and dapsone, prevention of nonsteroidal antiinflammatory drug (NSAID)-induced peptic ulcers, and use of erythromycin for diabetic gastroparesis. The percentages of centers providing correct overall responses were 70% for the ranitidine question, 90% for the didanosine-dapsone question, 8% for the NSAID question, and 20% for the erythromycin question. For the three patient-specific questions, the percentages of centers eliciting vital patient data were 27% for the didanosine-dapsone question, 86% for the NSAID question, and 5% for the erythromycin question. In providing pharmacotherapy consultations, drug information centers generally failed to obtain pertinent patient data, thereby risking incorrect responses and inappropriate recommendations.

Parkinson's disease: focus on management alternatives.

AUDIENCE: This activity is designed for physicians, pharmacists, nurses, health planners, directors of managed care organizations, and payers of health services. GOAL: To understand the impact that Parkinson's disease has on patients and to identify areas of drug therapy that can be optimized to improve a patient's quality of life. OBJECTIVES: 1. Discuss the epidemiology and pathophysiology of idiopathic Parkinson's disease (IPD). 2. Identify causes of secondary parkinsonism and medications associated with drug-induced parkinsonism. 3. Discuss the cardinal and secondary manifestations of IPD. 4. Outline the 6 stages of IPD. 5. Identify therapeutic alternatives for various levodopa treatment failures. 6. Identify the 3 newer antiparkinson agents and state their mechanisms of action, common adverse effects, drug interactions, and appropriate use. 7. Identify the appropriate use, common adverse effects, and drug interactions of dopamine agonists, anticholinergic agents, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors in Parkinson's disease therapy.

Spaceflight influences on ocular counterrolling and other neurovestibular reactions.

Exposure to extended periods of weightlessness in orbital flight has profound effects on the neurovestibular system and influences head and eye movements, postural control, and spatial orientation. The associated space motion sickness is among the earliest of the signs of adaptation to this new environment. This report both reviews the prominent neurovestibular phenomena associated with going into space and returning to earth and relates the issues to vestibular compensation and rehabilitation. New results from the Spacelab SLS-2 mission are included, showing significant reductions in postflight ocular counterrolling and changes in ocular counterrolling left/right asymmetries after 2 weeks in space.

The etiology of ski injuries: an eight year study of the skier and his equipment.

Detailed ski injury statistics have been maintained at Waterville Valley, New Hampshire, since the opening of the area as a major ski resort in 1966. These statistics were examined to uncover some of the major contributory factors involved in ski accidents. The characteristics that set this study aside from other such reports are the inclusion of both an adequately sized normal control population and the longitudinal collection of comparable data from a relatively stable skiing population over an eight year period, to reveal trends in the number and type of accidents.

Selective habituation of vestibular nystagmus by visual stimulation in the monkey.

Four monkeys were exposed to a series of unidirectional rotating visual fields, of the type known to produce circularvection in man. As in the human case, the vestibulo-ocular reflex for rotation in the direction of the optokinetic nystagmus and circularvection during the preceding visual stimulation--was markedly decreased following that visual stimulation, whereas that in the opposite direction was increased. This finding corresponds to the results of nystagmus and psychophysical circularvection experiments on man. It suggests a link between single unit studies performed under identical conditions in monkey and psychophysical investigations.

Subjective detection of vertical acceleration: a velocity-dependent response?

Human subjective thresholds and directional sensitivity were investigated as a function of vertical linear acceleration with head erect. A hyperbolic (r=0.94) relation emerged between threshold latency and acceleration magnitude (range 0.005 to 0.06 g). This implies that detection was determined by attainment of a given velocity (21.6+/-2.65 cm/sec) rather than the acceleration magnitude per se. Re-analysis of previous data from horizontal accelerations conducted with head erect and supine revealed similar hyperbolic relations (r=0.98 in both cases) with velocity constants of 22.6+/-1.28 and 32.4+1.96 cm/sec respectively. From these findings it is inferred that with head erect (i.e. normal attitude re gravity) the thresholds to predominantly utricular (horizontal accel.) and saccular (vert. accel.) stimulation were similar (P greater than 0.7). However, with head "supine" the saccular threshold was increased to approx. 1.5Xnormal (P less than 0.001). The results also confirmed a previously reported difficulty in the subjective detection of the direction of vertical movement.