Increased blood-oxygen binding affinity in Tibetan and Han Chinese residents at 4200 m.

High-altitude natives are challenged by hypoxia, and a potential compensatory mechanism could be reduced blood oxygen-binding affinity (P50), as seen in several high-altitude mammalian species. In 21 Qinghai Tibetan and nine Han Chinese men, all resident at 4200 m, standard P50 was calculated from measurements of arterial PO2 and forehead oximeter oxygen saturation, which was validated in a separate examination of 13 healthy subjects residing at sea level. In both Tibetans and Han Chinese, standard P50 was 24.5 ± 1.4 and 24.5 ± 2.0 mmHg, respectively, and was lower than in the sea-level subjects (26.2 ± 0.6 mmHg, P < 0.01). There was no relationship between P50 and haemoglobin concentration (the latter ranging from 15.2 to 22.9 g dl(-1) in Tibetans). During peak exercise, P50 was not associated with alveolar-arterial PO2 difference or peak O2 uptake per kilogram. There appears to be no apparent benefit of a lower P50 in this adult high-altitude Tibetan population.

Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3ß in P301L tau transgenic mice.

Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3ß and HIF-1α, with more interleukin-1ß and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3ß and HIF-1α play a prominent role.

Production and fate of the sea lamprey migratory pheromone.

Biochemical studies demonstrate that three steroids postulated to function as the sea lamprey migratory pheromone are released in sufficient quantities, and possess adequate stability and binding characteristics, to function as a multi-component pheromone in natural river waters. Mass spectrometric (MS) analyses of the holding water of recently fed larval lamprey demonstrated that each of these compounds is released at rates of 5-25 ng larva(-1) h(-1), adequate to produce picomolar (biologically relevant) concentrations in river waters. Petromyzonamine disulfate (PSDS) was released at about twice the rate of the other two components, petromyzonamine disulfate (PADS) and petromyzonol sulfate (PS). Unfed larvae also released all three steroids but only at about two-thirds the rate of fed larvae and in a different ratio. However, a behavioral test of fed and unfed larval holding waters suggested this change in pheromone ratio does not diminish pheromonal signal function in the winter when larvae are not feeding. A study of steroid degradation found that PADS and PSDS had half-lives of about 3 days, similar to values previously described for PS and sufficiently slow for the entire pheromone to persist in river mouths. Finally, both MS and electro-olfactogram recording found that contrary to previous suggestions, natural levels of natural organic matter found in streams do not bind to these steroids in ways that diminish their natural biological potency. In conclusion, it appears highly likely that a mixture of PADS, PSDS and PS is present at biologically relevant concentrations and ratios in many Great Lakes streams where it functions as a pheromonal attractant.

Intranasal deferoxamine affects memory loss, oxidation, and the insulin pathway in the streptozotocin rat model of Alzheimer's disease.

Accumulation of metal and the accompanying increase in oxidative stress and inflammation plays an important role in neurodegenerative disease. Deferoxamine (DFO) is a metal chelator found to be beneficial in several animal models of neurodegenerative disease and insult including Alzheimer's disease, Parkinson's disease, stroke, and subarachnoid hemorrhage. In this study, we determine whether intranasally (IN) administered DFO is beneficial in the intracerebroventricular streptozotocin (ICV STZ) rat model of sporadic Alzheimer's disease, which is different from previous models in that it exhibits dysregulation of insulin metabolism as well as oxidative stress and inflammation. Surgical induction of the model included ICV injections of either STZ or citrate buffer (sham in rats), which were treated IN with either saline or DFO (n=10-15/group). Treatment started either before or after injection of STZ to induce the model, and continued throughout the study. IN treatment continued three times per week for three weeks before behavior tests started followed by eventual euthanasia with tissue collection. Spatial memory tests with the Morris water maze showed that STZ rats treated with IN DFO both before and after model induction had significantly shorter escape latencies. Pre-treatment with IN DFO also significantly decreased footslips on the tapered balance beam test. Brain tissue analyses showed DFO treatment decreased oxidation as measured by oxyblot and increased insulin receptor expression. These results further support the potential of IN DFO for use as a treatment for Alzheimer's disease, and show benefit in a non-amyloid/tau rodent model.

Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia.

BACKGROUND: Although medical practice guidelines exist, there have been no large-scale studies assessing the relationship between initial antimicrobial therapy and medical outcomes for patients hospitalized with pneumonia. OBJECTIVE: To determine the associations between initial antimicrobial therapy and 30-day mortality for these patients. METHODS: Hospital records for 12945 Medicare inpatients (> or = 65 years of age) with pneumonia were reviewed. Associations between initial antimicrobial regimens and 30-day mortality were assessed with Cox proportional hazards models, adjusting for baseline differences in patient characteristics, illness severity, and processes of care. Comparisons were made with patients treated with a non-pseudomonal third-generation cephalosporin alone (the reference group). RESULTS: Initial treatment with a second-generation cephalosporin plus macrolide (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.96), a non-pseudomonal third-generation cephalosporin plus macrolide (HR, 0.74; 95% CI, 0.60-0.92), or a fluoroquinolone alone (HR, 0.64; 95% CI, 0.43-0.94) was independently associated with lower 30-day mortality. Adjusted mortality among patients initially treated with these 3 regimens became significantly lower than that in the reference group beginning 2, 3, and 7 days, respectively, after hospital admission. Use of a beta-lactam/beta-lactamase inhibitor plus macrolide (HR, 1.77; 95% CI, 1.28-2.46) and an aminoglycoside plus another agent (HR, 1.21; 95% CI, 1.02-1.43) were associated with an increased 30-day mortality. CONCLUSIONS: In this study of primarily community-dwelling elderly patients hospitalized with pneumonia, 3 initial empiric antimicrobial regimens were independently associated with a lower 30-day mortality. The more widespread use of these antimicrobial regimens is likely to improve the medical outcomes for elderly patients with pneumonia.

mu-chain disease. Report of two new cases.

We report two cases of mu-heavy-chain disease. Both patients were affected with a lymphoproliferative disease that shared several suggestive features with the previously reported cases of mu-chain disease: the presence of vacuolated plasma cells in bone marrow, a small amount of alpha 2 moving abnormal mu-chain protein, and urinary kappa Bence Jones protein in one case.

Clinical and biological features in the 12 months preceding onset of AIDS in HIV-infected subjects.

Biological markers of HIV infection were studied in 17 asymptomatic HIV seropositive subjects in the 12 months preceding the onset of the disease. No single marker of HIV infection preceded the development of AIDS. Therefore, the clinical care of asymptomatic seropositive subjects should include a number of tests to evaluate HIV activity and immune suppression.

Albumin Paris 2: a new genetic variant distinguished by isoelectric focusing.

Until recently, the characterization of genetic variants of human serum albumin was performed by electrophoretic typing prior to the determination of their amino acid substitutions. We describe a procedure using isoelectric focusing in the presence of urea for the analysis of the genetic variation of albumin. This procedure allowed a clear distinction of a new variant, previously found to be identical with albumin Sondrio according to its relative electrophoretic mobilities at 3 pHs. This new variant, the third rare albumin allotype identified in the Ile-de-France region, was called albumin Paris 2.

A sensitive double-diffusion microassay suitable for the detection of idiotype-antiidiotype precipitates.

Using agarose gel coated on GelBond film sheets and using Coomassie blue stain followed by silver stain, a sensitive double-diffusion microassay has been developed for detecting small amounts of precipitate forming during idiotype-antiidiotype reactions. The sensitivity of the method is 10-100 times greater than classical immunodiffusion tests. Other advantages include the need for minimal amounts of unconcentrated sample, the absence of radioactive or toxic substrates, no interference due to a second or third antibody coat such as are used in immunoenzymatic techniques, and the possibility of a direct evaluation of qualitative data such as identity, cross-reactivity or non-identity. As little as 40 ng antibody could be detected, corresponding to an antibody concentration of 8 micrograms/ml, making the microassay useful for rapid screening of idiotype-antiidiotype precipitates during routine analysis of hybridoma supernatants.

A statewide initiative to improve the care of hospitalized pneumonia patients: The Connecticut Pneumonia Pathway Project.

PURPOSE: A statewide quality improvement initiative was conducted in Connecticut to improve process-of-care performance and to decrease length of stay for patients hospitalized with community-acquired pneumonia. SETTING AND METHODS: Data were collected on 1,242 elderly (> or =65 years) pneumonia patients hospitalized at 31 of 32 acute care hospitals between January 16, 1995, and March 15, 1996, and on 1,146 patients hospitalized between January 1, 1997, and June 30, 1997. Interventions included feedback of performance data (Qualidigm, the Connecticut Peer Review Organization), dissemination of an evidence-based pneumonia critical pathway (Connecticut Thoracic Society), and sharing of pathway implementation experiences (hospitals). Process and outcome measures included early antibiotic administration, blood culture collection, oxygenation assessment, length of stay, 30-day mortality, and 30-day readmission rates. Analyses were adjusted for severity of illness and hospital-specific practice patterns. RESULTS: After the statewide initiative, improvements were noted in antibiotic administration within 8 hours of hospital arrival (improvement from 83.4% to 88.8%, relative risk [RR] = 1.21; 95% confidence interval [CI]: 1.10 to 1.32), oxygenation assessment within 24 hours of hospital arrival (93.6% to 95.4%; RR = 1.23, 95% CI: 1.11 to 1.38), and length of stay (7 days to 5 days, P <0.001). There were no significant changes in blood culture collection within 24 hours of hospital arrival, blood culture collection before antibiotic administration, 30-day mortality, or 30-day readmission rates. CONCLUSIONS: Statewide improvements were demonstrated in the care of hospitalized pneumonia patients concurrent with a multifaceted quality improvement intervention. Further research is needed to separate the effects of the quality improvement interventions from secular trends.

Potential bronchoconstrictor stimuli in acid fog.

Acid fog is complex and contains multiple stimuli that may be capable of inducing bronchoconstriction. These stimuli include sulfuric and niric acids, the principal inorganic acids present; sulfites, formed in the atmosphere as a reaction product of sulfur dioxide and water droplets; fog water itself, a hypoosmolar aerosol; the organic acid hydroxymethanesulfonate, the bisulfite adduct of formaldehyde; and gaseous pollutants, e.g., sulfur dioxide, oxides of nitrogen, ozone. Given this complexity, evaluation of the respiratory health effects of naturally occurring acid fog requires assessment of the bronchoconstrictor potency of each component stimulus and possible interactions among these stimuli. We summarize the results of three studies that involve characterization of the bronchoconstrictor potency of acid fog stimuli and/or their interaction in subjects with asthma. The results of the first study indicate that titratable acidity appears to be a more important stimulus to bronchoconstriction than is pH. The results of the second study demonstrate that sulfite species are capable of inducing bronchoconstriction, especially when inhaled at acid pH. The results of the third study suggest that acidity can potentiate hypoosmolar fog-induced bronchoconstriction.

Epithelium removal alters responsiveness of guinea pig trachea to substance P.

Removal of epithelium from mammalian tracheae has been shown to enhance responsiveness to a variety of contractile and relaxant agents. One of the most dramatic shifts reported has been for guinea pig tracheal tissue denuded of epithelium and treated with substance P. We investigated whether this shift in responsiveness was because of 1) removal of an epithelium-associated enzyme, neutral endopeptidase, which degrades substance P and 2) loss of an epithelium-derived noncyclooxygenase relaxant factor. Using a muscle bath preparation we performed concentration-response curves with substance P and acetylcholine on indomethacin-treated tissues with and without intact epithelium and with and without pretreatment with the neutral endopeptidase inhibitor, phosphoramidon. Epithelium removal potentiated the mean agonist concentration calculated to causes 30% of the maximal contractile response by 148-fold for substance P and by 7-fold for acetylcholine. Phosphoramidon potentiated the contractile response to substance P, but not to acetylcholine, by both the epithelium-intact and denuded tissues (P less than 0.05). However, the degree of enhancement by phosphoramidon was much greater in the intact tissues. With phosphoramidon treatment, therefore, the difference in responsiveness to substance P between the intact and denuded tissues was reduced from 148-fold to 18-fold. This effect of phosphoramidon suggests that the hyperresponsiveness to substance P of epithelium-denuded airway tissue is largely because of removal of neutral endopeptidase. Because all tissues were treated with indomethacin, the leftward shifts in substance P and in acetylcholine responsiveness induced by epithelium removal further suggest that an epithelium-derived noncyclooxygenase factor other than neutral endopeptidase also modulates the contractile response to substance P and to acetylcholine.

The alpha 2 macroglobulin/thrombin interaction in the presence of hydroxylamine.

The influence of a primary amine, hydroxylamine, on the interaction between alpha 2 macroglobulin (alpha 2M) and thrombin was analyzed by electrophoretic and enzymatic methods. Hydroxylamine (final concentrations 0.01 M and 0.1 M) was added to the alpha 2M solution 3 to 5 min before thrombin. In these conditions hydroxylamine had no direct influence on alpha 2M itself. The inhibition of thrombin activity by alpha 2M was still possible and alpha 2M/thrombin complexes were observed. However the rate of inhibition of the clotting activity of thrombin was diminished in function of the hydroxylamine concentration. The complexes obtained in the absence of the nucleophylic agent were resistant to SDS dissociation, whereas those obtained in the presence of hydroxylamine were dissociated by SDS. In both cases, the amount of alpha 2M polypeptide chains cleaved by thrombin was the same (50%). In conclusion, hydroxylamine does not prevent the formation of alpha 2M/thrombin complexes, but it reduces the covalent binding of the enzyme to the inhibitor in a concentration dependent fashion, leading to the formation of "abnormal" complexes.

Airway inflammation and occupational asthma.

Airway inflammation due to exposure to a wide variety of agents encountered in the workplace is a major cause of occupational asthma. This article reviews major examples of occupational asthma linked to airway inflammation, including their epidemiology, pathophysiology, and clinical course.

Metal fume fever: characterization of clinical and plasma IL-6 responses in controlled human exposures to zinc oxide fume at and below the threshold limit value.

Results from animal and preliminary human exposure studies have called into question whether the 5 mg/m3 8-hour time-weighted average threshold limit value (TLV) for zinc oxide fume is sufficient to protect workers against metal fume fever. The objectives of this study were to determine the clinical effects of exposures to low concentrations of zinc oxide and to ascertain whether these exposures elevated circulating levels of specific cytokines, which could account for the symptoms of the metal fume fever syndrome. Thirteen resting naive subjects inhaled, on separate days, air and 2.5 and 5 mg/m3 of furnace-generated zinc oxide fume for 2 hours. Subjects recorded symptoms and temperature and had blood drawn before and after each exposure. The mean (+/- SE) maximum rise in oral temperature at 6 to 12 hours after exposure was 1.4 +/- 0.3 degrees F after 5 mg/m3, compared with 0.6 +/- 0.5 degrees F after air exposure (P < 0.05). Mean temperature was also elevated after exposure to 2.5 mg/m3 zinc oxide (1.2 +/- 0.3 degrees F). In a parallel fashion, plasma levels of interleukin 6 (IL-6), a pyrogen, were significantly elevated after exposure to 5 mg/m3 zinc oxide. Mean IL-6 values (pg/mL) at pre-exposure and at 3 and 6 hours post-exposure were 1.9 (+/- 0.6), 2.8 (+/- 0.7), and 2.9 (+/- 0.6), respectively, on the air day and 1.6 (+/- 0.6), 4.4 (+/- 1.2), and 6.4 (+/- 1.1) on the 5 mg/m3 zinc oxide day. Zinc oxide exposure did not significantly affect plasma levels of tumor necrosis factor. Total symptom scores peaked 9 hours after the 5 mg/m3 zinc oxide exposure. Myalgias, cough, and fatigue were the predominant symptoms reported. Inhalation of zinc oxide for 2 hours at the current TLV of 5 mg/m3 produces fever and symptoms along with elevation in plasma IL-6 levels.

Characterization of clinical tolerance to inhaled zinc oxide in naive subjects and sheet metal workers.

Clinical tolerance to the acute effects of zinc oxide inhalation develops in workers during periods of repeated exposure. The aims of this study were to determine whether clinical tolerance is accompanied by a reduction in the acute pulmonary inflammatory and cytokine responses to zinc oxide exposure and whether tolerance can be demonstrated in sheet metal workers who chronically inhale low levels of zinc oxide. Naive (never-exposed) subjects inhaled 5 mg/m3 zinc oxide on 1 or 3 days and underwent bronchoalveolar lavage 20 hours after the final exposure. Sheet metal workers inhaled zinc oxide on 1 day and control furnace gas on another day. Among naive subjects in whom tolerance was induced, bronchoalveolar lavage fluid percent neutrophils and interleukin-6 (IL-6) levels were significantly decreased compared with subjects who underwent only a single exposure. Sheet metal workers were much less symptomatic, but they still experienced a significant increase in plasma IL-6. The results indicate that clinical tolerance to zinc oxide is accompanied by reduced pulmonary inflammation and that chronically exposed sheet metal workers are not clinically affected by exposure to zinc oxide fume at the Occupational Safety and Health Administration Permissible Exposure Limit. The increase in IL-6 levels observed in the clinically responsive, and to a lesser extent, tolerant, states following zinc oxide inhalation is consistent with the dual role of IL-6 as a pyrogen and anti-inflammatory agent.

Factors inhibiting use of the pneumococcal polysaccharide vaccine: a survey of Connecticut physicians.

BACKGROUND: The pneumococcal polysaccharide vaccine (PPV) is effective in preventing invasive pneumococcal disease, but remains underutilized. Prior surveys of physicians revealed concern regarding the safety and efficacy of the vaccine, but there has been little information published in the last 10 years that sheds light on why the vaccine remains underutilized. Although there is currently emphasis on providing PPV to hospitalized patients, there is even less known about what factors prevent PPV use in the hospital setting and chronic care setting. We performed a survey of physicians in Connecticut to determine what factors prevent utilization of the vaccine in three patient care settings. METHODS: A survey of internists and family practitioners in Connecticut that ascertained their frequency of utilization of PPV and what factors inhibited utilization of PPV. RESULTS: Three hundred ninety-seven responses are included in the analysis. Forgetting to administer the vaccine (59% of respondents) and patient refusal (55% of respondents) were the factors most frequently noted as being important in preventing vaccination in the outpatient setting. In the inpatient and chronic care settings, difficulty in determining the patient's vaccine status was also noted. Concerns regarding the efficacy or safety of the vaccine did not seem to be important. The factor that correlated most closely with the respondents' reported frequency of vaccine use was forgetting to vaccinate. CONCLUSIONS: Physicians, although accepting the efficacy of PPV, are inhibited from its more frequent use by several factors.

[Hashimoto's thyroiditis and monoclonal gammapathy (two cases) (author's transl)]. / Thyroïdite d'Hashimoto et gammapathie monoclonale. Deux observations.

The authors describe two cases of Hashimoto's thyroiditis with a monoclonal dysproteinemia (IgG lambda in one case and IgG kappa in the other). They show that the antithyroid activity (anti-microsomial in the first case, anti thyroglobulin in the second case) is not carried by the abnormal gammaglobulin. The two diseases, therefore, appear to be separate but can both be considered as the consequence of a particular immunological state.

Intranasally-administered deferoxamine mitigates toxicity of 6-OHDA in a rat model of Parkinson׳s disease.

Deferoxamine (DFO) has shown therapeutic promise for the treatment of Parkinson׳s disease (PD) as it has reduced both behavioral and biochemical deficits when injected into the brain of rodent models of PD. Intranasally administered DFO targets the brain directly but non-invasively and has been effective in animal models of stroke and Alzheimer׳s disease. In this study we sought to determine whether intranasal (IN) DFO could be neuroprotective for PD in a rat model. PD was induced with a unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, while sham surgery rats received saline injections. Rats were pre-treated three times with either IN DFO or saline (starting 4 days before 6-OHDA), and post-treated twice/wk for one month before behavioral tests. In the apomorphine-induced rotational test, IN DFO significantly decreased the number of contralateral turns after injection of apomorphine HCl (p<0.05). Also, IN DFO significantly decreased limb asymmetry in the rearing tube as measured with contralateral limb touches (p<0.05). The IN DFO treatment yielded a trend towards decreased contralateral foot-slips on the tapered balance beam, though the difference was not significant. Finally, IN DFO-treated rats had increased preservation of tyrosine hydroxylase immunoreactive neurons in the substantia nigra (p<0.05). These results confirm that DFO is beneficial in a 6-OHDA model and demonstrate improvement in motor deficits and dopaminergic neuronal survival with non-invasive intranasal delivery, making this an attractive potential treatment for PD.

Removal of sedimentation decreases relative deposition of coarse particles in the lung periphery.

Lung deposition of >0.5-µm particles is strongly influenced by gravitational sedimentation, with deposition being reduced in microgravity (µG) compared with normal gravity (1G). Gravity not only affects total deposition, but may also alter regional deposition. Using gamma scintigraphy, we measured the distribution of regional deposition and retention of radiolabeled particles ((99m)Tc-labeled sulfur colloid, 5-µm diameter) in five healthy volunteers. Particles were inhaled in a controlled fashion (0.5 l/s, 15 breaths/min) during multiple periods of µG aboard the National Aeronautics and Space Administration Microgravity Research Aircraft and in 1G. In both cases, deposition scans were obtained immediately postinhalation and at 1 h 30 min, 4 h, and 22 h postinhalation. Regional deposition was characterized by the central-to-peripheral ratio and by the skew of the distribution of deposited particles on scans acquired directly postinhalation. Relative distribution of deposition between the airways and the alveolar region was derived from data acquired at the various time points. Compared with inhalation in 1G, subjects show an increase in central-to-peripheral ratio (P = 0.043), skew (P = 0.043), and tracheobronchial deposition (P < 0.001) when particles were inhaled in µG. The absence of gravity caused fewer particles to deposit in the lung periphery than in the central region where deposition occurred mainly in the airways in µG. Furthermore, the increased skew observed in µG likely illustrates the presence of localized areas of deposition, i.e., "hot spots", resulting from inertial impaction. In conclusion, gravity has a significant effect on deposition patterns of coarse particles, with most of deposition occurring in the alveolar region in 1G but in the large airways in µG.