Nanoparticle distribution during systemic inflammation is size-dependent and organ-specific.

This study comprehensively investigates the changing biodistribution of fluorescent-labelled polystyrene latex bead nanoparticles in a mouse model of inflammation. Since inflammation alters systemic circulatory properties, increases vessel permeability and modulates the immune system, we theorised that systemic inflammation would alter nanoparticle distribution within the body. This has implications for prospective nanocarrier-based therapies targeting inflammatory diseases. Low dose lipopolysaccharide (LPS), a bacterial endotoxin, was used to induce an inflammatory response, and 20 nm, 100 nm or 500 nm polystyrene nanoparticles were administered after 16 hours. HPLC analysis was used to accurately quantify nanoparticle retention by each vital organ, and tissue sections revealed the precise locations of nanoparticle deposition within key tissues. During inflammation, nanoparticles of all sizes redistributed, particularly to the marginal zones of the spleen. We found that LPS-induced inflammation induces splenic macrophage polarisation and alters leukocyte uptake of nanoparticles, with size-dependent effects. In addition, spleen vasculature becomes significantly more permeable following LPS treatment. We conclude that systemic inflammation affects nanoparticle distribution by multiple mechanisms, in a size dependent manner.

Determinants of Perceived Physical Environment Barriers among Community-Dwelling Elderly in Taiwan.

OBJECTIVES: To test the hypothesis that mobility, activities of daily living, and the interaction between them can play a key role in determining perceived physical environment barriers among community-dwelling elderly. DESIGN: Cross-sectional. SETTING: Community. PARTICIPANTS: One hundred and ninety-seven community-dwelling elderly with more than 7 points on the Short Portable Mental State Questionnaire and less than 7 points on the Geriatric Depression Scale (15 items). INTERVENTION: None. MEASUREMENTS: Time Get-up and Go test (TUG), the subscales of basic activity of daily living (BADL)/instrumental activities of daily living (IADL) of the Hierarchy of Care Required (HCR), and the physical/structural subscale of the Craig Hospital Inventory of Environmental Factors in Community-dwelling Elderly in Taiwan were used to measure mobility, activities of daily living and perceived physical environment barriers, respectively. Hierarchical linear regression analyses were used to test the study hypothesis. RESULTS: Significant and positive relations were found to exist between perceived physical environment barriers and (1) the TUG time (ß=.300, p<.05), and (2) the IADL score for the HCR (ß=.322, p<.05), respectively. A significant and negative relation existed between perceived physical environment barriers and the interaction term (the TUG time and the IADL score for the HCR) (ß=-.211, p<.05). CONCLUSION: Mobility, IADL and the interaction between them are found to be significant determinants of perceived physical environment barriers in the community-dwelling elderly under consideration. Strategies targeting the enhancement of mobility among community-dwelling elderly are suggested to lead to improvements in the degree to which physical environment barriers are perceived. This beneficial effect could be greater in the case of elderly individuals with better IADL function.

Lower availability of midbrain serotonin transporter between healthy subjects with and without a family history of major depressive disorder - a preliminary two-ligand SPECT study.

PURPOSE: Serotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD. METHODS: Eight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [¹²³I] 2-((2-((dimethylamino) methyl) phenyl)thio)-5-iodophenylamine (ADAM) and [(99m)Tc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment. RESULTS: SERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups. CONCLUSIONS: The results with regard to the midbrain SERT level suggest the heritability of MDD.

Diffusion tensor imaging correlates with the clinical assessment of disease severity in cervical spondylotic myelopathy and predicts outcome following surgery.

BACKGROUND AND PURPOSE: CSM is a common neurologic disease that results in progressive disability and eventual paralysis without appropriate treatment. Imaging plays a significant role in the evaluation of CSM and has evolved with recent technical advances. We sought to systematically explore the relationship between clinical disease severity and DTI in CSM, and to investigate the potential use of DTI in surgical decision-making models. MATERIALS AND METHODS: MR imaging studies and clinical assessments were prospectively collected on 30 patients with CSM. Spearman correlations were used to investigate associations between clinical disease severity and FA at the time of diagnosis. Clinical assessment was performed using mJOA, Nurick, Short Form-36, and NDI scores. Fifteen patients with CSM subsequently underwent decompressive surgery; Spearman correlation and logistic regression were applied to this cohort to study the relationship between baseline DTI measurements and postoperative outcome. Conventional imaging (spinal cord T2 signal intensity and degree of stenosis) was evaluated for comparison with DTI. RESULTS: At diagnosis, FA demonstrated a strong correlation with baseline mJOA (r = 0.62, P < .01) and Nurick (r = -0.46, P = .01) scores. After surgery, recovery of function demonstrated by improvement in NDI score was associated with higher FA values on preoperative DTI (r = -0.61, P = .04). Severely affected patients with CSM with disproportionately high FA tended to achieve greater mJOA scores after surgery compared with subjects with lower FA (P = .08). T2 signal intensity was associated with functional status at baseline but did not predict postoperative outcome; degree of stenosis lacked any significant correlation with clinical parameters. CONCLUSIONS: DTI may be a useful diagnostic tool for assessing disease severity in CSM. The predictive value of DTI regarding postoperative outcome may improve surgical decision-making and facilitate health care outcomes research.

Clinical presentations and skin denervation in amyloid neuropathy due to transthyretin Ala97Ser.

OBJECTIVE: Familial amyloid polyneuropathy (FAP) due to amyloidogenic transthyretin (TTR) is often associated with impairment of thermonociceptive functions. This study investigated skin innervation and its clinical significance in genetically defined FAP due to a hot-spot Ala97Ser TTR mutation (Ala97Ser). METHODS: Skin biopsies were performed on the distal leg of patients with Ala97Ser, and intraepidermal nerve fiber (IENF) densities were quantified. RESULTS: There were 19 unrelated patients with Ala97Ser manifesting a late-onset (59.47 +/- 5.70 years) generalized neuropathy with disabling motor, sensory, and autonomic symptoms. Against a background of a slowly progressive course, 7 patients (36.8%) exhibited additional rapid declines in neurologic deficits, which were associated with elevation of the protein content in the CSF (p < 0.001). The IENF density was markedly reduced in Ala97Ser patients compared to age- and gender-matched controls (0.99 +/- 1.11 vs 8.31 +/- 2.87 fibers/mm, p < 0.001). Skin denervation was present in all patients and was lower in patients with a higher disability grade (0.17 +/- 0.26 vs 1.37 +/- 1.16 fibers/mm, p = 0.003). Albuminocytologic dissociation in the CSF was observed in 14 patients (73.7%), and the IENF density was negatively correlated with the CSF protein concentration (p = 0.015). CONCLUSIONS: Skin denervation was common in Ala97Ser, and degeneration of cutaneous nerve terminals was correlated with the severity of clinical phenotypes and the level of CSF protein.

Desorption kinetics of naphthalene from sediment particles: batch and stepwise desorption approach.

We investigated three major parameters in simulating desorption behaviours: the pre-contamination period, dilution by clean water mass (dilution ratio) and the length of the time interval between dilutions, in both batch and stepwise desorption experiments using particles pre-contaminated with a polycyclic aromatic hydrocarbon, naphthalene (NAPH). We found that the dilution ratio plays a major role in batch desorption, whereas the pre-contamination period plays a major role in stepwise desorption (SD). In addition, the diffusion process was found to be the rate-determining step for our study of SD kinetics. Based on the results of our batch experiments, we were able to derive a mathematical expression capable of correlating the SD rate constant with the length of time interval between dilutions. This expression can be applied in numerical modelling of various naturally occurring processes such as the dispersion and dilution of a heavily contaminated water mass in a marine environment due to an oil spill incident.

Patterns of combined prescriptions of aspirin-Ginkgo biloba in Taiwan: a population-based study.

BACKGROUND AND OBJECTIVES: Although interactions between aspirin and Ginkgo biloba extract (GBE) have been documented, the extent to which these two drugs are used in combination remains unclear. The aim of this study was to estimate the extent and utilization patterns of combined prescriptions of aspirin and GBE in Taiwan based on an analysis of a nationwide database. METHODS: A representative nationwide sample of 200 000 National Health Insurance (NHI) beneficiaries in Taiwan was used. The prescription details of ambulatory care claims for this sample of beneficiaries for the period 1997-2003 were analysed. The prevalence of aspirin and GBE prescriptions was evaluated. The extent of co-prescription of the two drugs was assessed together with the associated patient characteristics. RESULTS: There was an increase in the number of aspirin prescriptions (from 29 986 out of 2 454 879 (1.2%) in 1997, to 50 614 out of 2 499 605 (2.0%) in 2003). Aspirin was mostly prescribed to patients over 50 years old. The percentage of prescriptions with aspirin increased rapidly from 57% to 84%, among those over 50 years old. The number of prescriptions with GBE also increased from 3039 to 6171 and 78-84% was prescribed to those 50 years or older. During the study period, combined prescriptions of aspirin and GBE dramatically increased four times. Most prescriptions were longer than 14 days and 42.4% of combined prescriptions were found to be at the same ambulatory care visit. CONCLUSION: The findings of this study suggest that there is an increasing trend in co-prescription of aspirin and GBE for Taiwan's elderly population during 1997-2003. This trend is of concern and worthy of note.

Organization-based performance measures of cancer care quality: core measure development for breast cancer in Taiwan.

The purpose of the study was to develop organization-based core performance measures (CPMs) for breast cancer patients treated in hospitals that participated in cancer quality improvement programmes in Taiwan. CPMs were developed in three stages that included a preparation, a consensus building stage, and two stages of stakeholder feedback. Three criteria and seven subcriteria were applied in the development process. Indicators listed in a Delphi questionnaire were based on a literature search, indicators developed by relevant institutions and discussion by authors. Each indicator needed to meet inclusion criteria as a final indicator. Evidence-based guidelines, expert opinions from panel group, 27 hospitals and empirical data were all applied to develop and revise the core measures. Fifteen out of 28 indicators were selected and modified after the three stages. There were two pre-treatment indicators for screening and diagnosis, nine treatment-related indicators, and four monitoring-related indicators. Six indicators were supported by evidence level I, and four indicators by level II evidence. The CPMs for breast cancer can be developed systematically and be applied for internal quality improvement and external surveillance. Our experience can be extended to other cancer sites and adapted to link with pay for performance or certification program in cancer care.

Studies of the kinetics and thermochemistry of the forward and reverse reaction Cl + C6H6 = HCl + C6H5.

The laser flash photolysis resonance fluorescence technique was used to monitor atomic Cl kinetics. Loss of Cl following photolysis of CCl4 and NaCl was used to determine k(Cl + C6H6) = 6.4 x 10(-12) exp(-18.1 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) over 578-922 K and k(Cl + C6D6) = 6.2 x 10(-12) exp(-22.8 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) over 635-922 K. Inclusion of literature data at room temperature leads to a recommendation of k(Cl + C6H6) = 6.1 x 10(-11) exp(-31.6 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) for 296-922 K. Monitoring growth of Cl during the reaction of phenyl with HCl led to k(C6H5 + HCl) = 1.14 x 10(-12) exp(+5.2 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) over 294-748 K, k(C6H5 + DCl) = 7.7 x 10(-13) exp(+4.9 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) over 292-546 K, an approximate k(C6H5 + C6H5I) = 2 x 10(-11) cm(3) molecule(-1) s(-1) over 300-750 K, and an upper limit k(Cl + C6H5I) < or = 5.3 x 10(-12) exp(+2.8 kJ mol(-1)/RT) cm(3) molecule(-1) s(-1) over 300-750 K. Confidence limits are discussed in the text. Third-law analysis of the equilibrium constant yields the bond dissociation enthalpy D(298)(C6H5-H) = 472.1 +/- 2.5 kJ mol(-1) and thus the enthalpy of formation Delta(f)H(298)(C6H5) = 337.0 +/- 2.5 kJ mol(-1).

p53 downstream target DDA3 is a novel microtubule-associated protein that interacts with end-binding protein EB3 and activates beta-catenin pathway.

We have previously identified mouse DDA3 as a p53-inducible gene. To explore the functional role of DDA3, we screened a mouse brain cDNA library by the yeast two-hybrid assay, and identified the microtubule plus-end binding protein EB3 as a DDA3-interacting protein. Binding of DDA3 to EB3 was verified by glutathione S-transferase (GST) pull-down assay and subcellular colocalization; co-immunoprecipitation further indicated that interaction of these two proteins within cells required intact microtubules. Domains of DDA3-EB3 interaction were mapped by GST pull-down assay to amino acids 118-241 and 242-329 of DDA3 and the N- and C-termini of EB3. Immunofluorescence analysis revealed colocalization of DDA3 with microtubules in various cell phases, and regions encompassing aa 118-241 and 242-329 contained microtubule-interacting and bundling activities. In vitro microtubule-binding assay showed that DDA3 and EB3 associated directly with microtubules, and cooperated with each other for microtubule binding. In addition, DDA3 bound to the EB3 interacting partner adenomatous polyposis coli 2 (APC2), a homolog of the tumor suppressor APC, which is a component of the beta-catenin destruction complex. Ectopic expression of DDA3 and EB3 enhanced beta-catenin-dependent transactivation and cyclin D1 production, whereas knockdown of endogenous DDA3 or EB3 inhibited beta-catenin-mediated transactivation and the ability of cells to form colonies. Together, our results identify DDA3 as a novel microtubule-associated protein that binds to EB3, and implicate DDA3 and EB3 in the beta-catenin-mediated growth signaling.

Thermochemistry is not a lower bound to the activation energy of endothermic reactions: a kinetic study of the gas-phase reaction of atomic chlorine with ammonia.

The rate constant for Cl + NH3 --> HCl + NH2 has been measured over 290-570 K by the time-resolved resonance fluorescence technique. Ground-state Cl atoms were generated by 193 nm excimer laser photolysis of CCl4 and reacted under pseudo-first-order conditions with excess NH3. The forward rate constant was fit by the expression k1 = (1.08 +/- 0.05) x 10(-11) exp(-11.47 +/- 0.16 kJ mol(-1)/RT) cm3 molecule(-1) s(-1), where the uncertainties in the Arrhenius parameters are +/-1 sigma and the 95% confidence limits for k1 are +/-11%. To rationalize the activation energy, which is 7.4 kJ mol(-1) below the endothermicity in the middle of the 1/T range, the potential energy surface was characterized with MPWB1K/6-31++G(2df,2p) theory. The products NH2 + HCl form a hydrogen-bonded adduct, separated from Cl + NH3 by a transition state lower in energy than the products. The rate constant for the reverse process k(-1) was derived via modified transition state theory, and the computed k(-1) exhibits a negative activation energy, which in combination with the experimental equilibrium constant yields k1 in fair accord with experiment.

Posterior endoscopic lumbar discectomy using a thoracoport as a tubular retractor.

OBJECTIVE: To make lumbar discectomy simple and feasible, we developed an endoscopic surgical technique that uses a Thoracoport as a tubular retractor. SURGICAL TECHNIQUE: The patient was placed in a 60-degree forwardly inclined lateral position with the side of the lesion on the top. After radiological confirmation of the index level, a Thoracoport was inserted through a 2-cm paramedian transverse skin incision. A 0-degree rod lens endoscope was mounted to a scope holder and placed into the retractor for magnification and illumination. Laminotomy was performed with a high-speed drill to reach the insertion of the yellow ligament to the upper lamina. A 2-mm undercutting of the upper facet was performed with a punch to expose the lateral edge of the nerve root. Surgical instruments were inserted next to the endoscope for manipulation. The herniated disc was identified and removed with pituitary rongeurs as in a standard microdiscectomy. With this technique, a sufficient amount of bone is resected to expose the disc lateral to the nerve root; hemostasis is easily achieved and the incidence of nerve root injury is reduced. CONCLUSION: We have successfully performed an endoscopic lumbar discectomy in 20 patients by using a Thoracoport as a tubular retractor. No specially designed instruments were required. This technique was a safe and effective minimally invasive approach to treating lumbar disc disease according to our preliminary experience.

Endoscopic removal of thalamic hematoma: a technical note.

OBJECT: To minimize invasiveness, an endoscopic surgical technique under stereotactic guidance is described for removal of thalamic hematoma. SURGICAL TECHNIQUE: A burr hole is placed at a point 3 cm above the glabella and 3 cm lateral from the midline. A transcortical transventricular puncture is performed with a stainless steel tube under stereotactic guidance. The tube is mounted to a metal holder. Through this tube, a rod-lens working channel endoscope and surgical instruments are inserted for visualization of the thalamus and evacuation of the hematoma. Compared with the endoscopic approach through the shortest distance of viable brain tissue, this technique allows removal of the hematoma in the ventricular space and thalamus simultaneously. The case of one patient with thalamic hemorrhage and obstructive hydrocephalus, caused by an intraventricular blood clot, is reported for surgical demonstration. CONCLUSION: An endoscopic technique for removal of thalamic hematoma with the aid of stereotactic guidance, which allows precise targeting of the lesion, is reported.

Successful resuscitation of acute massive pulmonary embolism with extracorporeal membrane oxygenation and open embolectomy.

Acute massive pulmonary embolism is usually fatal if not treated aggressively, but the management is not standardized. Open pulmonary embolectomy retains a role in the treatment of this disastrous disease. Extracorporeal membrane oxygenation has been used for cardiopulmonary support in some patients with life-threatening pulmonary embolism. This article details our experience of a 58-year-old woman suffering from acute cardiopulmonary collapse caused by massive pulmonary embolism. Under extracorporeal membrane oxygenation support, the patient received pulmonary angiography and underwent open embolectomy for a definitive treatment.

A series of enediynes as novel inhibitors of topoisomerase I.

A series of acyclic enediynes, 2-((6-substituted)-3-hexen-1,5-diynyl)benzonitriles (8--11), display potent inhibition against topoisomerase I without the formation of active biradical intermediates and show inhibitory activity against topoisomerase I at 10 microM, which is five times that of camptothecin from the results of agarose gel electrophoresis.

Cloning, expression, and purification of a thermostable nonhomodimeric restriction enzyme, BslI.

BslI is a thermostable type II restriction endonuclease with interrupted recognition sequence CCNNNNN/NNGG (/, cleavage position). The BslI restriction-modification system from Bacillus species was cloned and expressed in Escherichia coli. The system is encoded by three genes: the 2,739-bp BslI methylase gene (bslIM), the bslIRalpha gene, and the bslIRbeta gene. The alpha and beta subunits of BslI can be expressed independently in E. coli in the absence of BslI methylase (M.BslI) protection. BslI endonuclease activity can be reconstituted in vitro by mixing the two subunits together. Gel filtration chromatography and native polyacrylamide gel electrophoresis indicated that BslI forms heterodimers (alphabeta), heterotetramers (alpha(2)beta(2)), and possibly oligomers in solution. Two beta subunits can be cross-linked by a chemical cross-linking agent, indicating formation of heterotetramer BslI complex (alpha(2)beta(2)). In DNA mobility shift assays, neither subunit alone can bind DNA. DNA mobility shift activity was detected after mixing the two subunits together. Because of the symmetric recognition sequence of the BslI endonuclease, we propose that its active form is alpha(2)beta(2). M.BslI contains nine conserved motifs of N-4 cytosine DNA methylases within the beta group of aminomethyltransferase. Synthetic duplex deoxyoligonucleotides containing cytosine hemimethylated or fully methylated at N-4 in BslI sites in the first or second cytosine are resistant to BslI digestion. C-5 methylation of the second cytosine on both strands within the recognition sequence also renders the site refractory to BslI digestion. Two putative zinc fingers are found in the alpha subunit of BslI endonuclease.

Case mix adjustment in nursing systems research: the case of resident outcomes in nursing homes.

Case mix indicates, for a resident population, the degree of risk for developing favorable or unfavorable outcomes. In a study of 164 nursing homes, we explored two methods for combining resident assessment data into a case mix index (CMI). We compared a facility-level, composite CMI to a prevalence-based CMI comprised of 22 separate resident characteristics for their adequacy in explaining resident outcomes. The prevalence-based CMI consistently explained more variance in outcomes than the facility level, composite CMI. This study indicates a reasonable method for using administrative databases containing resident assessment data to adjust for the influence of case mix on nursing home resident outcomes.

Computerized tomography-guided stereotactic aspiration of brain abscesses: experience with 28 cases.

BACKGROUND: Computerized tomography (CT)-guided stereotactic techniques allow accurate identification of brain abscesses and provide promising results for the management of brain abscesses. METHODS: We reviewed the results of stereotactic aspiration of brain abscesses in 28 consecutive patients from 1984 to 1995. In all patients, the diagnosis of brain abscess was made by computerized tomography (CT). All patients underwent stereotactic aspiration of abscesses as the primary surgical therapy. Intravenous antibiotics were administered preoperatively and adjusted according to organism type and sensitivity to antibiotics. In patients with multiple lesions, aspirations were performed on abscesses larger than 2 cm in diameter or on those causing significant mass effects. CT was performed weekly to monitor abscess growth or failure to resolve. Patients were followed on an outpatient basis. This report is a retrospective review of clinical features, diagnostic methods, treatment and postoperative results. RESULTS: A total of 19 patients had good recoveries and six patients had mild neurologic sequelae. One patient had persistent conscious impairment. Intracranial hemorrhage occurred in one patient. Two deaths occurred during hospitalization. One patient with a fungal infection underwent additional surgical excision of the abscess. Most patients had resolution of abscesses after stereotactic treatment within two months. The cure rate was 92% in patients with bacterial brain abscesses treated with stereotactic aspiration and intravenous antibiotics for six weeks. CONCLUSIONS: Stereotactic surgery is a procedure with minimal morbidity and mortality, and can be the treatment of choice for brain abscesses when combined with appropriate antibiotic therapy.

Resource allocation and resident outcomes in nursing homes: comparisons between the best and worst.

The purpose of this study was to identify patterns of resource allocation that relate to resident outcomes in nursing homes. Data on structure, staffing levels, salaries, cost, case mix, and resident outcomes were obtained from state-level, administrative databases on 494 nursing homes. We identified two sets of comparison groups and showed that the group of homes with the greatest percentage of improvement in resident outcomes had higher levels of registered nurse (RN) staffing and higher costs. However, comparison groups based on best-worst average outcomes did not differ in resource allocation patterns. Additional analysis demonstrated that when controlling for RN staffing, resident outcomes in high- and low-cost homes did not differ. The results suggest that, although RN staffing is more expensive, it is key to improving resident outcomes.