AP-1 Transcription Factor Serves as a Molecular Switch between Chlamydia pneumoniae Replication and Persistence.

Chlamydia pneumoniae is a Gram-negative bacterium that causes acute or chronic respiratory infections. As obligate intracellular pathogens, chlamydiae efficiently manipulate host cell processes to ensure their intracellular development. Here we focused on the interaction of chlamydiae with the host cell transcription factor activator protein 1 (AP-1) and its consequence on chlamydial development. During Chlamydia pneumoniae infection, the expression and activity of AP-1 family proteins c-Jun, c-Fos, and ATF-2 were regulated in a time- and dose-dependent manner. We observed that the c-Jun protein and its phosphorylation level significantly increased during C. pneumoniae development. Small interfering RNA knockdown of the c-Jun protein in HEp-2 cells reduced the chlamydial load, resulting in smaller inclusions and significantly lower chlamydial recovery. Furthermore, inhibition of the c-Jun-containing AP-1 complexes using tanshinone IIA changed the replicative infection phenotype into a persistent one. Tanshinone IIA-dependent persistence was characterized by smaller, aberrant inclusions, a strong decrease in the chlamydial load, and significantly reduced chlamydial recovery, as well as by the reversibility of the reduced recovery after the removal of tanshinone IIA. Interestingly, not only was tanshinone IIA treatment accompanied by a significant decrease of ATP levels, but fluorescence live cell imaging analysis by two-photon microscopy revealed that tanshinone IIA treatment also resulted in a decreased fluorescence lifetime of protein-bound NAD(P)H inside the chlamydial inclusion, indicating that chlamydial reticulate bodies have decreased metabolic activity. In all, these data demonstrate that the AP-1 transcription factor is involved in C. pneumoniae development, with tanshinone IIA treatment resulting in persistence.

Haemophilia prophylaxis: how can we justify the costs?

Severe haemophilia results in increased mortality and poorer quality of life. Factor prophylaxis leads to a more normal life, but is very costly; most of the cost is due to the high cost of replacement factor. Despite its high cost, factor prophylaxis has been adopted throughout the developed world--even in different health care systems. We argue that there are at least five possible reasons why societies may value factor prophylaxis despite its cost: (i) it is directed towards an inherited disease, (ii) the treatment is largely directed towards children, (iii) the disease is rare and the overall cost to society is small, (iv) the treatment is preventative, and v) the high cost is largely the result of providing safe products. In an era of rising health care costs, there is a strong research agenda to establish the factors that determine the value of expensive therapies for rare diseases like haemophilia.

[Recurrence of stress cardiomyopathy after an earthquake: report of one case]. / Recurrencia de miocardiopatía por estrés posterior a terremoto en Chile: Reporte de un caso clínico.

Stress-induced cardiomyopathy is characterized by transient systolic dysfunction of the apical or mid segments of the left ventricle that mimics myocardial infarction in the absence of obstructive coronary artery disease. Symptoms recur after a physical or emotional stress. We report a 77-year-old female that in 2004, suffered an episode of stress cardiomyopathy after an intense physical effort. In February 2010, immediately after the earthquake that occurred in Chile, the patient consulted for chest pain, ST segment elevation and enzyme elevation. An echocardiography showed a left ventricular anteroseptal akinesia with an ejection fraction of 35%. Coronary arteriography did not show significant alterations.

Recurrencia de miocardiopatía por estrés posterior a terremoto en Chile: Reporte de un caso clínico / Recurrence of stress cardiomyopathy after an earthquake: Report of one case

Stress-induced cardiomyopathy is characterized by transient systolic dysfunction ofthe apical or mid segments ofthe left ventricle that mimics myocardial infarction in the absence of obstructive coronary artery disease. Symptoms recur after a phy-sical or emotional stress. We report a 77 years oíd femóle that in 2004, suffered an episode of stress cardiomyopathy after an intense physical effort. In February 2010, immediately after the earthquake that occurred in Chile, the patient consulted for chestpain, STsegment elevation and enzyme elevation. An echocardiography showed a left ventricular anteroseptal akinesia with an ejection fraction of 35 percent. Coronary arteriography did not show significant alterations.

[Gaussian distribution of intelligence in VLBW preterm infants at age 5: very low correlation with very low birth weight]. / Normalverteilung der Intelligenz von VLBW-Frühgeborenen mit 5 Jahren: sehr geringe Korrelation mit sehr geringem Geburtsgewicht.

BACKGROUND: Preterm infants with very low birth weight < 1500 g (VLBW) have a higher risk of developmental disorders. In addition to the common estimation of the mean intelligence values, we studied the distribution of intelligence at preschool age in VLBW infants and the risk factors influencing this distribution. PATIENTS AND METHODS: A prospective cohort study of 277 VLBW infants < 32 weeks born in 1991-1995 and treated according to a standardized regimen in one Perinatal Center was carried out, including measurement of intelligence (Kaufman-Assessment Battery for Children) at age 5. Statistical methods employed were: explorative data analysis, correlation, chi (2)- and t-tests; the tested variables were: small for gestational age (< third percentile), perinatal acidemia (umbilical arterial pH < 7.10), perinatal hypoxia (BE < - 10), hypothermia (< 36 degrees C), hypoglycemia after the first day of life (< 30 mg / dL), bronchopulmonary dysplasia (FiO (2) > 0.21 > or = 36 weeks), intraventricular hemorrhage, ventricular dilation, periventricular leukomalacia, seizures, abnormal acoustic evoked potentials, and hyperexcitability at discharge. RESULTS: The distribution of intelligence in 137 VLBW infants < 32 weeks (60 % follow-up rate) was similar to a symmetrical Gaussian bell curve. The intelligence increased very slightly with birth weight (Pearson correlation: 0.172; p = 0.045) and was significantly lower in children with hypoglycemia after the first day of life (- 13.35; 95 % confidence interval: - 20.08 to - 6.63; p = 0.002), hyperexcitability at discharge (- 16.28; 95 % confidence interval: - 25.26 to - 7.31; p = 0.005), and bronchopulmonary dysplasia (- 7.00; 95 % confidence interval - 11.71 to - 2.29; p = 0.039). CONCLUSIONS: At preschool age, the intelligence of VLBW infants is normally distributed and correlates only slightly with the very low birth weight. Hypoglycemia after the first day of life and bronchopulmonary dysplasia are risk factors for lower intelligence. Hyperexcitability at discharge seemed to represent a promising prognostic factor for a later intelligence reduction.

Recommendations for reporting economic evaluations of haemophilia prophylaxis: a nominal groups consensus statement on behalf of the Economics Expert Working Group of The International Prophylaxis Study Group.

BACKGROUND: The need for clearly reported studies evaluating the cost of prophylaxis and its overall outcomes has been recommended from previous literature. OBJECTIVES: To establish minimal ''core standards'' that can be followed when conducting and reporting economic evaluations of hemophilia prophylaxis. METHODS: Ten members of the IPSG Economic Analysis Working Group participated in a consensus process using the Nominal Groups Technique (NGT). The following topics relating to the economic analysis of prophylaxis studies were addressed; Whose perspective should be taken? Which is the best methodological approach? Is micro- or macro-costing the best costing strategy? What information must be presented about costs and outcomes in order to facilitate local and international interpretation? RESULTS: The group suggests studies on the economic impact of prophylaxis should be viewed from a societal perspective and be reported using a Cost Utility Analysis (CUA) (with consideration of also reporting Cost Benefit Analysis [CBA]). All costs that exceed $500 should be used to measure the costs of prophylaxis (macro strategy) including items such as clotting factor costs, hospitalizations, surgical procedures, productivity loss and number of days lost from school or work. Generic and disease specific quality of lífe and utility measures should be used to report the outcomes of the study. CONCLUSIONS: The IPSG has suggested minimal core standards to be applied to the reporting of economic evaluations of hemophilia prophylaxis. Standardized reporting will facilitate the comparison of studies and will allow for more rational policy decisions and treatment choices.

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors.

Treatment of acute bleeding episodes in patients with haemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing haemostatic agents, such as activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa). We constructed a cost minimization model to compare the costs of initial treatment with aPCC vs. rFVIIa in the home treatment of minor bleeding episodes. We developed a clinical scenario describing such a case and presented it to a panel of US haemophilia specialists. For each product class, we asked panellists to provide dosing regimens required to achieve complete resolution of a minor haemarthrosis in a child with high-titre inhibitors, and for the probabilities of success at two time points (8-12 and 24 h). Consensus among the panellists was refined by a second round of the process, and the median values resulting were used as inputs to a decision analysis model. Sensitivity analyses were conducted to determine threshold values for key variables. The base case model found that initial treatment with aPCC would result in a mean cost per episode of 21 000 dollars, compared with 33 400 dollars for initial treatment with rFVIIa. Sensitivity analyses over a range of clinically plausible values for cost, dosing, and efficacy did not change the selection of aPCC as the dominant strategy.

The economic impact of factor VIII inhibitors in patients with haemophilia.

The impact on the cost of care for haemophilia patients with inhibitors is not well defined. To quantify the effect on health care expenditures associated with inhibitors to factor VIII (FVIII) or FIX, we conducted a retrospective cohort study examining product use and outcomes in adult and paediatric haemophilia patients with and without inhibitors. Twelve patients with inhibitors to FVIII or FIX (cases) identified in the haemophilia surveillance system (HSS) at two centres were matched on age, severity of haemophilia, and treatment centre to haemophilia patients without inhibitors. Patients with HIV or significant liver disease were excluded from the study. All eligible non-inhibitor control patients were selected for inclusion in the study, resulting in a total of 28 controls. We then tracked product usage and hospitalizations from programme entry until 1998 or loss to follow-up, producing a total database of 184 person-years of experience. A descriptive matched analysis was conducted to examine annual differences in the cost of product used and hospitalizations. We found that the median cost for factor products among haemophilia patients with inhibitors was $55,853/year, $2,760 less than comparable haemophilia patients without inhibitors. The median number of hospitalizations per year was 1.0 for both inhibitor and non-inhibitor patients and the median number of days hospitalized was virtually the same. Although these findings do not appear to support the belief that there is a substantial increase in the cost of care for haemophilia patients with inhibitors, it does document that a few outlier patients can drive the cost of treatment for this disease. As the largest component of the cost of care is that of factor concentrate, it becomes imperative in the current health care environment to better define the true costs and benefits of treatments designed to eradicate or manage inhibitors. A careful cost accounting of immune tolerance induction (ITI) and other therapeutic strategies, taking into account successes and failures and duration and intensity of therapy, should help to better define the costs and benefits of such approaches. Methods to identify high cost inhibitor patients should be developed so that these strategies may be targeted to appropriate candidates.

Field-specific visual-evoked potentials: identifying field defects in vigabatrin-treated children.

OBJECTIVE: To derive a visual-evoked potential (VEP) technique for identifying visual field defects in children with epilepsy treated with vigabatrin and unable to perform perimetry. BACKGROUND: Studies have linked vigabatrin to a specific pattern of visual field loss. Few studies have included the pediatric population because of difficulties in assessing the visual field by perimetry below a developmental age of 9 years. METHODS: A field-specific VEP was developed with a central (0 degrees to 5 degrees radius) and peripheral stimulus (30 degrees to 60 degrees radius). Stimuli consisted of black and white checks that increased in size with eccentricity. Checks reversed at different rates, allowing separate central and peripheral responses to be recorded. Five vigabatrin-treated young adults with field defects were identified using this stimulus. Electroretinograms (ERG) were recorded to examine the effects of vigabatrin on retinal function. Thirty-nine children aged 3 to 15 years were included in the study. Twelve patients were examined by both the field-specific stimulus test and perimetry. The diagnostic performance of the field-specific stimulus test was compared with that of perimetry. RESULTS: Thirty-five of 39 children complied with the field-specific stimulus, 26 of 39 complied with the ERG, and 12 of 39 complied with perimetry. Using the summed amplitude of the peripheral response from O(2) and O(1), responses below 10 microV were deemed abnormal. The field-specific stimulus identified 3 of 4 abnormal perimetry results and 7 of 8 normal perimetry results, giving a sensitivity of 75% and a specificity of 87.5%. When comparing perimetry results with the ERG parameters, only the 30-Hz flicker amplitude, with a cutoff below 70 microV, gave a useful indication of visual field loss. CONCLUSION: Field-specific VEP are well tolerated by children older than 2 years of age and are sensitive and specific in identifying vigabatrin-associated peripheral field defects.

Porcine factor VIII: pharmacoeconomics of inhibitor therapy.

The treatment of acquired haemophilia is characteristically exceedingly expensive and thus a cost-benefit analysis of the several available treatment strategies is urgently needed. To address this issue, decision-analysis techniques were used to construct a cost-minimization model to compare the cost of treatment with porcine factor VIII (pFVIII), human FVIII (hFVIII) or an activated prothrombin complex concentrate (APCC). This model was based upon the results of a comprehensive literature search of all relevant clinical studies and case series. To supplement these data, a panel of haemophilia specialists was presented with a clinical scenario describing an acquired haemophilia patient with an acute haemorrhage in whom the human and porcine inhibitor titres were initially unknown. Based on this scenario and on their own clinical experience, the expert panel assessed the applicability of the model as initially constructed, assigned probabilities of success to each treatment and recommended appropriate initial dosing and follow-up regimens. This information was incorporated into the model and a simulation was conducted from which the costs of care were calculated. Sensitivity analyses were then conducted on all parameters. The results of the model show that treatment initiated with pFVIII would be more cost effective compared with treatment sequences initiated with an APCC or hFVIII, respectively. The model indicates that initial treatment with pFVIII in this scenario may be the preferred strategy clinically, as well as on economic grounds.

Predictors of uncontrolled hypertension in ambulatory patients.

Hypertension remains poorly controlled in the United States. Improvement of its management will require an understanding of the patient characteristics and treatment factors associated with uncontrolled hypertension. We studied antihypertensive medication use, comorbidity, and blood pressure measurements for 525 hypertensive patients in 3 different healthcare systems over a 1-year period. We concomitantly conducted comprehensive patient interviews covering demographic factors, knowledge of hypertension and its treatment, and medication side effects. Ordinal logistic regression was used to identify factors associated with poor blood pressure control. Mean age of the patients was 65+/-11 years. Mean systolic blood pressure (SBP) was 143+/-15 mm Hg; and mean diastolic blood pressure (DBP), 80+/-9 mm Hg. Only 39% (203/525) of patients had mean blood pressure <140/90 mm Hg during the study period; about half (257/525) had stage 1 hypertension (mean SBP 140 to 159 mm Hg and/or mean DBP 90 to 99 mm Hg), and 12% (65/525) had stage 2 or greater hypertension (SBP >160 mm Hgand/or DBP >100 mm Hg). Multivariate analysis revealed several independent predictors of poor control: older age, multi-drug regimens, lack of knowledge by the patient of their target SBP, and a report of antihypertensive drug side effects. Patients with angina had a higher likelihood of adequate blood pressure control. Fewer than 40% of the treated patients studied had a mean blood pressure

Molecular structure and conformation of cyclopropylbenzene as determined by ab initio molecular orbital calculations, pulsed-jet fourier transform microwave spectroscopic, and gas-phase electron diffraction investigations.

Ab initio computational, microwave spectroscopic, and electron diffraction techniques have been used to study the gas-phase structure of cyclopropylbenzene. Theoretical calculations at the HF, B3LYP, and MP2 levels for basis sets 6-31G(d) and 6-311G(d) have been carried out. Both MP2 and B3LYP calculations showed the bisected form to be lower in energy (245/157 and 660/985 cal mol(-1), respectively, for basis sets 6-311G(d)/6-31G(d)). Rotational constants for the bisected form of the parent and eight singly substituted (13)C isotopic species were obtained. The selection rules of the observed rotational transitions and the facts that eight (rather than six) singly substituted (13)C isotopers are observed and assigned and that seven of the compound's nine carbon atoms lie in the molecule's symmetry plane required the molecule to exist in the bisected conformation. No transition from the perpendicular form was observed in the pulsed-jet microwave experiment. Gas-phase electron diffraction data were collected at a nozzle-tip temperature of 265 K. Least squares analyses were carried out using ED data alone and with the inclusion of microwave rotational constants. The principal structural results (r(g) and angle(alpha)) obtained from the combined ED/MW least-squares analysis are r(C-H)(av) = 1.093(6) A, r(C(7)-C(8))(v) = 1.514(20) A, r(C(8)-C(9))(d) = 1.507(26) A, r(C(7)-C(1)) = 1.520(25) A, r(C-C)(Ph) = 1.395(1) A, angleC(1)C(7)C(8) = 119.6(17) degrees, angleC(2)C(1)C(7) = 122.5(25) degrees, angleC(1)C(2)C(3) = 120.9(35) degrees, angleHC(8)C(9) = 116.7(20) degrees, angleHCC(Ph) = 120.0 degrees (assumed).

Hazardous benzodiazepine regimens in the elderly: effects of half-life, dosage, and duration on risk of hip fracture.

OBJECTIVE: While benzodiazepine treatment is known to increase the risk of hip fracture in older populations, controversy persists over which characteristics of benzodiazepine use (e.g., elimination half-life, dosage, duration of use) are most associated with such risks. METHOD: The authors reviewed the health care utilization data of 1,222 hip fracture patients and 4,888 comparison patients frequency matched on the basis of age and gender (all were at least 65 years old). Patients were enrolled in Medicare as well as in the New Jersey Medicaid or Pharmaceutical Assistance to the Aged and Disabled programs. Benzodiazepine use, as well as other covariates, were assessed before the index date (which was either the date of hospital admission for hip fracture surgical repair or, for the comparison subjects, a randomly assigned, frequency-matched date). RESULTS: All benzodiazepine doses > or =3 mg/day in diazepam equivalents significantly increased the adjusted risk of hip fracture by 50%. Significantly increased adjusted risks of hip fracture were seen during the initial 2 weeks of use (60% increase) and after more than 1 month of continuous use (80% increase) but not for 2-4 weeks of continuous use. Use of benzodiazepines other than long-acting agents significantly increased the risk of hip fracture by 50%. CONCLUSIONS: Even at modest doses, including some low doses currently advocated in prescribing guidelines for older patients, treatment with benzodiazepines appears to increase the risk of hip fracture. Patients appear to be particularly vulnerable immediately after initiating therapy and after more than 1 month of continuous use. Benzodiazepines with shorter half-lives appear to be no safer than longer half-life agents. Clinicians should be aware of these risks and weigh them against potential benefits when prescribing for elderly patients.

Zolpidem use and hip fractures in older people.

OBJECTIVES: The widespread use of sedative-hypnotics in older populations makes it imperative to identify hazardous regimens that should be avoided and safer regimens that may be used preferentially by older people. Although benzodiazepines have been shown to increase fall and fracture risk, zolpidem, a nonbenzodiazepine hypnotic, has been advocated as a safer alternative. DESIGN: Case-control study of hip fracture cases and controls in 1994. SETTING: All subjects were age 65 and older and enrolled in Medicare, and in Medicaid or the Pharmaceutical Assistance to the Aged and Disabled program of New Jersey. PARTICIPANTS: Cases (n=1,222) were patients who underwent surgical repair of a hip fracture. They were frequency-matched to four controls (n=4,888) based on age and gender. MEASUREMENTS: Use of sedative-hypnotics and other medications was assessed in the 180 days before the index event. We assessed other covariates, including demographic, clinical, and healthcare utilization variables in the prior 180 days. RESULTS: Zolpidem use was associated with a significant increased risk of hip fracture (adjusted odds ratio (AOR) 1.95; 95% confidence interval (CI)=1.09-3.51). Other psychotropic medication classes with significantly increased risks included benzodiazepines (AOR 1.46; 95% CI=1.21-1.76), antipsychotic medications (AOR 1.61; 95% CI=1.29-2.01), and antidepressants (AOR 1.46; 95% CI=1.22-1.75). In subanalyses, preferential use of zolpidem by subjects at greater risk of hip fracture did not appear to explain the apparent risk of hip fracture with zolpidem use. CONCLUSION: Use of zolpidem by older people was associated with nearly twice the risk of hip fracture, even after controlling for possible demographic and clinical confounders. Rather than being a safer alternative, zolpidem may be associated with risks that are as great as those seen with conventional benzodiazepines in older patients.

Adherence to guidelines for oral anticoagulation after venous thrombosis and pulmonary embolism.

OBJECTIVE: Guidelines for oral anticoagulation after deep venous thrombosis (DVT) or pulmonary embolism (PE) have recommended that patients be anticoagulated for at least 3 months after hospital discharge. We sought to determine whether this recommendation was being followed and what patient characteristics predict a shorter than recommended duration of therapy. DESIGN: Retrospective cohort study using linked health care claims data. SETTING: Routine clinical practice. PATIENTS: Five hundred seventy-three members of New Jersey's Medicaid or Pharmacy Assistance for the Aged and Disabled programs aged 65 years and older who were hospitalized for DVT or PE between January 1, 1991 and June 30, 1994. RESULTS: Of the 573 patients, 129 (23%) filled prescriptions covering less than 90 days of oral anticoagulant therapy. In multivariate models, African-American race was associated with an increased risk of a shorter than recommended duration of therapy (odds ratio [OR], 1.87; 95% confidence interval [CI], 1.14 to 3.08), but age and gender were not. Patients who used anticoagulants in the year prior to admission were less likely to have a short duration of therapy (OR, 0.30; 95% CI, 0.12 to 0.78), than were patients with PE (OR, 0.58; 95% CI, 0.38 to 0.88). CONCLUSIONS: Nearly a quarter of those anticoagulated following DVT or PE received therapy for less than the recommended length of time after hospital discharge, with African Americans more likely to have a shorter than recommended course of treatment. Further research is needed to evaluate the causes of shorter than recommended duration of therapy and racial disparities in anticoagulant use.