Testing the harvesting hypothesis by time-domain regression analysis. I: baseline analysis

Although the association between air pollution and daily mortality is well established, the mechanisms by which air pollution results in excess mortality are not yet well understood. In particular, there exists debate over whether air pollution has a direct effect on mortality in the general population or simply shortens the life span of frail individuals, a hypothesis referred to as "harvesting." The goal of this investigation is to test the harvesting hypothesis using the time-domain regression method of Dominici et al. (2003a). We conducted simulations based on a two-compartment model that divides the population into a larger group of healthy individuals and a frail subpopulation. Death from air pollution is assumed to take place in two steps, by first moving from healthy population to the frail pool, then death with probability related to the level of air pollution. Using time-domain analysis, we seek to identify data patterns that would be characteristic of harvesting under different scenarios. For a pure harvesting model, time-domain analysis indicates that mortality is associated with a short-term air pollution episode of less than 2 d if the mean residency time in the frail pool is short. If both entrants and deaths depend on the level of air pollution and the rates of entry to and exit from the frail pool are about the same, the log relative risk estimates are essentially unchanged at all time scales. If pollution affects mortality in the frail pool more than entrants, larger effects will occur at shorter time scales.     

Diclofenac salts. III. Alkaline and earth alkaline salts

Diclofenac salts containing the alkaline and two earth alkaline cations have been prepared and characterized by scanning electron microscopy (SEM) and EDAX spectroscopy; and by thermal and thermogravimetric analysis (TGA): all of them crystallize as hydrate when precipitated from water. The salts dehydrate at room temperature and more easily on heating, but recovery the hydration, when placed in a humid environment. X-ray diffraction spectra suggest that on dehydration new peaks appear on diffractograms and the lattice of the salts partially looses crystallinity. This phenomenon is readily visible in the case of the calcium and magnesium salts, whose thermograms display a crystallization exotherm, before melting or decomposing at temperatures near or above 200 degrees C; these last salts appear to form solvates, when prepared from methanol. The thermogram of each salt shows a complex endotherm of dehydration about 100 degrees C; the calcium salt displays two endotherms, well separated at about 120 and 160 degrees C, which disappear after prolonged heating. Decomposition exotherms, before or soon after the melting, appear below 300 degrees C. The ammonium salt is thermally unstable and, when heated to start dehydration, dissociates and leaves acidic diclofenac.     

DNA fragmentation and DNA repair synthesis induced in rat and human thyroid cells by four rat thyroid carcinogens

Four chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measures by the Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the four test compounds: 2,4-diaminoanisole (DAA) from 0.10 to 1.0 mM, 4,4'-methylene-bis(N,N-dimethyl)benzenamine (MDB) from 0.32 to 1.8 mM, propylthiouracil (PTU) from 1.8 to 5.6 mM, and 4,4'-thiodianiline (THA) from 0.032 to 0.18 mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in thyreocytes exposed to DAA but absent after treatment with MDB, PTU, and THA. Consistent with their thyroid-specific carcinogenic activity, all the four chemicals, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid, whereas any substantial evidence of DNA lesions was absent in liver, kidney, and lung, which, with the exception of liver tumors caused by THA, are not targets of the carcinogenic activity of the four test compounds. These findings indicate that the DNA damage observed in thyroid cells was consistent with the carcinogenicity of the four test compounds, and suggest that DAA, MDB, PTU, and THA might be carcinogenic to thyroid in humans.     

Analysis of morphologic patterns of fine-needle aspiration of the breast to reduce false-negative results in breast cytology

BACKGROUND: The identification of specific morphologic diagnostic criteria is of paramount importance to optimize the accuracy of fine-needle aspiration cytology (FNAC) and to reduce the rate of false-negative results. In the current study, the authors reviewed a consecutive series of false-negative findings observed in the study center to define the presence and degree of cytologic abnormalities. False-negative cases were randomly mixed with true-negative cases and were reviewed by a panel of expert readers in a blinded fashion. The main objective of the current study was to identify a morphologic pattern that may permit the reduction of false-negative findings while maintaining the specificity of FNAC. METHODS: A blind review of a set of 41 consecutive false-negative and 49 true-negative breast aspiration samples was performed by a panel of 10 expert cytologists who were asked to give a final report and to classify the samples according to classic morphologic parameters. RESULTS: The majority final report sensitivity was 54% (range, 19-61%) and specificity was 73% (range, 65-92%). The average concordance with the majority report, adjusted for chance agreement (kappa statistic), was moderate at 0.54 (range, 0.40-0.65). Enlarged nuclear size, a hyperchromatic nucleus, the absence of naked nuclei, and the absence of apocrine metaplasia were reported more frequently in carcinoma cases, although not to a significant extent. The only variable found to be associated significantly (P = 0.041) with a diagnosis of carcinoma was the presence of microcalcifications, which nevertheless were found to occur in only a minority of carcinoma cases (7 of 41 cases) or controls (2 of 49 controls). Multivariate analysis demonstrated that the presence of microcalcifications (odds ration [OR] of 3.0; 95% confidence interval [95% CI], 1.2-7.4), the absence of naked nuclei (OR of 2.4; 95% CI, 1.3-4.4), and enlargement of the nucleus (OR of 1.9; 95% CI, 1.1-3.4) were all independently associated with false-negative findings. Diagnostic accuracy using a morphology-based score did not appear to improve the results substantially compared with the final report (sensitivity of 0.46 vs. 0.54 [P = 0.508] and a specificity of 0.80 vs. 0.73 [P = 0.218]). CONCLUSIONS: The results of the current study confirm that breast FNAC false-negative results are at least partially the result of underreporting of abnormalities that may be noted at review. Detailed analysis of a single morphologic characteristic was found to be of limited diagnostic value, suggesting that operators do perceive abnormalities but cannot translate these findings into distinct morphologic categories.     

Tricuspid valve repair in an infant with multiple obstructive Candida mycetomas

Neonatal fungal valve endocarditis is an uncommon and highly lethal disease. The ideal management strategy is still controversial. Current options include antifungal chemotherapy and surgical intervention, the latter being often limited by risks inherent with valve operations in low body weight infants. We present a case of a premature infant with multiple Candida tricuspid valve mycetomas. Eradication of infection was achieved by combined liposomal amphotericin therapy and complex tricuspid valve repair. Indications, technical aspects, and outcome of treatment in infants are reviewed.     

Increased levels of circulating endothelial cells in chronic periaortitis as a marker of active disease

BACKGROUND: The pathogenesis of chronic periaortitis (CP) has not been clarified. The histologic features and the association with autoimmune diseases suggest an immune-mediated disorder with marked inflammatory vascular and perivascular lesions. To clarify the role of vascular damage we looked for the presence and the surface phenotype of circulating endothelial cells (CECs) in the peripheral blood of patients with chronic periaortitis. METHODS: Eleven patients with CP were evaluated for the presence of CECs; 9 patients had active and 2 inactive disease. Three patients with active disease were also evaluated 3 months after therapy. Ten atherosclerotic patients, 10 patients with renal insufficiency of variable degree and etiology, and 40 healthy subjects were evaluated as controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31, P1H12, and CD36 positive, and activated CECs as CD45 negative and P1H12, CD62 positive. RESULTS: The median number of CECs in patients with CP (10(6) cells/mL) was significantly higher than in healthy controls (16 cells/mL, P= 0.0004) and atherosclerotic patients (25 cells/mL, P= 0.0005) Two patients with inactive disease had a CEC count comparable to that of normal subjects. In 2 of the 3 patients reevaluated, 3 months after therapy CEC numbers normalized. Almost all CECs were microvascular in origin and showed an activated phenotype. CONCLUSION: The presence of a high number of CECs in the active phase of chronic periaortitis and their normalization during inactive disease suggest that endothelial damage may play a role in the pathogenesis of the disease.     

Effects of surgical repair of congenital diaphragmatic hernia on cerebral hemodynamics evaluated by near-infrared spectroscopy

Background

Cardiorespiratory stabilization is recommended before surgical repair of congenital diaphragmatic hernia (CDH) because surgery may induce a transitory deterioration of chest compliance and gas exchange. It is not known if surgical intervention can affect cerebral circulation and oxygenation.

Aim

The aim of the study was to assess noninvasively, by near-infrared spectroscopy, the possible changes in cerebral hemodynamics and oxygenation associated with surgical repair of CDH.

Subjects

Twenty-five newborns with severe CDH (birth weight, 3057 ± 354 g; gestational age, 37.8 ± 1.8 weeks; male/female newborns, 15/10; left/right CDH, 19/6) were sedated, paralyzed, and mechanically ventilated by conventional gentle ventilation and surgically corrected at a median age of 2.7 days (min-max, 2-14 days) after cardiorespiratory stabilization.

Methods

Heart rate (HR [beats per minute]), preductal transcutaneous oxygen saturation (tcSao₂ [%]), carbon dioxide tension (tcPco₂ [Torr]), and mean arterial blood pressure (mm Hg) were continuously monitored. Inspired fractional oxygen concentration (Fio₂) was adjusted to maintain and preductal tcSao₂ of greater than 80%, whereas the ventilator's settings were kept unchanged throughout the surgical procedure. Cerebral hemodynamics was assessed by near-infrared spectroscopy (NIRO 300, Hamamatsu Photonics, Japan), recording continuously and noninvasively the relative changes in concentration of oxygenated (ΔO₂Hb [μmol/L]), deoxygenated (ΔHHb [μmol/L]), and total (ΔtHb [μmol/L]) hemoglobin; the tissue oxygenation index (TOI [%]) was also calculated (TOI = O₂Hb/O₂Hb + HHb). Total hemoglobin concentration is considered to be representative of cerebral blood volume. Arterial blood gases were also measured at the beginning (T₁) and at the end of surgery (T₂). For all measurements, results at T₁ and at T₂, as well as the differences between T₁ and T₂, have been expressed as means or medians and SDs or 95% confidence intervals or ranges. The differences between T₁ and T₂ were considered statistically significant for a P value of less than .05 by the Student t test for paired values.

Results

At T₁, mean tcSao₂% was 94.1 % (SD, 4.6) with a Fio₂ of 0.25 (SD, 0.1); at T₂, to obtain similar values of tcSao₂ (93.4%; SD, 4.4), it was necessary to increase the Fio₂ to 0.37 (SD, 0.14; P < .001). Mean HR at T₁ was 149.5 beats per minute (SD, 9.1) and increased significantly (P < .05) at T₂ (165.2 beats per minute; SD, 14.2). Mean arterial blood pressure was 54.7 mm Hg (SD, 7.7) at T₁ and did not change appreciably at T₂ (55.6 mm Hg; SD, 8.1). Moreover, tcPco₂ did not change significantly during the procedure (mean tcPco₂ = 49.9 Torr [SD, 12.8] at T₁ and 57.3 mm Hg [SD, 17.9] at T₂). O₂Hb and tHb decreased (P < .001 and <.005) and HHb increased (P < .05) significantly during the surgical procedure (mean Δ [SD]: ΔO₂Hb= −10.9 μmol/L [9.7], ΔtHb = −7.5 μmol/L [11.7], and ΔHHb = −3.5 μmol/L [6.8]). Mean TOI was 70% at T₁ (normal values >60%) and decreased significantly at T₂ (mean ΔTOI = −6.1% [SD, 10.6]). In all infants, the greatest changes occurred when the viscera were positioned into the abdomen.

Conclusions

Notwithstanding the initial cardiorespiratory stabilization, surgical repair of CDH was associated with a rise in HR and oxygen requirement and a drop in cerebral tHb and O₂Hb, suggesting a reduction in cerebral blood volume and oxygenation. These events were probably due to the combined effects of an increase in right to left shunting (as indicated by the increased oxygen requirement) and a decrease in venous return (possibly due to compression of the inferior vena cava by the viscera positioned into the abdomen). These preliminary results reinforce the importance of achieving a good cardiorespiratory stability before undertaking surgical correction of CDH to minimize the possible interference of the procedure with cerebral circulation and oxygenation.     

V(H)3 and V(H)6 immunoglobulin M repertoire reconstitution after hematopoietic stem-cell transplantation in children

BACKGROUND: Immune reconstitution after hematopoietic stem-cell transplantation (HSCT) occurs gradually. Thus, a variable period of immunodeficiency may be present, leading to immunomediated complications, such as graft-versus-host disease (GVHD) and opportunistic infections. METHODS: To better understand the kinetics of B-cell repertoire reconstitution in children, 49 pediatric patients were analyzed before and after transplantation by immunoglobulin (Ig) HCDR3 fingerprinting, which is a molecular technique that analyzes one of the hypervariable segments of the Ig heavy chain, which provides the amino acid residues that are essential to interact with antigens. RESULTS: In healthy donors, the CDR3 fingerprinting profile shows 16 to 20 bands, and each band corresponds to a particular length of CDR3. This situation is considered polyclonal. Patients analyzed just after transplantation show strong oligoclonality, because only a few CDR3 bands are detected within the first 3 to 6 months. CONCLUSIONS: The authors' data show a significant lag in diversification of the B-cell repertoire, which reaches the polyclonal situation of normal healthy donors approximately 6 months after HSCT. This period may vary depending on the type of transplant (autologous vs. allogeneic) and on the immunosuppressive therapy related to GVHD.     

Predictors of cardiovascular death in ESRD

End stage renal disease (ESRD) is a situation with a cardiovascular risk profile of almost unique severity. While traditional risk factors dominate the scene in the general population, non traditional risk factors like inflammation (high C Reactive Protein, CRP), high brain natriuretic peptide, as an expression of left ventricular hypertrophy and left ventricular dysfunction, and accumulation of the endogenous inhibitor of the NO synthase, asymmetric dimethyl arginine are all markers of high CV risk of ESRD patients. To obtain a quantitative insight on the predictive power of traditional and emerging risk factors in ESRD, we performed a detailed multivariate survival analysis in the cardiovascular risk extended evaluation (CREED) cohort database. As expected, traditional risk factors (ie, age, sex, smoking, diabetes, and risk factors peculiar to the uremic state such as low serum albumin level) and treatment modality contributed to explain the all-cause mortality (37%) and cardiovascular variation mortality (24%) variation as well. When cardiovascular comorbidities were considered in this analysis, the explained variation in mortality increased to 45.4% and 36.4%, respectively. Furthermore, a combined score based on 2 biomarkers (brain natriuretic peptide and C-reactive protein levels) increased the explanatory power of these models by about 10%. In conclusion, traditional risk factors explain about half of all-cause and cardiovascular mortality variation in the ESRD population. The combined use of 2 biomarkers reflecting inflammation and left ventricular mass and function increases by about one fifth the explained mortality variation in this population. Biomarkers give information beyond that provided by traditional risk factors and therefore represent an useful adjunct for the definition of the risk profile of ESRD patients.     

Radiation-induced intracranial meningiomas: review of six operated cases

It is well known that radiation can induce meningiomas. These tumors usually arise in patients with a history of low-dose radiation to the scalp for treatment of tinea capitis or high-dose radiation for a previous brain tumor. Radiation-associated meningiomas (RAMs) morphologically resemble their spontaneously arising counterparts. However, RAMs frequently present a more malignant phenotype and, as such, are diagnosed as atypical or aggressive meningiomas and occur predominantly in younger patients. This paper describes six cases of radiation-associated intracranial meningiomas in patients previously treated with low-dose radiation to the scalp for tinea capitis.