Revisiting detrended fluctuation analysis.

Half a century ago Hurst introduced Rescaled Range (R/S) Analysis to study fluctuations in time series. Thousands of works have investigated or applied the original methodology and similar techniques, with Detrended Fluctuation Analysis becoming preferred due to its purported ability to mitigate nonstationaries. We show Detrended Fluctuation Analysis introduces artifacts for nonlinear trends, in contrast to common expectation, and demonstrate that the empirically observed curvature induced is a serious finite-size effect which will always be present. Explicit detrending followed by measurement of the diffusional spread of a signals' associated random walk is preferable, a surprising conclusion given that Detrended Fluctuation Analysis was crafted specifically to replace this approach. The implications are simple yet sweeping: there is no compelling reason to apply Detrended Fluctuation Analysis as it 1) introduces uncontrolled bias; 2) is computationally more expensive than the unbiased estimator; and 3) cannot provide generic or useful protection against nonstationaries.

A randomized, double-blind, placebo-controlled trial of valacyclovir prophylaxis to prevent zoster recurrence from months 4 to 24 after BMT.

Reactivation of latent VZV remains a significant cause of morbidity after SCT. Twenty-five percent or more of patients undergoing SCT will experience zoster within the first year after transplant. Short-course (<1 year) prophylaxis with acyclovir has been shown to be effective, but compliance with five times daily dosing may be problematic. We conducted a randomized, double-blind, placebo-controlled trial of valacyclovir (VACV) 1000 mg twice daily from 4 through 24 months after SCT for the prevention of VZV. Fifty-three VZV-seropositive transplant recipients (17 auto-SCT, 36 allo-SCT) were randomized at a median of 163 days after SCT. In a modified intent-to-treat analysis of 49 patients who took study drug, 0 of 22 in the VACV arm experienced zoster reactivation, compared with 6 of 26 (23%) in the placebo arm (P=0.025). Thirty-two subjects completed therapy through the second year post transplant or first episode of zoster. Adverse events resulting in discontinuation were more frequent in the placebo group (5 of 26 vs 3 of 27 for placebo and study drug, respectively). VACV at a dose of 1000 mg twice daily through 24 months after transplant is well tolerated and effective in suppressing shingles after SCT.

Prospective study of extracorporeal photopheresis in steroid-refractory or steroid-resistant extensive chronic graft-versus-host disease: analysis of response and survival incorporating prognostic factors.

We enrolled 25 patients with extensive, steroid-refractory chronic graft-versus-host disease (cGVHD) in a prospective trial evaluating the efficacy of extracorporeal photophoresis (ECP) in both skin and visceral cGVHD. The median time from transplant to initiation of ECP was 790 days. ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once a week in eight patients until best response or stable disease. The median duration of therapy was 9 months (range 3-24 months). In all, 20 patients had improvement in cutaneous GVHD and six had healing of oral ulcerations. Steroid sparing or discontinuation of immunosuppressive medications was possible in 80% of patients. Response rates were similar between patients receiving treatment weekly vs every 2 weeks and in patients commencing ECP less than vs greater than 18 months from transplant (70 vs 66%). When patients were stratified based on the Akpek prognostic score, there was no difference in overall response between the favorable (Akpek score<2.5) and unfavorable risk groups, but patients with progressive onset cGVHD tended to have a higher response than those with de novo onset. In summary, we report improvement in skin and/or visceral cGVHD in 71% overall and 61% of high-risk patients.

A novel reduced intensity regimen for allogeneic hematopoietic stem cell transplantation associated with a reduced incidence of graft-versus-host disease.

SUMMARY: In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age of 50 years and 31% had undergone a prior HSCT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Full donor chimerism was documented in 98% by day +100. The 1000-day nonrelapse mortality was 11%. The median follow-up is 502 days (154-1104 days). The 1- and 2-year overall survival (OS) and event-free survival (EFS) are 67, 58 and 55%, and 47%, respectively. Patients who had not received a prior HSCT or had less than three prior chemotherapy regimens had a 71% OS and 67% EFS at 1 year. Greater than grade II aGVHD developed in 9% and chronic GVHD (cGVHD) in 43%, and extensive in 12% and limited in 31%. Of the patients, 86% who engrafted had a disease response, 72% had complete and 14% partial responses. This novel reduced intensity preparative regimen was well tolerated and associated with a low incidence of transplant-related mortality and serious acute and cGVHD.

Effects of rapacuronium on respiratory function during general anesthesia: a comparison with cis-atracurium.

BACKGROUND: With its introduction for widespread clinical use, there has been an increase in reports of bronchospasm related to the administration of rapacuronium. As it is commonly used for rapid sequence intubation, it has been suggested that these effects may be related to an inadequate depth of anesthesia. The current study examines the airway effects of rapacuronium in tracheally intubated, anesthetized adults. METHODS: Endotracheal intubation was accomplished without the use of neuromuscular blocking agents. Dynamic compliance, tidal volume, peak inspiratory flow rate, peak expiratory flow rate, and peak inflating pressure were measured after administration of either rapacuronium (1.5 mg/kg) or cis-atracurium (0.2 mg/kg) to 20 adult patients (10 received rapacuronium and 10 received cis-atracurium) anesthetized with propofol-remifentanil. RESULTS: Statistically significant increases in peak inflating pressure (22 +/- 6 to 28 +/- 9 cm H2O, P = 0.0012) and decreases in dynamic compliance (108 +/- 43 to 77 +/- 41 ml/cm H2O, P = 0.0001), peak inspiratory flow rate (0.43 +/- 0.11 to 0.39 +/- 0.09 l/s, P = 0.0062), peak expiratory flow rate (0.67 +/- 0.10 to 0.59 +/- 0.09 l/s, P = 0.0015), and tidal volume (744 +/- 152 to 647 +/- 135 ml, P = 0.0293) occurred after administration of rapacuronium. No changes were seen after administration of cis-atracurium. CONCLUSION: These data demonstrate that rapacuronium, but not cis-atracurium, has significant airway effects in intubated, mechanically ventilated adults.

Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation.

Peripheral blood cell (PBC) rescue has become the mainstay for autologous transplantation in patients with lymphoma, multiple myeloma, and solid tumors. Different methods of hematopoietic progenitor cell (HPC) mobilization are in use without an established standard. Forty-seven patients with relapsed or refractory lymphoma received salvage chemotherapy and were randomized to have HPC mobilization using filgrastim [granulocyte-colony-stimulating factor (G-CSF)] alone for 4 days at 10 microg/kg per day (arm A) or cyclophosphamide (5 g/m(2)) and G-CSF at 10 microg/kg per day until hematologic recovery (arm B). Engraftment and ease of PBC collection were primary outcomes. All patients underwent the same high-dose chemotherapy followed by reinfusion of PBCs. There were no differences in median time to neutrophil engraftment (11 days in both arms; P =.5) or platelet engraftment (14 days in arm A, 13 days in arm B; P =.35). Combined chemotherapy and G-CSF resulted in higher CD34(+) cell collection than G-CSF alone (median, 7.2 vs 2.5 x 10(6) cells/kg; P =.004), but this did not impact engraftment. No differences were found in other PBC harvest outcomes or resource utilization measures. A high degree of tumor contamination, as studied by consensus CDR3 polymerase chain reaction of the mobilized PBCs, was present in both arms (92% in arm A vs 90% in arm B; P = 1). No differences were found in overall survival or progression-free survival at a median follow-up of 21 months. This randomized trial provides clinical evidence that the use of G-CSF alone is adequate for HPC mobilization, even in heavily pretreated patients with relapsed lymphoma.

Immunomodulatory effects of extracorporeal photochemotherapy in patients with extensive chronic graft-versus-host disease.

Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed. Seven patients had a response and 3 had no change in clinical manifestations of cGVHD. One patient died from catheter-related sepsis. Immunologic effects observed after ECP included normalization of inverted ratios of CD4 to CD8 cells, an increase in the number of CD3-CD56+ natural killer (NK) cells, and a decrease in CD80+ and CD123+ circulating dendritic cells. The results suggest that ECP modulates both NK cells and APC populations in patients with cGVHD.

TATA-Binding protein-TATA interaction is a key determinant of differential transcription of silkworm constitutive and silk gland-specific tRNA(Ala) genes.

We have investigated the contribution of specific TATA-binding protein (TBP)-TATA interactions to the promoter activity of a constitutively expressed silkworm tRNA(C)(Ala) gene and have also asked whether the lack of similar interactions accounts for the low promoter activity of a silk gland-specific tRNA(SG)(Ala) gene. We compared TBP binding, TFIIIB-promoter complex stability (measured by heparin resistance), and in vitro transcriptional activity in a series of mutant tRNA(C)(Ala) promoters and found that specific TBP-TATA contacts are important for TFIIIB-promoter interaction and for transcriptional activity. Although the wild-type tRNA(C)(Ala) promoter contains two functional TBP binding sequences that overlap, the tRNA(SG)(Ala) promoter lacks any TBP binding site in the corresponding region. This feature appears to account for the inefficiency of the tRNA(SG)(Ala) promoter since provision of either of the wild-type TATA sequences derived from the tRNA(C)(Ala) promoter confers robust transcriptional activity. Transcriptional impairment of the wild-type tRNA(SG)(Ala) gene is not due to reduced incorporation of TBP into transcription complexes since both the tRNA(C)(Ala) and tRNA(SG)(Ala) promoters form transcription complexes that contain the same amount of TBP. Thus, the deleterious consequences of the lack of appropriate TBP-TATA contacts in the tRNA(SG)(Ala) promoter must come from failure to incorporate some other essential transcription factor(s) or to stabilize the complete complex in an active conformation.

Noninvasive ventilation in respiratory failure due to cystic fibrosis.

BACKGROUND: Noninvasive positive-pressure ventilation (NIPPV) is increasingly used as an effective means of avoiding endotracheal intubation and mechanical ventilation in patients with respiratory insufficiency or failure. METHODS: We retrospectively reviewed our experience with NIPPV to treat respiratory failure in five patients with cystic fibrosis (CF). RESULTS: Despite chronic lung disease related to CF, none of our cases were end-stage. All patients had recent pulmonary function tests showing a forced expiratory volume in 1 second (FEV1) of more than 30% predicted for age. All patients had progressive atelectasis, hypoxemia, and impending respiratory failure related to an acute pulmonary exacerbation or upper abdominal surgical procedure (open gastrostomy tube placement). Respiratory rates decreased, oxygen saturation increased, fraction of inspired oxygen (FiO2) requirement decreased, transcutaneous CO2 decreased, and atelectasis resolved with NIPPV. CONCLUSIONS: Use of NIPPV provides effective respiratory support while avoiding the need for endotracheal intubation. The applications of NIPPV, reports of its use in patients with CF, and the equipment required are reviewed.

A TATA element is required for tRNA promoter activity and confers TATA-binding protein responsiveness in Drosophila Schneider-2 cells.

In contrast to yeast and mammalian systems, which depend principally on internal promoter elements for tRNA gene transcription, insect systems require additional upstream sequences. To understand the function of the upstream sequences, we have asked whether the Bombyx mori tRNACAla and tRNASGAla genes, which are absolutely dependent on these sequences in vitro, also require them for transcription in vivo. We introduced wild-type and mutant versions of the Bombyx tRNAAla genes into Drosophila Schneider-2 cells and found that the tRNACAla gene is efficiently transcribed and that its transcription depends strongly on the distal segment of its upstream promoter. In contrast, the tRNASGAla gene is inefficiently transcribed, and this inefficiency results from lack of a specific sequence within the distal tRNACAla upstream promoter. This sequence, 5'-TTTATAT-3', is sufficient to increase the activity of the tRNASGAla promoter to that of the tRNACAla promoter. Moreover, promoters containing the 5'-TTTATAT-3' element are stimulated by increased levels of cellular TATA-binding protein. Together these results indicate that, in insect cells, a TATA-like element is specifically required to form functional TATA-binding protein-containing complexes that promote efficient transcription of tRNA genes.

Extramedullary tumors of myeloid blasts in adults as a pattern of relapse following allogeneic bone marrow transplantation.

BACKGROUND: Extramedullary tumors of lymphoid and myeloid blasts outside the well-defined sanctuaries following allogeneic bone marrow transplantation (allo-BMT) are rare. Little is known about the biology, treatment, and outcome of these tumors in this setting. METHODS: In this retrospective analysis, 134 consecutive patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) who underwent allo-BMT at a single institution between 1990 and 1998 were reviewed. Five cases of isolated extramedullary myeloid sarcoma that occurred as patterns of recurrence following allo-BMT between 1990 and 1998 are reported. These patients were treated with radiotherapy, systemic chemotherapy, or a second allo-BMT. Clinical outcome is compared with posttransplantation bone marrow relapses observed during the same period at the same institution. The literature on the clinical characteristics, currently available treatment, and outcome of posttransplantation myeloid sarcoma patients was reviewed. RESULTS: Excluding isolated skin and central nervous system recurrences, the frequency of extramedullary myeloid sarcoma encountered as a relapse pattern following allo-BMT was determined to be 3.7% among patients with acute or chronic leukemia of myeloid origin. The survival of patients who were managed with radiotherapy and systemic chemotherapy was less than 4 months. A patient who underwent a second allo-BMT following local radiotherapy is alive and in complete remission more than 33 months after the diagnosis of myeloid sarcoma. The median survival of 17 patients with posttransplantation bone marrow relapse following allo-BMT was 2.2 months. When posttransplantation medullary recurrences are analyzed, patients with CML had a median survival of 12 months, with a significantly better 5-year survival rate than patients with AML (0 vs. 60%, P = 0.015; median survival, 12 months). CONCLUSIONS: The clinical outcomes of patients with recurrent isolated extramedullary myeloid sarcoma following allo-BMT are poor, as in any leukemic relapse, with the exception of patients with CML in this setting.

Cloning and characterization of the TATA-binding protein of the silkworm Bombyx mori.

The TATA-binding protein is a general transcription factor required by all three eukaryotic nuclear RNA polymerases. In order to study the function of this protein in the transcription of tRNA genes in the silkworm Bombyx mori, we have cloned TBP cDNA from a silkworm cDNA library. As in most other eukaryotes, TBP in silkworms is encoded by a single copy gene and contains a highly conserved C-terminal domain that includes a basic region and two direct repeats. In the less conserved N-terminal domain, silkworm TBP exhibits characteristics such as a glutamine-rich stretch and three imperfect Pro-Met-Thr-like repeats that are also found in Drosophila and human TBP. Silkworm TBP expressed in Escherichia coli and purified to apparent homogeneity binds the TATA element of the wild-type adenovirus major late promoter with nanomolar affinity.

Risk factors, prevention methods, and wound care for patients with pressure ulcers.

The purposes of this study about patients with pressure ulcers were to: (a) examine demographic characteristics, laboratory values, Braden Scale scores, and presence of pressure ulcer prevention methods and (b) examine pressure ulcers in terms of classification, stage, wound care, and documentation. The investigation was a prospective, descriptive study; the methods used were patient observations and data recordings from the medical record. Of the patients followed (n = 694), 71 had pressure ulcers. Patients with pressure ulcers were significantly older, with longer lengths of stay, more comorbid conditions, lower blood hemoglobin, lower serum albumin, higher white blood cell counts, and lower Braden Scale scores than patients without pressure ulcers. The presence of pressure ulcer prevention methods was greatly lacking. Nosocomial pressure ulcers tended to be a lower stage compared with pressure ulcers present on admission. Dressings used for wound care were generally gauze or a hydrocolloid. Nurses' charting about pressure ulcers was complete for only 35% of notations. The results of this study indicate that advanced practice nurses have a critical role in caring for patients with pressure ulcers and educating care providers.

A one year study of the macular pigment: the effect of 140 days of a lutein supplement.

A low density of macular pigment may represent a risk factor for age-related macular degeneration (AMD) by permitting greater blue light damage. This study was carried out to determine the effects on macular pigment optical density of dietary supplementation with lutein, one of the pigment constituents. Two subjects consumed lutein esters, equivalent to 30 mg of free lutein per day, for a period of 140 days. Macular pigment optical density was determined by heterochromatic flicker photometry before, during, and after the supplementation period. Serum lutein concentration was also obtained through the analysis of blood samples by high-performance liquid chromatography. Twenty to 40 days after the subjects commenced taking the lutein supplement, their macular pigment optical density began to increase uniformly at an average rate of 1.13+/-0.12 milliabsorbance units/day. During this same period, the serum concentration of lutein increased roughly tenfold, approaching a steady state plateau. The optical density curve eventually levelled off 40 to 50 days after the subjects discontinued the supplement. During the same 40 to 50 days, the serum concentration returned to baseline. Thereafter, little or no decrease in optical density was observed. The mean increases in the macular pigment optical density were 39% and 21% in the eyes of the two subjects respectively. In conclusion, the modest period of supplementation has been estimated to have produced in the subjects a 30 to 40% reduction in blue light reaching the photoreceptors, Bruch's membrane, and the retinal pigment epithelium, the vulnerable tissues affected by AMD.

Presence of pressure ulcer prevention methods used among patients considered at risk versus those considered not at risk.

PURPOSE: This study examined pressure ulcer-prevention strategies available for patients considered at risk versus those considered not at risk. DESIGN: The study used a prospective, longitudinal design. SETTING AND SUBJECTS: Six hundred ninety-four patients from units of five acute care hospitals, a rehabilitation facility, and two nurses' home care caseloads participated in the investigation. INSTRUMENTS: Data-collection instruments included the Braden Scale for risk assessment, demographic information, and the Pressure Ulcer-Prevention Strategies tool, which assessed for the presence of 16 pressure ulcer-prevention strategies. METHODS: All patients admitted to a participating unit during a 2-month period were followed up until discharge. Depending on the site, patients were assessed for the presence of pressure ulcer-prevention strategies one to three times per week. RESULTS: Patients in the at-risk group versus those in the not-at-risk group were more likely (p < 0.01) to have the head of the bed in a low position, a pressure-reducing bed surface, pressure ulcer prevention charted, a positioning wedge, incontinence cleanser and ointment, heel protection, a prevention care plan, a trapeze, and a posted turning schedule. The at-risk group had significantly (p < 0.01) more prevention strategies present than did the not-at-risk group. However, the percentage of patients placed on a pressure ulcer-prevention program was low for both groups. CONCLUSIONS: Pressure ulcer prevention was evident for the at-risk group, but at a low rate. Institutions must continue to explore this critical area affecting patient outcomes.

Occurrence of skin lesions/conditions in ill persons.

The purpose of this study was to examine the occurrence of common skin lesions that potentially may be misdiagnosed as a pressure ulcer, and to examine the characteristics of ill persons who have these skin changes. This was a prospective, descriptive study which included five acute care hospitals, a rehabilitation hospital, and a home care agency. Results indicated that patients with skin lesions/conditions were significantly older and had longer lengths of stay, more diseases, lower Braden Scale scores, and lower serum albumin levels. Nurses must gain knowledge about identifying and treating skin conditions. Assessment of the patient's skin should occur throughout their length of stay.

Silkworm TFIIIB binds both constitutive and silk gland-specific tRNA Ala promoters but protects only the constitutive promoter from DNase I cleavage.

We have identified a complex between TFIIIB and the upstream promoter of silkworm tRNA Ala genes that is detectable by gel retardation and DNase I footprinting. Formation of this complex depends on the integrity of previously identified upstream promoter elements and on the presence of other silkworm transcription factors, either TFIIID or a fraction that contains both TFIIIC and TFIIID. We have used this complex to compare the interactions of TFIIIB with two kinds of tRNA Ala genes whose different in vitro transcription properties are conferred by the upstream segments of their promoters. These are the tRNA C Ala genes, which are transcribed constitutively, and the tRNA SG Ala genes, which are transcribed only in the silk gland. We find that TFIIIB binds tRNA SG Ala genes with lower affinity than it binds tRNA C Ala genes. In addition, the TFIIIB complex formed on tRNA SG Ala genes differ qualitatively from those formed on tRNA C Ala genes. Both the transcriptional activity of tRNA SG Ala complexes and the ability of the complexes to protect upstream DNA from DNase I digestion are reduced.