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PubMed2006

Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis.

Amphotericin B is the main therapeutic agent for the treatment of invasive fungal infections; however, it is associated with significant toxicities that limit its use. Other systemic antifungal agents have been developed to improve tolerability while maintaining the efficacy profile of conventional amphotericin B. Fifty-four studies involving 9,228 patients were assessed for the frequency of adverse effects of the main systemic antifungal agents. While the results suggest that liposomal amphotericin B is the least nephrotoxic of the lipid formulations (14.6%), that conventional amphotericin B is the most nephrotoxic (33.2%), and that itraconazole is the most hepatotoxic (31.5%), the lack of standard definitions of antifungal-related adverse effects limits the validity of these results. Furthermore, heterogeneous patient pools and differing protocols make it difficult to draw direct comparisons between studies. With the advent of newer classes of systemic antifungal agents, future trials should conform to definitions that are universally applicable and clinically relevant to allow for such comparisons and to enable evidence-based decision-making.

Antifungal Agents↗

PubMedDate not supplied

A unique subpopulation of Tbr1-expressing deep layer neurons in the developing cerebral cortex.

Cells of the subplate (SP) and deep cortical plate (CP) are among the pioneer neurons of the developing cerebral cortex, an important group of early-born cells that impact cortical organization and function. Similarities between pioneer neurons in different cortical positions and heterogeneities in pioneer cells in the same cortical location, however, have made it difficult to appreciate the characteristics and functions of particular sets of these cells. Here, we provide a tool to illuminate a unique subset of SP and deep CP neurons: expression of a Tbrain-1 (Tbr1)-driven transgene. Transgene-expressing cells were consistently positive for neuronal but not glial markers, were born early in corticogenesis, representing just a subset of SP and deep CP neurons, were morphologically complex during the formation of the cortex, and were maintained into maturity. This analysis reveals a novel group of pioneer neurons and demonstrates unrecognized diversity within this cortical population. In the future, this information will help to uncover the roles of discrete pioneer populations in cortical development.

Animals↗

PubMed2006

Micro-computed tomography evaluation of the glenoid fossa and mandibular condyle bone after bilateral vertical ramus mandibular distraction in a canine model.

The aim of this study was to quantify bone microarchitecture within the glenoid fossa and mandibular condyle following mandibular distraction osteogenesis. Eight 6- to 9-month-old male beagle dogs underwent bilateral vertical mandibular distraction with semiburied distractors (12 days of distraction at 1 mm per day). One unoperated animal served as control. After distraction the animals were divided into two groups (N = 4) and killed after 1 or 2 months of consolidation. Three-dimensional trabecular architecture was analyzed by micro-computed tomography (microCT). At both sites the overall trends were similar. In the glenoid fossa, there was decreased bone volume, trabecular number, and connectivity density and increased trabecular separation at 1 month and decreased trabecular thickness and increased structure model index compared with the control (P < 0.05). In the mandibular condyle, there was decreased bone volume, trabecular number, and connectivity density at both 1 and 2 months, with decreased trabecular thickness and increased structure model index at 2 months only compared with the control (P < 0.05). The bone became less dense and more rodlike. These bone changes are similar to those seen by the effects of aging or impaired normal function. Thus, in the short term, changes occur in the bone microstructure of the glenoid fossa and mandibular condyle after vertical mandibular ramus distraction in the canine model.

Animals↗

PubMed2006

Pediatric facial fractures: recent advances in prevention, diagnosis and management.

During the last 25 years, there have been considerable advances in the prevention, diagnosis and management of craniomaxillofacial injuries in children. When compared to adults, the pattern of fractures and frequency of associated injuries are similar but the overall incidence is much lower. Diagnosis is more difficult than in adults and fractures are easily overlooked. Clinical diagnosis is best confirmed by computed tomographic (CT) scans. Treatment is usually performed without delay and can be limited to observation or closed reduction in non-displaced or minimally displaced fractures. Operative management should involve minimal manipulation and may be modified by the stage of skeletal and dental development. Open reduction and rigid internal fixation is indicated for severely displaced fractures. Primary bone grafting is preferred over secondary reconstruction and alloplastic materials should be avoided when possible. Children require long-term follow-up to monitor potential growth abnormalities. This article is a review of the epidemiology, diagnosis and management of facial fractures in children.

Bone Transplantation↗

PubMed2005

FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.

BACKGROUND: FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to lymph nodes. This is the first study to evaluate the efficacy and safety of FTY720 in de novo renal transplantation. METHODS: This phase 2a, multicenter, open-label, dose-finding study compared FTY720 (0.25, 0.5, 1.0, or 2.5 mg) with mycophenolate mofetil (MMF), in combination with cyclosporine and corticosteroids. Patients (n=208) received FTY720 (n=167) or MMF (n=41) for 3 months followed by a 3-month follow-up. RESULTS: The incidence of biopsy-confirmed acute rejection at month 3 was 23.3%, 34.9%, 17.5%, and 9.8%, respectively, with FTY720 at doses of 0.25, 0.5, 1.0, and 2.5 mg, versus 17.1% with MMF. The incidence for the composite endpoint (biopsy-confirmed acute rejection, graft loss, or death) was lowest with FTY720 at a dose of 2.5 mg at month 3 (14.6%) compared with FTY720 at doses of 0.25 mg (25.6%), 0.5 mg (34.9%), and 1.0 mg (17.5%), and MMF (19.5%). Safety was comparable between FTY720 and MMF group. The main difference in tolerability was a mild and transient reduction in heart rate. A decrease in peripheral lymphocytes occurred in patients receiving FTY720, as expected from the mode of action, and this was reversible after treatment cessation. CONCLUSIONS: FTY720 at 2.5 mg was found to be as effective as MMF in combination with cyclosporine for the prevention of acute rejection after renal transplantation. FTY720 was well tolerated and not associated with the side effects commonly observed with immunosuppressant therapies.

Adolescent↗

PubMed2000

Erratum: analysis of DNA elements that modulate myosin VIIa expression in humans.

Usher syndromeIb (USH1B), an autosomal recessive disorder caused by mutations in myosin VIIa (MYO7A), is characterized by congenital profound hearing loss, vestibular abnormalities and retinitis pigmentosa. Promoter elements in the 5 kb upstream of the translation start were identified using adult retinal pigment epithelium cells (ARPE-19) as a model system. A 160 bp minimal promoter within the first intron was active in ARPE-19 cells, but not in HeLa cells that do not express MYO7A. A 100 bp sequence, 5' of the first exon, and repeated with 90% homology within the first intron, appeared to modulate expression in both cell lines. Segments containing these elements were screened by heteroduplex analysis. No heteroduplexes were detected in the minimal promoter, suggesting that this sequence is conserved. A -2568 A>T transversion in the 5' 100 bp repeat, eliminating a CCAAT element, was found only in USH1B patients. However, in all 5 families, -2568 A>T was in cis with the same missense mutation in the myosin VIIa tail (Arg1240Gln), and 4 of the 5 families were Dutch. These observations suggest either 1) linkage disequilibrium or 2)that a combination of a promoter mutation with a less active myosin VIIa protein results in USH1B.

Amino Acid Substitution↗

PubMed2001

CYP1A2 is expressed along with CYP1A1 in the human lung.

The expression and activity of CYP1A1 were examined in fresh, small-sized lung biopsy specimens from nine human subjects. CYP1A1 transcripts were detected by reverse transcription-polymerase chain reaction (RT-PCR) analysis of total lung RNA. CYP1A2 transcripts were detected in the RNA samples as well, and bioactivation of 2-aminofluorene (2-AF) or 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), a CYP1A2-preferential activity, was catalyzed by the lung S(9) fractions also. Two major bands were detected in the whole homogenate by western blot analysis using CD3, a mouse anti rat CYP1A1 monoclonal that cross-reacts with rat CYP1A2 as well as with human CYP1A1 and CYP1A2. S(9) fractions from the tissues catalyzed the bioactivation of benzo[a]pyrene (B[a]P), a CYP1A1-preferential activity, to mutagens in the Ames assay. Our findings are in agreement with the known presence of CYP1A1 in the human lung, and provide strong evidence for the expression of catalytically functional CYP1A2 in the tissue.

Animals↗

PubMed1990

Diagnostic value of a new myocardial perfusion agent, teboroxime (SO 30,217), utilizing a rapid planar imaging protocol: preliminary results.

Technetium-99m-labeled agents have advantages over thallium-201 in terms of photon statistics, cost and clinical availability. They have been suggested as an alternative to thallium for myocardial perfusion imaging. Teboroxime is a new boronic acid adduct of technetium dioxime (BATO) compound that demonstrates favorable characteristics in preliminary studies. With use of a novel (seated) patient positioning technique and a rapid dynamic acquisition protocol, 30 patients underwent planar imaging with teboroxoime while at rest and after maximal treadmill exercise. Postexercise scans were completed in an average time (mean +/- SD) of 4.4 +/- 1.6 min, with 4.8 +/- 1.5 min for the views at rest. These results were compared with coronary arteriography or thallium scintigraphy after treadmill exercise, or both. Diagnostic agreement (abnormal versus normal) was present in 28 of the 30 patients (p less than 0.001). Regarding physiologic assessment as compared with thallium scintigraphy, the finding of infarction and ischemia was concordant in 89% and 86% of patients, respectively. This report describes the initial use of teboroxime with a rapid dynamic planar imaging technique, resulting in a high correlation with exercise thallium scintigraphy. Delayed postexercise images obtained 5 to 10 min after exercise demonstrated rapid disappearance of exercise-induced defects noted on the initial (0 to 5 min) postexercise views. The rapid differential washout with teboroxime has not been previously described and the possible clinical significance is discussed.

Adult↗

PubMed1990

Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography.

Serum levels of DHEA sulfate are inversely associated with cardiovascular death in men, and urinary dehydroepiandrosterone (DHEA) levels are inversely associated with clinical manifestations of coronary artery disease. These observations may be related to the antiproliferative effects of DHEA, resulting in inhibition of atherosclerotic intimal hyperplasia. To examine the relation between these steroids and a direct measure of coronary atherosclerosis, plasma DHEA and DHEA sulfate levels were determined in 206 middle-aged patients (103 men, 103 women) undergoing elective coronary angiography. Plasma DHEA sulfate levels were lower in men with at least one stenosis greater than or equal to 50% compared with those without any stenosis greater than or equal to 50% (4.9 +/- 2.7 versus 6.1 +/- 3.5 nmol/ml, p = 0.05). Levels of DHEA sulfate were also inversely related to the number of diseased coronary vessels (r = -0.20, p = 0.05) and a continuous measure of the extent of coronary atherosclerosis (r = -0.25, p = 0.01) in men. The association between DHEA sulfate levels and extent of coronary artery disease was independent of age and other conventional risk factors for coronary disease. In women, there was no association between plasma DHEA or DHEA sulfate levels and coronary disease. These data demonstrate a consistent, independent, inverse, dose-response relation between plasma DHEA sulfate levels and angiographically defined coronary atherosclerosis in men. Plasma DHEA sulfate may be another important and potentially modifiable risk factor for the development and progression of coronary atherosclerosis.

Adult↗

PubMed1999

Service utilization among homeless and runaway youth in Los Angeles, California: rates and reasons.

PURPOSE: To describe the service utilization patterns of homeless and runaway youth in a "service-rich" area of Los Angeles, California; identify demographic and other correlates of utilization; and contextualize the findings with qualitative data. METHOD: During Phase 1 of this study, survey data were collected from an ethnically diverse sample of 296 youth aged 13-23 years, recruited from both service and natural "hang-out" sites using systematic sampling methods. During Phase 2, qualitative data were collected from 46 youth of varying ethnicities and lengths of time homeless. RESULTS: Drop-in centers and shelters were the most commonly used services (reported by 78% and 40%, respectively). Other services were used less frequently [e.g., medical services (28%), substance abuse treatment (10%) and mental health services (9%)]. Utilization rates differed by ethnicity, length of time in Los Angeles, and city of first homeless episode (Los Angeles versus all others). Shelter use was strongly associated with use of all other services. Despite youths' generally positive reactions to services, barriers were described including rules perceived to be restrictive, and concerns youth had about confidentiality and mandated reporting. Youth suggested improvements including more targeted services, more long-term services, revised age restrictions, and more and/or better job training and transitional services to get them off the streets. CONCLUSIONS: Because shelters and drop-in centers act as gateways to other services and offer intervention potential for these hard-to-reach youth, it is vital that we understand the perceived barriers to service utilization.

Adolescent↗

PubMed2002

Formins direct Arp2/3-independent actin filament assembly to polarize cell growth in yeast.

Formins have been implicated in the regulation of cytoskeletal structure in animals and fungi. Here we show that the formins Bni1 and Bnr1 of budding yeast stimulate the assembly of actin filaments that function as precursors to tropomyosin-stabilized cables that direct polarized cell growth. With loss of formin function, cables disassemble,whereas increased formin activity causes the hyperaccumulation of cable-like filaments. Unlike the assembly of cortical actin patches, cable assembly requires profilin but not the Arp2/3 complex. Thus formins control a distinct pathway for assembling actin filaments that organize the overall polarity of the cell.

Acetyltransferases↗

PubMed2004

Cancer chemopreventive activity of rotenoids from Derris trifoliata.

A study of the chemical constituents of the stems of Derris trifoliata Lour. (Leguminosae) led to the isolation and identification of one new rotenoid, 6aalpha,12aalpha-12a-hydroxyelliptone ( 3), together with five other known rotenoids. In a search for novel cancer chemopreventive agents (anti-tumor promoters), we carried out a primary screening of five of the rotenoids isolated from the plant for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12- O-tetradecanoylphorbol 13-acetate (TPA) in Raji cells. The inhibitory activity of 3 was found to be equivalent to that of beta-carotene without any cytotoxicity. Deguelin ( 4) and alpha-toxicarol ( 5) exhibited a marked inhibitory effect on mouse skin tumor promotion in an in vivo two-stage carcinogenesis test. This investigation indicated that rotenoids might be valuable anti-tumor promoters.

Animals↗

PubMed2006

Baseline predictors of three types of antiretroviral therapy (ART) adherence: A 2-year follow-up.

The purposes of the study were to measure adherence with antiretroviral therapy to dose, schedule, and dietary instructions in a sample of patients with HIV infection in Stockholm, Sweden, over a 2-year period and identify baseline predictors of the three types of adherence. The study cohort consists of 144 patients who completed at least six out of seven follow-up self-reported adherence questionnaires. Baseline self-administrated questionnaire examined socio-demographics, medication-related, psychological, cognitive, and social context factors and self-reported adherence. Biomedical data were obtained through patients' medical records. Summary dose, schedule, and dietary instructions adherence scores provided outcome measures reflecting 100% adherence across all time points or not 100% adherence during at least one measurement period. A total of 61% maintained consistent full-dose adherence throughout baseline and all follow-up visits and equivalent proportion of 100% schedule adherence was 39%. Among patients with dietary instructions, 37% retained consistent adherence at all visits. Only schedule adherence was predicted by baseline data; perceived pressures from medical staff to take HIV medications (OR 0.51, p < .05), life stress (OR 0.13, p < .01), ART health concerns (OR 0.19, p < .01), and ART prolongs one's life (OR 0.39, p < .05) predicted reduced schedule adherence over time. Perceived medication pressures from those close to the patient (OR 1.76, p < .05), post-traumatic stress disorder symptoms (OR 1.07 p<.01), and adherence self-efficacy (OR 3.50, p < .05) predicted positive schedule adherence over time. These results clearly illustrate difficulties in sustaining ART adherent behaviour, in particular schedule and dietary restrictions, over time and thus emphasizes the importance of multiple periodic assessments of all three types of adherence. Interventions aimed at improving schedule adherence should in particular focus on psychological and cognitive factors.

Adult↗

PubMed1996

Nucleolar accumulation of poly (A)+ RNA in heat-shocked yeast cells: implication of nucleolar involvement in mRNA transport.

Transport of mRNA from the nucleus to the cytoplasm plays an important role in gene expression in eukaryotic cells. In wild-type Schizosaccharomyces pombe cells poly(A)+ RNA is uniformly distributed throughout the nucleoplasm and cytoplasm. However, we found that a severe heat shock blocks mRNA transport in S. pombe, resulting in the accumulation of bulk poly(A)+ RNA, as well as a specific intron-less transcript, in the nucleoli. Pretreatment of cells with a mild heat shock, which induces heat shock proteins, before a severe heat shock protects the mRNA transport machinery and allows mRNA transport to proceed unimpeded. In heat-shocked S. pombe cells, the nucleolar region condensed into a few compact structures. Interestingly, poly(A)+ RNA accumulated predominantly in the condensed nucleolar regions of the heat-shocked cells. These data suggest that the yeast nucleolus may play a role in mRNA transport in addition to its roles in rRNA synthesis and preribosome assembly.

Base Sequence↗

PubMed2000

Characterization of an unusual tRNA-like sequence found inserted in a Neurospora retroplasmid.

We characterized an unusual tRNA-like sequence that had been found inserted in suppressive variants of the mitochondrial retroplasmid of Neurospora intermedia strain Varkud. We previously identified two forms of the tRNA-like sequence, one of 64 nt (TRL-64)and the other of 78 nt (TRL-78) containing a 14-nt internal insertion in the anticodon stem at a position expected for a nuclear tRNA intron. Here, we show that TRL-78 is encoded in Varkud mitochondrial (mt)DNA within a 7 kb sequence that is not present in Neurospora crassa wild-type 74A mtDNA. This 7-kb insertion also contains a perfectly duplicated tRNA(Trp)gene, segments of several mitochondrial plasmids and numerous GC-rich pallindromic sequences that are repeated elsewhere in the mtDNA. The mtDNA-encoded copy of TRL-78 is transcribed and apparently undergoes 5'- and 3'-end processing and 3' nucleotide addition by tRNA nucleotidyl transferase to yield a discrete tRNA-sized molecule. However, the 14 nt intron-like sequence in TRL-78, which is missing in the TRL-64 form, is not spliced detectably in vivo or in vitro. Our results show that TRL-78 is an unusual tRNA-like species that could be incorporated into suppressive retroplasmids by the same reverse transcription mechanism used to incorporate mt tRNAs. The tRNA-like sequence may have been derived from an intron-containing nuclear tRNA gene or it may serve some function, like tmRNA. Our results suggest that mtRNAs or tRNA-like species may be integrated into mtDNA via reverse transcription, analogous to SINE elements in animal cells.

Base Sequence↗

PubMed1990

Liver glucose transporter: a basolateral protein in hepatocytes and intestine and kidney cells.

The "liver" isoform of the facilitated diffusion glucose transporter is expressed predominantly in liver, intestine, kidney, and pancreatic islet beta-cells. The apparent molecular mass of the transporter in liver, kidney, and intestine is different, as detected by Western blot analysis of membrane proteins using antipeptide antibodies. However, as assessed by Northern blot analysis and molecular cloning, the same mRNA is expressed in these tissues, indicating that there are tissue-specific posttranslational modifications of the same transporter polypeptide. As determined by immunofluorescence analysis on frozen tissue sections, the liver glucose transporter is present on the sinusoidal membrane of hepatocytes, on the basolateral membrane of fully differentiated absorptive intestine epithelial cells, and on the basolateral membrane of proximal tubule cells of the kidney nephron. This localization is consistent with the involvement of the liver glucose transporter in several key steps of glucose metabolism: glucose uptake and release by the liver and absorption or reabsorption by epithelial cells of the intestine and kidney, respectively.

Animals↗

PubMed1992

Cage allocation designs for rodent carcinogenicity experiments.

Cage allocation designs for rodent carcinogenicity experiments are discussed and presented with the goal of avoiding dosage group biases related to cage location. Considerations in selecting a cage design are first discussed in general terms. Specific designs are presented for use in experiments involving three, four, and five dose groups and with one, four, and five rodents per cage. Priorities for balancing treatment groups include horizontal position on shelf and shelf of rack, nearest neighbor balance, and male-female balance. It is proposed that these balance criteria be considered together with practical issues, such as the ability to accurately conform to a design and to determine a sensible and efficient design for each experiment.

Animals↗

PubMed1995

Delayed activation of altered fusion glycoprotein in a chronic measles virus variant that causes subacute sclerosing panencephalitis.

We compared the intracellular processing of the fusion (F) glycoproteins of an acute measles virus (MV) Nagahata strain and its relative Biken strain that caused subacute sclerosing panencephalitis (SSPE), Nagahata strain synthesizes a precursor F0 which acquires three asparagine (N)-linked oligosaccharide chains sequentially in 1 h. One oligosaccharide chain on the partially glycosylated F0 is less accessible to endo-beta-N-acetylglucosaminidase H (endo-H) but becomes accessible as the protein becomes fully glycosylated, suggesting a protein conformational change. Biken strain SSPE virus synthesizes a similarly glycosylated F0. However, one oligosaccharide chain on the Biken F0 remains less accessible to endo-H even after the protein is fully glycosylated. The Nagahata F0 is cleaved into the F1 and F2 subunits with a half life of 1 h. The Biken F0 is cleaved with a half life of 4 h. We cloned the F genes of Nagahata and Biken strains and showed by transfection that the defect causing delayed cleavage of F0 resides in the Biken F gene. Sequence analysis predicts a mutation in the cleavage recognition sequence, a truncated carboxyl-terminus, and multiple mutations in F1 of the Biken F protein. Expression of chimeric F genes showed the mutated cleavage recognition sequence and the carboxyl-terminal truncation do not delay cleavage of F0. Instead, delayed F0 cleavage is due to multiple mutations in the extracellular domain of F1, and four amino acid substitutions near the transmembrane region impair endo-H access to the oligosaccharide chain. These results provide detailed information on the normal maturation process of the F protein of MV and additional clues to the mechanisms of MV persistence in the CNS.

Animals↗