bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurosurgery for mental disorder
Authors: Christmas David , Morrison Colin , Eljamel Muftah S. , Matthews Keith
Published: May 2004

The authors review contemporary indications for neurosurgical interventions in the management of chronic and refractory mental disorder, the procedures involved, their efficacy and known adverse effects. These data are presented within the context of a brief historical overview of the use of neurosurgery for mental disorder. In addition to a consideration of neurosurgical procedures that rely on the creation of putative therapeutic lesions, we also review two novel, non-destructive neurosurgical electrostimulation treatments that may represent viable alternatives to conventional ablative neurosurgery: vagus nerve stimulation and deep brain stimulation.
Improving the general health of people with learning disabilities
Authors: Kerr Mike
Published: May 2004

People with learning disabilities suffer an increase in common morbidity, communication difficulties, a high prevalence of serious conditions such as epilepsy, and specific patterns of health needs associated with the aetiology of their disability. Unfortunately, this combination of need is mirrored by a consistent picture of poor health promotion uptake, inadequate care for serious morbidity, unrecognised health need and poor access to health care. Consequently, there is a great disparity between the health of learning-disabled people and that of the general population. Psychiatrists can address this disparity in clinical practice by focusing on these patients' mental health, epilepsy management and the impact of behaviour on health. They can also influence health planning and service development.
Aspects of morbid jealousy
Authors: Kingham Michael , Gordon Harvey
Published: May 2004

Morbid jealousy is encountered in general, old age and forensic psychiatry, and clinicians in each specialty should be familiar with its recognition and management. As well as clinical matters, the issue of risk to the patient and others is prominent in the consideration of morbid jealousy. Hospitalisation is sometimes required, the use of compulsory admission is not infrequent and treatment in secure settings is occasionally warranted. This review addresses the nature of morbid jealousy, its psychopathology, diagnostic issues, associations, risks and management.
Poverty, social inequality and mental health
Authors: Murali Vijaya , Oyebode Femi
Published: May 2004

The World Health Organization has described poverty as the greatest cause of suffering on earth. This article considers the direct and indirect effects of relative poverty on the development of emotional, behavioural and psychiatric problems, in the context of the growing inequality between rich and poor. The problems of children in particular are reviewed. Targets to reduce inequality have been set both nationally and internationally.
Cell-Specific Knockout of Steroidogenic Factor 1 Reveals Its Essential Roles in Gonadal Function
Authors: Jeyasuria Pancharatnam , Ikeda Yayoi , Jamin Soazik P. , Zhao Liping , de Rooij Dirk G. , Themmen Axel P. N. , Behringer Richard R. , Parker Keith L.
Published: May 2004

Knockout (KO) mice lacking the orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated Nr5a1) have a compound endocrine phenotype that includes adrenal and gonadal agenesis, impaired expression of pituitary gonadotropins, and structural abnormalities of the ventromedial hypothalamic nucleus. To inactivate a conditional SF-1 allele in the gonads, we targeted the expression of Cre recombinase with a knock-in allele of the anti-Müllerian hormone type 2 receptor locus. In testes, Cre was expressed in Leydig cells. The testes of adult gonad-specific SF-1 KO mice remained at the level of the bladder and were markedly hypoplastic, due at least partly to impaired spermatogenesis. Histological abnormalities of the testes were seen from early developmental stages and were associated with markedly decreased Leydig cell expression of two essential components of testosterone biosynthesis, Cyp11a and the steroidogenic acute regulatory protein. In females, the anti-Müllerian hormone type 2 receptor-Cre allele directed Cre expression to granulosa cells. Although wild-type and SF-1 KO ovaries were indistinguishable during embryogenesis and at birth, adult females were sterile and their ovaries lacked corpora lutea and contained hemorrhagic cysts resembling those in estrogen receptor α and aromatase KO mice. Collectively, these studies establish definitively that SF-1 expression in the gonads is essential for normal reproductive development and function.
The zebrafishiguanalocus encodes Dzip1, a novel zinc-finger protein required for proper regulation of Hedgehog signaling
Authors: Sekimizu Kohshin , Nishioka Noriyuki , Sasaki Hiroshi , Takeda Hiroyuki , Karlstrom Rolf O. , Kawakami Atsushi
Published: May 2004

Members of the Hedgehog (Hh) family of intercellular signaling molecules play crucial roles in animal development. Aberrant regulation of Hh signaling in humans causes developmental defects, and leads to various genetic disorders and cancers. We have characterized a novel regulator of Hh signaling through the analysis of the zebrafish midline mutant iguana (igu). Mutations in igu lead to reduced expression of Hh target genes in the ventral neural tube, similar to the phenotype seen in zebrafish mutants known to affect Hh signaling. Contradictory at first sight, igu mutations lead to expanded Hh target gene expression in somites. Genetic and pharmacological analyses revealed that the expression of Hh target genes in igu mutants requires Gli activator function but does not depend on Smoothened function. Our results show that the ability of Gli proteins to activate Hh target gene expression in response to Hh signals is generally reduced in igu mutants both in the neural tube and in somites. Although this reduced Hh signaling activity leads to a loss of Hh target gene expression in the neural tube, the same low levels of Hh signaling appear to be sufficient to activate Hh target genes throughout somites because of different threshold responses to Hh signals. We also show that Hh target gene expression in igu mutants is resistant to increased protein kinase A activity that normally represses Hh signaling. Together, our data indicate that igu mutations impair both the full activation of Gli proteins in response to Hh signals, and the negative regulation of Hh signaling in tissues more distant from the source of Hh. Positional cloning revealed that the igu locus encodes Dzip1, a novel intracellular protein that contains a single zinc-finger protein-protein interaction domain. Overexpression of Igu/Dzip1 proteins suggested that Igu/Dzip1 functions in a permissive way in the Hh signaling pathway. Taken together, our studies show that Igu/Dzip1 functions as a permissive factor that is required for the proper regulation of Hh target genes in response to Hh signals.
FGF signaling functions in the hypodermis to regulate fluid balance inC. elegans
Authors: Huang Peng , Stern Michael J.
Published: May 2004

Signaling by the Caenorhabditis elegans fibroblast growth factor receptor EGL-15 is activated by LET-756, a fibroblast growth factor, and attenuated by CLR-1, a receptor tyrosine phosphatase. Hyperactive EGL-15 signaling results in a dramatic Clr phenotype characterized by the accumulation of clear fluid within the pseudocoelomic space, suggesting that regulated EGL-15 signaling is essential for fluid homeostasis in C. elegans. To determine the cellular focus of EGL-15 signaling, we identified an enhancer element (e15) within the egl-15promoter, which is both necessary for the promoter activity and sufficient when duplicated to drive either egl-15 or clr-1 rescue activity. This enhancer drives GFP expression in hypodermal cells. Consistent with this finding, immunofluorescence studies of EGL-15 indicate that EGL-15 is expressed in hypodermal cells, and hypodermal promoters can drive full clr-1 and egl-15 rescue activity. Moreover, a mosaic analysis of mpk-1, which acts downstream of egl-15, suggests that its suppression of Clr (Soc) function is required in the hypodermis. These results suggest that EGL-15 and CLR-1 act in the hypodermis to regulate fluid homeostasis in worms.
YeastARL1encodes a regulator of K+ influx
Authors: Munson Amanda M. , Haydon Devon H. , Love Sherie L. , Fell Gillian L. , Palanivel Vikram R. , Rosenwald Anne G.
Published: May 2004

A molecular genetic approach was undertaken in Saccharomyces cerevisiae to examine the functions of ARL1, encoding a G protein of the Ras superfamily. We show here that ARL1 is an important component of the control of intracellular K+. The arl1 mutant was sensitive to toxic cations, including hygromycin B and other aminoglycoside antibiotics, tetramethylammonium ions, methylammonium ions and protons. The hygromycin-B-sensitive phenotype was suppressed by the inclusion of K+ and complemented by wild-type ARL1 and an allele of ARL1 predicted to be unbound to nucleotide in vivo. The arl1 mutant strain internalized ∼25% more [14C]-methylammonium ion than did the wild type, consistent with hyperpolarization of the plasma membrane. The arl1 strain took up 30-40% less 86Rb+ than did the wild type, showing an inability to regulate K+ import properly, contributing to membrane hyperpolarity. By contrast, K+ and H+ efflux were undisturbed. The loss of ARL1 had no effect on the steady-state level or the localization of a tagged version of Trk1p. High copy suppressors of the hygromycin-B phenotype included SAP155, encoding a protein that interacts with the cell cycle regulator Sit4p, and HAL4 and HAL5, encoding Ser/Thr kinases that regulate the K+-influx mediators Trk1p and Trk2p. These results are consistent with a model in which ARL1, via regulation of HAL4/HAL5, governs K+ homeostasis in cells.
Overexpression of the C-terminal PG-M/versican domain impairs growth of tumor cells by intervening in the interaction between epidermal growth factor receptor and β1-integrin
Authors: Wu Yaojiong , Chen Liwen , Cao Liu , Sheng Wang , Yang Burton B.
Published: May 2004

Versican is highly expressed in many types of tumors. In a previous study, we found that a G3 mutant [G3ΔEGF; a versican G3 domain lacking two epidermal growth factor (EGF)-like motifs] exerted a dominant-negative effect on versican secretion and binding. Here, we report that astrocytoma U87 cells expressing the versican G3 mutant lost the hallmark of cell transformation and tumorigenesis in vitro and in vivo. U87 cells expressing G3ΔEGF had enhanced cell adhesion and spreading, but lost the tumor characteristic of anchorage-independent growth. When U87 cells were deprived of serum, FAK was quickly dephosphorylated, integrin/EGF-receptor (EGFR) complexes dissociated and the cells retained an appropriate level of EGFR phosphorylation. These cells quickly detached, migrated, rounded, reorganized and survived. However, after serum withdrawal from G3ΔEGF-transfected U87 cells, sustained FAK phosphorylation and integrin-EGFR association were observed, but a greatly reduced EGFR phosphorylation. These cells remained spread and continued to grow before undergoing massive apoptosis. The addition of EGF promoted U87 cell rounding but had little effect on G3ΔEGF-transfected cells owing to reduced EGFR phosphorylation. Our study sheds light on the question of how the matrix molecule versican modulates tumorigenesis by affecting integrin and EGFR signals.
Cross-linking ATP synthase complexes in vivo eliminates mitochondrial cristae
Authors: Gavin Paul D. , Prescott Mark , Luff Susan E. , Devenish Rodney J.
Published: May 2004

We have used the tetrameric nature of the fluorescent protein DsRed to cross-link F1FO-ATPase complexes incorporating a subunit γ-DsRed fusion protein in vivo. Cells expressing such a fusion protein have impaired growth relative to control cells. Strikingly, fluorescence microscopy of these cells revealed aberrant mitochondrial morphology. Electron microscopy of cell sections revealed the absence of cristae and multiple layers of unfolded inner mitochondrial membrane. Complexes recovered from detergent lysates of mitochondria were present largely as tetramers. Co-expression of `free' DsRed targeted to the mitochondria reduced F1FO-ATPase oligomerisation and partially reversed the impaired growth and abnormal mitochondrial morphology. We conclude that the correct arrangement of F1FO-ATPase complexes within the mitochondrial inner membrane is crucial for the genesis and/or maintenance of mitochondrial cristae and morphology. Our findings further suggest that F1FO-ATPase can exist in oligomeric associations within the membrane during respiratory growth.
Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation
Authors: Egberts Friederike , Heinrich Michael , Jensen Jens-Michael , Winoto-Morbach Supandi , Pfeiffer Stephan , Wickel Marc , Schunck Michael , Steude Judith , Saftig Paul , Proksch Ehrhardt , Schütze Stefan
Published: May 2004

We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase. Increased expression of cathepsin D in the skin has been reported in wound healing, psoriasis and skin tumors. We explored specific functions of cathepsin D during epidermal differentiation. Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair. Treatment of cultured keratinocytes with exogenous cathepsin D increased the activity of transglutaminase 1, known to cross-link the cornified envelope proteins involucrin and loricrin during epidermal differentiation. Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1. Cathepsin D-deficient mice revealed reduced transglutaminase 1 activity and reduced protein levels of the cornified envelope proteins involucrin and loricrin. Also, amount and distribution of cornified envelope proteins involucrin, loricrin, filaggrin, and of the keratins K1 and K5 were significantly altered in cathepsin D-deficient mice. Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis. Our findings suggest a functional link between cathepsin D activation, transglutaminase 1 activity and protein expression of cornified envelope proteins during epidermal differentiation.
Membrane fusion of secretory vesicles of the sea urchin egg in the absence of NSF
Authors: Whalley Tim , Timmers Kim , Coorssen Jens , Bezrukov Ludmila , Kingsley David H. , Zimmerberg Joshua
Published: May 2004

The role of cytosolic ATPases such as N-ethylmaleimide (NEM)-sensitive fusion protein (NSF) in membrane fusion is controversial. We examined the physiology and biochemistry of ATP and NSF in the cortical system of the echinoderm egg to determine if NSF is an essential factor in membrane fusion during Ca2+-triggered exocytosis. Neither exocytosis in vitro, nor homotypic cortical vesicle (CV) fusion required soluble proteins or nucleotides, and both occurred in the presence of non-hydrolyzable analogs of ATP. While sensitive to thiol-specific reagents, CV exocytosis is not restored by the addition of cytosolic NSF, and fusion and NSF function are differentially sensitive to thiol-specific agents. To test participation of tightly bound, non-exchangeable NSF in CV-CV fusion, we cloned the sea urchin homolog and developed a species-specific antibody for western blots and physiological analysis. This antibody was without effect on CV exocytosis or homotypic fusion, despite being functionally inhibitory. NSF is detectable in intact cortices, cortices from which CVs had been removed and isolated CVs treated with ATP-γ-S and egg cytosol to reveal NSF binding sites. In contrast, isolated CVs, though all capable of Ca2+-triggered homotypic fusion, contain less than one hexamer of NSF per CV. Thus NSF is not a required component of the CV fusion machinery.
Suppression of a mitotic mutant by tRNA-Ala anticodon mutations that produce a dominant defect in late mitosis
Authors: Kimata Yuu , Yanagida Mitsuhiro
Published: May 2004

Cold-sensitive dominant mutants scn1 and scn2 of Schizosaccharomyces pombe were isolated by their ability to suppress temperature-sensitive cut9-665 defective in an essential subunit (human Apc6/budding yeast Cdc16 ortholog) of anaphase promoting complex/cyclosome (APC/C). APC/C mutants were defective in metaphase/anaphase transition, whereas single scn mutants showed the delay in anaphase spindle elongation at 20°C. The scn mutants lost viability because of chromosome missegregation, and were sensitive to a tubulin poison. To understand the scn phenotypes, mutant genes were identified. Surprisingly, scn1 and scn2 have the same substitution in the anticodon of two different tRNA-Ala (UGC) genes. UGC was altered to UGU so that the binding of the tRNA-Ala to the ACA Thr codon in mRNA became possible. As cut9-665 contained an Ala535Thr substitution, wild-type Cut9 protein was probably produced in scn mutants. Indeed, plasmid carrying tRNA-Ala (UGU) conferred cold-sensitivity to wild-type and suppressed cut9-665 in a dominant fashion. The previously identified scn1+ (renamed as scn3+) turned out to be a high copy suppressor for scn1 and scn2. These are the first tRNA mutants that cause a mitotic defect.
Cryptic O2–-generating NADPH oxidase in dendritic cells
Authors: Elsen Sylvie , Doussière Jacques , Villiers Christian L. , Faure Mathias , Berthier Rolande , Papaioannou Anne , Grandvaux Nathalie , Marche Patrice N. , Vignais Pierre V.
Published: May 2004

All the components of the O2–-generating NADPH oxidase typically found in neutrophils, namely a membrane-bound low potential flavocytochrome b and oxidase activation factors of cytosolic origin, are immunodetectable in murine dendritic cells (DCs). However, in contrast to neutrophils, DCs challenged with phorbol myristate acetate (PMA) can barely mount a significant respiratory burst. Nevertheless, DCs generate a substantial amount of O2– in the presence of PMA following preincubation with pro-inflammatory ligands such as lipopolysaccharide and pansorbin, and to a lesser extent with anti-CD40 or polyinosinic polycytidylic acid. We found that the virtual lack of the oxidase response to PMA alone is specifically controlled in DCs. Through the use of homologous and heterologous cell-free systems of oxidase activation, we showed the following: (1) a NADPH oxidase inhibitory factor is located in DC membranes; it exerts its effect on oxidase activation and not on the activated oxidase. (2) The inhibition is relieved by pretreatment of DC membranes with β-octylglucoside (β-OG). (3) The β-OG-extracted inhibitory factor prevents the activation of neutrophil oxidase. (4) The inhibitory activity is lost after treatment of DC membranes with proteinase K or heating, which points to the protein nature of the inhibitory factor. Overall, these data indicate that the O2–-generating oxidase in DCs is cryptic, owing to the presence of a membrane-bound inhibitor of protein nature that prevents oxidase activation. The inhibition is relieved under specific conditions, including a prolonged contact of DCs with pro-inflammatory ligands from microbial origin, allowing a substantial production of O2–, which may contribute to the response of DCs to a microbial exposure.
The GDP-bound form of Arf6 is located at the plasma membrane
Authors: Macia Eric , Luton Frédéric , Partisani Mariagrazia , Cherfils Jacqueline , Chardin Pierre , Franco Michel
Published: May 2004

The function of Arf6 has been investigated largely by using the T27N and the Q67L mutants, which are thought to be blocked in GDP- and GTP-bound states, respectively. However, these mutants have been poorly characterized biochemically. Here, we found that Arf6(T27N) is not an appropriate marker of the inactive GDP-bound form because it has a high tendency to lose its nucleotide in vitro and to denature. As a consequence, most of the protein is aggregated in vivo and localizes to detergent-insoluble structures. However, a small proportion of Arf6(T27N) is able to form a stable complex with its exchange factor EFA6 at the plasma membrane, accounting for its dominant-negative phenotype. To define the cellular localization of Arf6-GDP, we designed a new mutant, Arf6(T44N). In vitro, this mutant has a 30-fold decreased affinity for GTP. In vivo, it is mostly GDP bound and, in contrast to the wild type, does not switch to the active conformation when expressed with EFA6. This GDP-locked mutant is found at the plasma membrane, where it localizes with EFA6 and Ezrin in actin- and phosphatidylinositol (4,5)-bisphosphate-enriched domains. From these results, we conclude that the Arf6 GDP-GTP cycle takes place at the plasma membrane.
Chloroplast division site placement requires dimerization of the ARC11/AtMinD1 protein in Arabidopsis
Authors: Fujiwara Makoto T. , Nakamura Ayako , Itoh Ryuuichi , Shimada Yukihisa , Yoshida Shigeo , Møller Simon Geir
Published: May 2004

Chloroplast division is mediated by the coordinated action of a prokaryote-derived division system(s) and a host eukaryote-derived membrane fission system(s). The evolutionary conserved prokaryote-derived system comprises several nucleus-encoded proteins, two of which are thought to control division site placement at the midpoint of the organelle: a stromal ATPase MinD and a topological specificity factor MinE. Here, we show that arc11, one of 12 recessive accumulation and replication of chloroplasts (arc) mutants in Arabidopsis, contains highly elongated and multiple-arrayed chloroplasts in developing green tissues. Genomic sequence analysis revealed that arc11 contains a missense mutation in α-helix 11 of the chloroplast-targeted AtMinD1 changing an Ala at position 296 to Gly (A296G). Introduction of wild-type AtMinD1 restores the chloroplast division defects of arc11 and quantitative RT-PCR analysis showed that the degree of complementation was highly dependent on transgene expression levels. Overexpression of the mutant ARC11/AtMinD1 in transgenic plants results in the inhibition of chloroplast division, showing that the mutant protein has retained its division inhibition activity. However, in contrast to the defined and punctate intraplastidic localization patterns of an AtMinD1-YFP fusion protein, the single A296G point mutation in ARC11/AtMinD1 results in aberrant localization patterns inside chloroplasts. We further show that AtMinD1 is capable of forming homodimers and that this dimerization capacity is abolished by the A296G mutation in ARC11/AtMinD1. Our data show that arc11 is a loss-of-function mutant of AtMinD1 and suggest that the formation of functional AtMinD1 homodimers is paramount for appropriate AtMinD1 localization, ultimately ensuring correct division machinery placement and chloroplast division in plants.
Retention and stimulus-dependent recycling of dense core vesicle content in neuroendocrine cells
Authors: Bauer Roslyn A. , Overlease Ruth L. , Lieber Janet L. , Angleson Joseph K.
Published: May 2004

We have used fluorescence imaging of individual exocytic events in combination with immunogold electron microscopy and FM1-43 photoconversion to study the stimulus-dependent recycling of dense core vesicle content in isolated rat pituitary lactotrophs. Secretory stimulation with high external [K+] resulted in 100 exocytic sites per cell that were labeled by extracellular antibodies against the peptide hormone prolactin. Morphological analysis demonstrated that the prolactin was retained and internalized in intact dense cores. Vesicles containing non-secreted, internalized prolactin did not colocalize with DiI-LDL that had been chased into lysosomes but did transiently colocalize with internalized transferrin. The recycling vesicles also trafficked through a syntaxin 6-positive compartment but not the TGN38-positive trans-Golgi. Recycling vesicles, which returned to the cell surface in a slow basal manner, could also be stimulated to undergo exocytosis with a high release probability during subsequent exocytic stimulation with external K+. These studies suggest a functional role for recycling vesicles that retain prolactin.
PDE4-regulated cAMP degradation controls the assembly of integrin-dependent actin adhesion structures and REF52 cell migration
Authors: Fleming Yvonne M. , Frame Margaret C. , Houslay Miles D.
Published: May 2004

Plating of REF52 cells onto extracellular matrix components leads to the formation of integrin-dependent actin adhesion microspikes. We show that the formation of these structures is sensitive to chemical agents that regulate cAMP levels, such as forskolin and IBMX. In particular, by using the specific inhibitor rolipram, we identify the PDE4 family of cAMP-specific phosphodiesterases as critical regulators of this process. The effect of PDE4 on microspike formation is mediated by actions exerted through the activation of PKA – rather than through the alternative cAMP effector, Epac. We provide evidence that peripheral microspikes are RhoA-, ROCK- and myosin-dependent, and that this pathway is suppressed by PDE4 inhibition. In addition, PDE4 inhibition impairs cell locomotion that requires dynamic protrusion and retraction of peripheral spike structures. Our data demonstrate that PDE4 activity is a key modulator of integrin-induced actin assembly at the cell periphery which, in turn, controls cell migration.
Molecular mechanisms of E2F-dependent activation and pRB-mediated repression
Authors: Frolov Maxim V. , Dyson Nicholas J.
Published: May 2004

Alterations in transcription of genes regulated by members of the E2F family of transcription factors can be viewed as a measure of the ebb and flow in a constantly evolving battle between repressor and activator complexes. Various chromatin regulatory complexes have been linked to Rb/E2F proteins, and changes in histone modifications correlate with states of E2F-dependent transcription. E2F has traditionally been viewed in the context of cell-cycle control. However, several recent studies have revealed a new aspect of E2F function in which pRB/E2F-family proteins confer stable repression of transcription. Such repression is evident in both actively proliferating cells and in cells that have withdrawn from the cell cycle.
Anti-Thrombin III in the Management of Hematopoietic Stem-Cell Transplantation—Associated Toxicity
Authors: Ibrahim Rami B , Peres Edward , Dansey Roger , Abidi Muneer H , Abella Esteban M , Klein Jared
Published: May 2004

OBJECTIVE:

To describe the evidence assessing the use of anti-thrombin III (AT-III) in the management of toxicity associated with hematopoietic stem-cell transplantation (HSCT)—conditioning regimens.

DATA SOURCES:

Clinical literature was accessed through conference proceedings, EMBASE, the Cochrane database, and MEDLINE (1966-December 2003).

STUDY SELECTION AND DATA EXTRACTION:

Case reports, small case series, case—control and cohort studies, and randomized controlled trials of AT-III in HSCT were evaluated. Publications examining AT-III use in the non-HSCT setting were also explored. Key search terms included AT-III, transplantation, and veno-occlusive disease (VOD).

DATA SYNTHESIS:

Severe VOD and ensuing multiple organ dysfunction is associated with high mortality in HSCT. A low AT-III level has been shown to correlate with the development of organ dysfunction. Phase II trials, case series, and one small, randomized, placebo-controlled study suggest a benefit when AT-III therapy is instituted early in the course of VOD/multiple organ dysfunction syndrome. In all of these reports, AT-III use was devoid of adverse events.

CONCLUSIONS:

Although further studies are needed to ascertain the optimal target level, method, and duration of administration, AT-III is still a viable alternative for the treatment of severe VOD and ensuing multiple organ dysfunction.
Emtricitabine: A Once-Daily Nucleoside Reverse Transcriptase Inhibitor
Authors: Modrzejewski Krysten A , Herman Ronald A
Published: May 2004

OBJECTIVE:

To review the pharmacology, virology, pharmacokinetics, safety, and efficacy of the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine.

DATA SOURCES:

English-language reports were accessed using MEDLINE (1966-June 2003) and the Iowa Drug Information Service database (1966-June 2003) using emtricitabine and Coviracil as key words. (Coviracil was the proposed trade name for the product prior to approval.) The Internet was also searched using the terms HIV/AIDS conferences, then emtricitabine within the conference proceedings.

STUDY SELECTION AND DATA EXTRACTION:

Abstracts, posters, and oral presentations from scientific conferences, both published and unpublished, were included. Preference was given to published controlled trials. Studies providing a description of the pharmacology, virology, effectiveness, safety, or pharmacokinetics of emtricitabine were used in this review.

DATA SYNTHESIS:

Emtricitabine is an NRTI used to treat HIV-1 infection. Once-daily administration can decrease pill burden and potentially increase adherence to multidrug HIV therapy. Further, emtricitabine has shown equivalent or improved outcomes compared with lamivudine and stavudine.

CONCLUSIONS:

Emtricitabine is a safe and effective option for HIV-1 infection in adults as part of a multidrug regimen. It may be a better alternative than lamivudine for once-daily therapy because of its extended intracellular half-life and better than lamivudine and stavudine because of a possibly decreased potential for drug resistance.
Successful Treatment of Staphylococcus Epidermidis Hip Prosthesis Infection with Oral Linezolid
Authors: Mogenet Ingrid , Raetz-Dillon Sabine , Canonge Jean-Marie , Archambaud Maryse , Bonnet Eric
Published: May 2004

OBJECTIVE:

To report a case of Staphylococcus epidermidis infection of a hip prosthesis successfully treated with oral linezolid.

CASE SUMMARY:

A 46-year-old woman developed methicillin-resistant S. epidermidis (MRSE) infection of her prosthetic hip. She received oral linezolid 600 mg twice daily for one month; after that time, the biological inflammatory markers returned to normal.

DISCUSSION:

One of the most serious complications of arthroplasty is joint prosthesis infection. It is mainly caused by gram-positive bacteria, in particular those of the genus staphylococcus. The increasing prevalence of gram-positive cocci that are resistant to antimicrobial agents has complicated the treatment of serious infections.

CONCLUSIONS:

Oral linezolid appears to be an effective and well-tolerated treatment option for hip prosthesis infections due to MRSE.
Rash Associated with Piperacillin/Tazobactam Administration in Infectious Mononucleosis
Authors: LeClaire Aimée C , Martin Craig A , Hoven Ardis D
Published: May 2004

OBJECTIVE:

To report a case of piperacillin/tazobactam-induced rash in a patient with infectious mononucleosis.

CASE SUMMARY:

A 25-year-old white man developed a rash while receiving piperacillin/tazobactam 3.375 g intravenously every 6 hours and gentamicin for osteomyelitis complicating a left femur fracture secondary to a motorcycle accident. Due to progression of the rash following additional doses of piperacillin/tazobactam during hospitalization, the patient's antimicrobial regimen was changed to vancomycin and meropenem. Subsequently, a mononucleosis spot test was positive, and both Epstein—Barr virus (EBV) immunoglobulin (Ig) G and IgM antibodies were positive. The rash rapidly resolved with the discontinuation of piperacillin/tazobactam.

DISCUSSION:

Although the development of rash following the administration of several different antimicrobials, especially ampicillin, has been previously reported, this is the first report of piperacillin/tazobactam-induced rash in infectious mononucleosis. The rash is generally self-limiting and usually resolves within days of discontinuing the causative antimicrobial agent. An altered drug metabolism or an immune-mediated process has been suggested as the potential mechanism for rash development.

CONCLUSIONS:

Prior reports of antimicrobial-induced rash in infectious mononucleosis and a positive laboratory diagnosis of EBV in our patient with no history of penicillin allergy support the identification of piperacillin/tazobactam as the inducer of the rash. According to the Naranjo probability scale, the association of piperacillin/tazobactam with the rash was classified as probable.
Pharmacist and Physician Collaboration in the Patient's Home
Authors: Amruso Nadia A , O'Neal Michael L
Published: May 2004

OBJECTIVE:

To review the historical perspective and current incidence of home visits by physicians and pharmacists, discuss the concept of pharmacists providing care “incident-to” the physician, and introduce a new endeavor of collaborative, incident-to home visits by a pharmacist and physician.

DATA SOURCES:

A literature search was performed using MEDLINE (1966-May 2003). The search terms used were home visit, house call, incident-to, collaborative care, physician, and pharmacist.

STUDY SELECTION AND DATA EXTRACTION:

All pertinent articles were evaluated.

DATA SYNTHESIS:

Home visits were once considered a hallmark of patient care, but have decreased to an average of 0.4 home visits per week for primary care physicians. Home visits are essential for patients unable to commute to the office due to a disability or illness. However, home visits also allow the physician to determine how conditions affect a patient's everyday life, in addition to assessing the living environment. Minimal documented evidence exists of pharmacists making home visits and no documented evidence exists of pharmacists and physicians collaboratively making home visits. The pharmacist complements the value of the visit by assessing medication appropriateness as well as medication administration, storage, accessibility, and adherence.

CONCLUSIONS:

Current practice styles often compromise services that were once paramount to patient care, as evidenced by a decline in home visits. Recent trends in health care attempt to compensate for high-volume practices and managed care restrictions. A collaborative relationship between a pharmacist and physician with visits into the patient's home is a movement toward improved continuity of care.
Incidence of Hepatotoxicity Due to Antitubercular Medicines and Assessment of Risk Factors
Authors: Shakya Rajani , Rao B Subba , Shrestha Bhawana
Published: May 2004

BACKGROUND:

Antitubercular drugs cause derangement of hepatic function revealed by clinical examination and abnormal liver function test results. Potential hepatotoxicity of some of the first-line antitubercular agents remains a problem, especially during the initial period of treatment.

OBJECTIVE:

To determine the incidence of antitubercular drug—induced hepatotoxicity in a Nepalese urban population and assess the risk factors.

METHOD:

Fifty patients diagnosed with active tuberculosis infection with normal pretreatment liver function were monitored clinically as well as biochemically in a prospective cohort analysis.

RESULTS:

Antitubercular drugs were found to be associated with derangement of hepatic function, resulting in elevation of liver enzymes to a variable extent (t = −4.550, p < 0.01 for aspartate aminotransferase [AST]; t = −5.467, p < 0.01 for alanine aminotransferase [ALT] at 95% CI). Thirty-eight percent of patients had 2 times and 30% had >3 times elevation of ALT. Similarly, 40% and 29% of patients showed 2 and >3 times elevation of the AST level, respectively. Four patients (8%) developed drug-induced hepatotoxicity. Jaundice was the presenting symptom in all patients. The time interval for onset of hepatotoxicity after initiation of therapy was 12–60 days (median 28). Antitubercular drug—induced hepatotoxicity was found more often in younger patients (6% vs 2%; p = 0.368, OR 2.75). Female gender was also a higher risk (p = 0.219, OR 4.2). Most patients who had developed hepatitis were diagnosed per sputum-smear positive reactions. Nutritional status, assessed by body mass index and serum albumin level, was the next predisposing factor.

CONCLUSIONS:

A finding of an 8% incidence of hepatotoxicity is considerably high. Risk factors of hepatotoxicity included female gender, disease extent, and poor nutritional status. Timely detection and temporary withdrawal of the offending agent can completely cure antitubercular drug—induced hepatotoxicity.
Montelukast-Induced Generalized Urticaria
Authors: Minciullo Paola L , Saija Antonella , Bonanno Domenica , Ferlazzo Edoardo , Gangemi Sebastiano
Published: May 2004

OBJECTIVE:

To report a case of generalized urticaria induced by montelukast treatment.

CASE SUMMARY:

A 28-year-old man with allergic rhinitis and moderate persistent asthma developed generalized urticaria 5 days after the initiation of montelukast and inhaled fluticasone. Symptoms disappeared within one day after suspension of both drugs. Two months later, after the resumption of montelukast and fluticasone, the patient developed generalized urticaria and eyelid angioedema, which were successfully treated with intravenous betamethasone, achieving complete remission within hours. After 2 days, the patient resumed inhaled fluticasone only and continued this therapy for several months without any adverse reaction.

DISCUSSION:

We attributed the adverse reaction to montelukast because of the temporal relationship between use of montelukast and urticaria, the absence of other identified causative factors and other explanations for allergic reactions, and the positive dechallenge and rechallenge. The Naranjo probability scale showed a probable relationship between skin manifestations and montelukast treatment.

CONCLUSIONS:

The use of antileukotrienes is increasing in asthma therapy. In cases of generalized urticaria in asthmatic patients undergoing montelukast therapy, physicians should be aware of a potential adverse reaction to this drug.
Antimicrobial-Associated Renal Tubular Acidosis
Authors: Hemstreet Brian A
Published: May 2004

OBJECTIVE:

To review the literature documenting the association of various antimicrobial medications with the development of renal tubular acidosis (RTA).

DATA SOURCES:

A search of the English literature via MEDLINE (1966-November 2003) and International Pharmaceutical Abstracts (1970-November 2003) was conducted to identify human reports of RTA associated with various drugs from all available classes of antimicrobial agents. Major search terms included renal tubular acidosis, acidosis, antibiotics, and antimicrobials. Bibliographies of selected articles were also searched to identify additional reports of RTA.

STUDY SELECTION AND DATA EXTRACTION:

Case reports, observational studies, and experimental studies documenting the association of any antimicrobial agent with the development of RTA were included.

DATA SYNTHESIS:

Antimicrobial-associated RTA is a relatively uncommon adverse effect, with most reports involving amphotericin B, trimethoprim/sulfamethoxazole, and outdated tetracycline. These agents may induce RTA either through direct tubular toxicity or as a function of their pharmacologic action. The time course for the development of RTA varies depending on the antimicrobial utilized. In most instances, RTA is reversible; however, some patients may experience prolonged recovery after the offending agent is removed.

CONCLUSIONS:

Given that antimicrobial-associated RTA is a relatively uncommon adverse effect, review of the patient's drug regimen may reveal these agents as otherwise unrecognized causes of RTA. Likewise, underlying causes of RTA other than medications must be ruled out. Diagnosing antimicrobial-induced RTA may be difficult, given many of these agents may be used in combination and some are intrinsically nephrotoxic.
Postoperative Opiate Analgesia Requirements of Smokers and Nonsmokers
Authors: Creekmore Freddy M , Lugo Ralph A , Weiland Kevin J
Published: May 2004

BACKGROUND:

Smoking cigarettes and other forms of nicotine administration appear to blunt the perception of pain. Abrupt discontinuation of nicotine in nicotine-dependent patients appears to increase the perception of pain. The clinical importance of nicotine's effect on pain perception is not fully understood.

OBJECTIVE:

To determine whether smokers who abruptly discontinue smoking as a result of being hospitalized for coronary artery bypass graft (CABG) require more postoperative opiate analgesics than nonsmokers.

METHODS:

A retrospective review of patients who underwent a CABG was performed. Smokers (n = 20) were compared with nonsmokers (n = 69) with regard to opiate analgesic use during the first 48 hours postoperatively. The use of nonopiate sedatives was also compared between the groups.

RESULTS:

When normalized for weight and body mass index, smokers required 23% and 33%, respectively, more opiate analgesics than did nonsmokers (p = 0.027 and 0.023, respectively). The percentage of patients who received benzodiazepines postoperatively was similar in the 2 groups.

CONCLUSIONS:

In this study, smokers deprived of nicotine required a greater amount of opiates in the first 48 hours after CABG than did nonsmokers. Healthcare providers need to be aware of the potential for increased narcotic requirements among nicotine-deprived smokers. Further study is needed to determine whether nicotine replacement lessens the requirement for postoperative analgesics in smokers.
Rapid Intraoperative Immunoassay of Parathyroid Hormone and Other Hormones: A New Paradigm for Point-of-Care Testing
Authors: Sokoll Lori J , Wians Frank H , Remaley Alan T
Published: May 2004

Background: The first description of the use of a rapid assay for the measurement of intact parathyroid hormone (PTH) in patients undergoing parathyroidectomy for hyperparathyroidism was reported in 1988. Subsequent improvements in the analytical performance of the rapid intraoperative PTH assay allowed the establishment of its clinical utility in the surgical management of hyperparathyroidism. These modifications also allowed the assay to be performed in or near the operating suite.

Methods: We searched MEDLINE, using the following key words: intraoperative, rapid, quick, parathyroid hormone, hormone, and immunoassay. Relevant articles that focused on the analytical aspects and clinical utility of rapid intraoperative hormone immunoassays were selected for this review.

Content: On the basis of the positive impact that the rapid intraoperative PTH test has had on both patient outcomes and cost savings, other rapid intraoperative hormone immunoassays for the diagnosis and/or treatment of other endocrine-hormone-secreting tumors have been developed. These hormones share certain characteristics that make them suitable for use as rapid intraoperative tests, i.e., short analyte half-life and/or large analyte concentration gradient, rapid analysis time, and positive clinical utility. Initial studies with cortisol, gastrin, insulin, adrenocorticotropic hormone, and testosterone have shown promising results in preoperative localization studies and/or for assessing the effectiveness of tumor resection during surgery.

Conclusion: The emergence of these rapid intraoperative immunoassays indicates that this test format is likely to provide future opportunities to improve patient care by advances in clinical laboratory testing.
Pioglitazone Reduces Atherogenic Index of Plasma in Patients with Type 2 Diabetes
Authors: Tan Meng H , Johns Don , Glazer N Bradly
Published: May 2004

Background: Insulin resistance is often associated with increased triglyceride (TG) and decreased HDL-cholesterol (HDL-C) concentrations and increased small LDL particles. The Atherogenic Index of Plasma (AIP), defined as log(TG/HDL-C), has recently been proposed as a marker of plasma atherogenicity because it is increased in people at higher risk for coronary heart disease and is inversely correlated with LDL particle size. We studied the effect of pioglitazone, a thiazolidinedione that reduces insulin resistance, on the AIP of patients with type 2 diabetes.

Methods: The data for the analysis of AIP in this report were obtained from four randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trials. Pioglitazone was used as monotherapy in one study and in combination therapy in three studies. Fasting glucose, insulin, HDL-C, and TGs plus glycohemoglobin (HbA1C) were measured at baseline and various points during each study.

Results: Patients in this study population with type 2 diabetes had high AIP values at baseline. Pioglitazone treatment significantly decreased AIP from baseline in each of the study groups. Pioglitazone treatment groups had a significantly lower AIP compared with their respective placebo controls. Finally, AIP was inversely and significantly correlated with measures of insulin sensitivity, such as the homeostasis model assessment and quantitative insulin sensitivity check index. In contrast, AIP was not significantly correlated with HbA1C.

Conclusions: Pioglitazone reduced AIP when used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin. AIP was inversely correlated with measures of insulin sensitivity.
Brands as Beacons: A New Source of Loyalty to Multiproduct Firms
Authors: Anand Bharat N. , Shachar Ron
Published: May 2004

This study provides evidence that a multiproduct firm's portfolio of products affects consumer purchase decisions about each of the firm's products. The authors present a theory that explains this empirical regularity. The theory involves revising the information set of consumers to include the profile of multiproduct firms. The authors show that revision of the information set in this way introduces a new source of consumer loyalty and explains interesting empirical regularities in consumer behavior. For example, consumers are loyal to a multiproduct firm even when it does not offer a product that matches their preferences better than a product of competing firms. The authors estimate the model and test its implications using panel data on television viewing choices. The estimated model also allows for state-dependence parameters and unobserved heterogeneity. The empirical results support the model and its implications. The model offers a parsimonious framework for brand-extension strategies and maps new channels of spillovers in a multiproduct firm.
The Effect of Conceptual and Perceptual Fluency on Brand Evaluation
Authors: Lee Angela Y. , Labroo Aparna A.
Published: May 2004

According to the processing fluency model, advertising exposures enhance the ease with which consumers recognize and process a brand. In turn, this increased perceptual fluency leads to consumers having more favorable attitudes toward the brand. The authors extend the processing fluency model to examine the effect of conceptual fluency on attitudes. In three experiments, the authors show that when a target comes to mind more readily and becomes conceptually fluent, as when it is presented in a predictive context (e.g., a bottle of beer featured in an advertisement that shows a man entering a bar) or when it is primed by a related construct (e.g., an image of ketchup following an advertisement of mayonnaise), participants develop more favorable attitudes toward the target. It is believed that positive valence of fluent processing underlies these processing-fluency effects. When conceptual fluency is associated with negative valence (e.g., hair conditioner primed by a lice-killing shampoo), the authors observe less favorable attitudes.