bluuebunny/crossref_metadata_2025 huggingface dataset:
The Transmembrane Helix of the
Escherichia coli
Division Protein FtsI Localizes to the Septal Ring
Authors: Wissel Mark C. , Wendt Jennifer L. , Mitchell Calista J. , Weiss David S.
Published: December 2004

FtsI (also called PBP3) of
Escherichia coli
is a transpeptidase required for synthesis of peptidoglycan in the division septum and is one of about a dozen division proteins that localize to the septal ring. FtsI comprises a short amino-terminal cytoplasmic domain, a single transmembrane helix (TMH), and a large periplasmic domain that encodes the catalytic (transpeptidase) activity. We show here that a 26-amino-acid fragment of FtsI is sufficient to direct green fluorescent protein to the septal ring in cells depleted of wild-type FtsI. This fragment extends from W22 to V47 and corresponds to the TMH. This is a remarkable finding because it is usual for a TMH to target a protein to a site more specific than the membrane. Alanine-scanning mutagenesis of the TMH identified several residues important for septal localization. These residues cluster on one side of an alpha-helix, which we propose interacts directly with another division protein to recruit FtsI to the septal ring.
Fate of Predator and Prey Proteins during Growth of
Bdellovibrio bacteriovorus
on
Escherichia coli
and
Pseudomonas syringae
Prey
Authors: Barel Gilli , Sirota Alexandra , Volpin Hanne , Jurkevitch Edouard
Published: December 2004

A two-dimensional electrophoretic analysis of protein distribution followed by identification of selected proteins by mass spectrometry was performed on fresh bdellovibrio cultures containing attack phase cells of the predatory bacterium
Bdellovibrio bacteriovorus
strain 109J-1 and the remains of an
Escherichia coli
or a
Pseudomonas syringae
pv.
tomato
prey. Cleavage of the peptidoglycan-associated outer membrane proteins (OMPs) OmpA in
E. coli
and OprF in
P. syringae
occurred in both prey. The tryptic peptides obtained from the cleavage products of OmpA and OprF were all located within the 19-kDa pronase-resistant N-terminal parts of the corresponding proteins. The predator cell fraction was separated from the prey ghosts in fresh bdellovibrio cultures by centrifugation on a Percoll-sucrose cushion. Proteins from each fraction were separated by two-dimensional electrophoresis and identified by mass spectrometric analysis. As no prey OMP could be detected in the predator cell fraction, it was concluded that prey OMPs are not transferred to the predator, as had been suggested previously. However, a protein from the predator was found bound to ghost cell envelopes. This protein may correspond to a protein earlier suggested to be associated with the prey outer or cytoplasmic membranes. Along with recently described polypeptides from
B. bacteriovorus
strains 100 and 114, it forms a new family of putative outer membrane proteins.
New Temperature-Sensitive Alleles of
ftsZ
in
Escherichia coli
Authors: Addinall Stephen G. , Small Elaine , Whitaker Duncan , Sturrock Shane , Donachie William D. , Khattar Medhat M.
Published: December 2004

We isolated five new temperature-sensitive alleles of the essential cell division gene
ftsZ
in
Escherichia coli
, using P1-mediated, localized mutagenesis. The five resulting single amino acid changes (Gly
109
→Ser
109
for
ftsZ6460
, Ala
129
→Thr
129
for
ftsZ972
, Val
157
→Met
157
for
ftsZ2066
, Pro
203
→Leu
203
for
ftsZ9124
, and Ala
239
→Val
239
for
ftsZ2863
) are distributed throughout the FtsZ core region, and all confer a lethal cell division block at the nonpermissive temperature of 42°C. In each case the division block is associated with loss of Z-ring formation such that fewer than 2% of cells show Z rings at 42°C. The
ftsZ9124
and
ftsZ6460
mutations are of particular interest since both result in abnormal Z-ring formation at 30°C and therefore cause significant defects in FtsZ polymerization, even at the permissive temperature. Neither purified FtsZ9124 nor purified FtsZ6460 exhibited polymerization when it was assayed by light scattering or electron microscopy, even in the presence of calcium or DEAE-dextran. Hence, both mutations also cause defects in FtsZ polymerization in vitro. Interestingly, FtsZ9124 has detectable GTPase activity, although the activity is significantly reduced compared to that of the wild-type FtsZ protein. We demonstrate here that unlike expression of
ftsZ84
, multicopy expression of the
ftsZ6460
,
ftsZ972
, and
ftsZ9124
alleles does not complement the respective lethalities at the nonpermissive temperature. In addition, all five new mutant FtsZ proteins are stable at 42°C. Therefore, the novel isolates carrying single
ftsZ
(Ts) point mutations, which are the only such strains obtained since isolation of the classical
ftsZ84
mutation, offer significant opportunities for further genetic characterization of FtsZ and its role in cell division.
Depolymerization of β-1,6-N-Acetyl-d-Glucosamine Disrupts the Integrity of Diverse Bacterial Biofilms
Authors: Itoh Yoshikane , Wang Xin , Hinnebusch B. Joseph , Preston James F. , Romeo Tony
Published: December 2004

Polymeric β-1,6-N-acetyl-d-glucosamine (poly-β-1,6-GlcNAc) has been implicated as anEscherichia coliandStaphylococcus epidermidisbiofilm adhesin, the formation of which requires thepgaABCDandicaABCDloci, respectively. Enzymatic hydrolysis of poly-β-1,6-GlcNAc, demonstrated for the first time by chromatography and mass spectrometry, disrupts biofilm formation by these species and byYersinia pestisandPseudomonas fluorescens, which possesspgaABCDhomologues.
Natural Isolates of
Salmonella enterica
Serovar Dublin Carry a Single
nadA
Missense Mutation
Authors: Bergthorsson Ulfar , Roth John R.
Published: December 2004

Nicotinic acid is required by most isolates of
Salmonella enterica
(serovar Dublin), a pathogen of cattle. A single
nadA
missense mutation causes the nutritional requirement of all serovar Dublin isolates tested. Models for persistence of this allele are tested and discussed.
ThepbgPEoperon inPhotorhabdus luminescensIs Required for Pathogenicity and Symbiosis
Authors: Bennett H. P. J. , Clarke D. J.
Published: December 2004

Photorhabdusis a genus of gram-negativeEnterobacteriaceaethat is pathogenic to insect larvae while also maintaining a mutualistic relationship with nematodes from the familyHeterorhabditis, where the bacteria occupy the gut of the infective juvenile (IJ) stage of the nematode. In this study we describe the identification and characterization of a mutation in thepbgE1gene ofPhotorhabdus luminescensTT01, predicted to be the fifth gene in thepbgPEoperon. We show that this mutant, BMM305, is strongly attenuated in virulence against larvae of the greater wax moth,Galleria mellonella, and we report that BMM305 is more sensitive to the cationic antimicrobial peptide, polymyxin B, and growth in mildly acidic pH than the parental strain ofP. luminescens. Moreover, we also show that the lipopolysaccharide (LPS) present on the surface of BMM305 does not appear to contain any O antigen. Complementation studies reveal that the increased sensitivity to polymyxin B and growth in mildly acidic pH can be rescued by the intransexpression ofpbgE1, while the defects in O-antigen assembly and pathogenicity require the intransexpression ofpbgE1and the downstream genespbgE2andpbgE3. Finally, we show that BMM305 is defective in symbiosis as this mutant is unable to colonize the gut of the IJ stage of the nematode. Therefore, we conclude that thepbgPEoperon is required for both pathogenicity and symbiosis inP. luminescens.
The Epstein-Barr Virus Replication Protein BBLF2/3 Provides an Origin-Tethering Function through Interaction with the Zinc Finger DNA Binding Protein ZBRK1 and the KAP-1 Corepressor
Authors: Liao Gangling , Huang Jian , Fixman Elizabeth D. , Hayward S. Diane
Published: December 2004

Herpesviruses encode a set of core proteins essential for lytic replication of their genomes. Three of these proteins form a tripartite helix-primase complex that, in the case of Epstein-Barr virus (EBV), consists of the helicase BBLF4, the primase BSLF1, and the linker protein BBLF2/3. BBLF2/3 and its homologs in the other herpesviruses remain relatively poorly characterized. To better understand the contribution to replication made by BBLF2/3, a yeast two-hybrid screen was performed with BBLF2/3 as the bait protein. This screen identified as interactors a number of cell replication-related proteins such as DNA polymerase beta and subunits of DNA polymerase delta along with the EBV-encoded DNase BGLF5. The screen also identified the DNA binding zinc finger protein ZBRK1 and the ZBRK1 corepressor KAP-1 as BBLF2/3 interactors. Interaction between BBLF2/3 and ZBRK1 and KAP-1 was confirmed in coimmunoprecipitation assays. A binding site for ZBRK1 in the EBV oriLyt enhancer was identified by electrophoretic mobility shift assay. ZBRK1, KAP-1, and the ZBRK1 binding protein BRCA1 were shown by indirect immunofluorescence to be present in replication compartments in lytically induced D98-HR1 cells, and additionally, chromatin immunoprecipitation assays determined that these proteins associated with oriLyt DNA. Replication of an oriLyt plasmid and a variant oriLyt (ΔZBRK1) plasmid was examined in lytically induced D98-HR1 cells. Exogenous ZBRK1, KAP-1, or BRCA1 increased the efficiency of oriLyt replication, while deletion of the ZBRK1 binding site impaired replication. These experiments identify ZBRK1 as another cell protein that, through BBLF2/3, provides a tethering point on oriLyt for the EBV replication complex. The data also suggest that BBLF2/3 may serve as a contact interface for cell proteins involved in replication of EBV oriLyt.
Mitochondrial glycerol-3-phosphate acyltransferase-1 directs the metabolic fate of exogenous fatty acids in hepatocytes
Authors: Lewin Tal M. , Wang Shuli , Nagle Cynthia A. , Van Horn Cynthia G. , Coleman Rosalind A.
Published: December 2004

Because excess triacylglycerol (TAG) in nonadipose tissues is closely associated with the development of insulin resistance, interest has increased in the metabolism of long-chain acyl-CoAs toward β-oxidation or the synthesis and storage of TAG. To learn whether a mitochondrial isoform of glycerol-3-phosphate acyltransferase (mtGPAT1) competes with carnitine palmitoyltransferase I (CPT I) for acyl-CoAs and whether it contributes to the formation of TAG, we overexpressed rat mtGPAT1 13-fold in primary hepatocytes obtained from fasted rats. When 100, 250, or 750 μM oleate was present, both TAG mass and the incorporation of [14C]oleate into TAG increased more than twofold in hepatocytes overexpressing mtGPAT1 compared with vector controls. Although the incorporation of [14C]oleate into CO2and acid-soluble metabolites increased with increasing amounts of oleate in the media, these metabolites were ∼40% lower in the Ad-mtGPAT1 infected cells, consistent with competition for acyl-CoAs between CPT I and mtGPAT1. A 50–60% decrease was also observed in [14C]oleate incorporation into cholesteryl ester. With increasing amounts of exogenous oleate, [14C]TAG secretion increased appropriately in vector control-infected hepatocytes, suggesting that the machinery for VLDL-TAG biogenesis and secretion was unaffected. Despite the marked increases in TAG synthesis and storage in the Ad-mtGPAT1 cells, however, the Ad-mtGPAT1 cells secreted the same amount of [14C]TAG as the vector control cells. Thus, in isolated hepatocytes, mtGPAT1 may synthesize a cytosolic pool of TAG that cannot be secreted.
High glucose-induced oxidative stress inhibits Na+/glucose cotransporter activity in renal proximal tubule cells
Authors: Han Ho Jae , Lee Yun Jung , Park Su Hyung , Lee Jang Hern , Taub Mary
Published: December 2004

Oxidative stress plays an important role in the pathogenesis of renal diseases such as diabetic nephropathy. The metabolism of excessive intracellular glucose may involve a number of processes. One consequence of excessive intracellular glucose levels is an increased rate of oxidative phosphorylation under hyperglycemic conditions, whereas another consequence is an increase in the metabolism of glucose to sorbitol by aldose reductase. In addition, hyperglycemia may result in the activation of NADPH oxidase, the production of superoxide anion, and hydrogen peroxide (H2O2). In this report, we investigate the mechanisms responsible for the H2O2production that occurs as the consequence of hyperglycemia and the effect of H2O2on the activity of the Na+/glucose cotransport system (SGLT) in primary cultures of renal proximal tubule cells (PTCs). When primary PTCs were cultured in the presence of high glucose, one consequence was that the Na+/glucose cotransport system was inhibited, as indicated by uptake studies utilizing α-methyl-d-glucoside (α-MG), a nonmetabolizable analog of d-glucose. Pretreatment of the cultures with either 1) aminoguanidine or pyridoxamine [inhibitors of the accumulation of advanced glycation end products (AGEs)], 2) rotenone (an inhibitor of the mitochondrial electron transport chain), or 3) apocynin or diphenylene iodonium (DPI; inhibitors of NADPH oxidase) blocked the observed changes that occurred as a consequence of the incubation of the PTCs with high glucose. Included among these changes were the observed increase in H2O2levels, as well as an increase in lipid peroxide production, and a decrease both in the activity of catalase and in the level of glutathione (GSH), endogenous antioxidants. The high glucose-induced decrease in the level of the Na+/glucose cotransporter was similarly prevented by either aminoguanidine, rotenone, or apocynin. Thus the inhibitory effect of high glucose on both the level of the Na+/glucose cotransport system and the activity of the Na+/glucose cotransport system can be explained, at least in part, as being due to the effects of the H2O2, the consequent formation of AGEs, the increase in mitochondrial metabolism, and in NADPH oxidase activity in the PTCs. Other related changes observed in the PTCs that could be reversed by treatment with either aminoguanidine, pyridoxamine, rotenone, apocynin, or DPI included an increase in transforming growth factor-β1secretion and the activation of the NF-κB signal transduction pathway.
A procedure for generating infinite series identities
Authors: Ruffa Anthony A.
Published: December 2004

A procedure for generating infinite series identities makes use of the generalized method of exhaustion by analytically evaluating the inner series of the resulting double summation. Identities are generated involving both elementary and special functions. Infinite sums of special functions include those of the gamma and polygamma functions, the Hurwitz Zeta function, the polygamma function, the Gauss hypergeometric function, and the
Lerch transcendent. The procedure can be automated with Mathematica (or equivalent software).
Multiplicity results for asymmetric boundary value problems with indefinite weights
Authors: Dalbono Francesca
Published: December 2004

We prove existence and multiplicity of solutions, with prescribed nodal properties, to a boundary value problem of the form u″ + f(t, u) = 0, u(0) = u(T) = 0. The nonlinearity is supposed to satisfy asymmetric, asymptotically linear assumptions involving indefinite weights. We first study some auxiliary half‐linear, two‐weighted problems for which an eigenvalue theory holds. Multiplicity is ensured by assumptions expressed in terms of weighted eigenvalues. The proof is developed in the framework of topological methods and is based on some relations between rotation numbers and weighted eigenvalues.
Global existence and energy decay of solutions to the Cauchy problem for a wave equation with a weakly nonlinear dissipation
Authors: Benaissa Abbès , Mokeddem Soufiane
Published: December 2004

We prove the global existence and study decay properties of the solutions to the wave equation
with a weak nonlinear dissipative term by constructing a stable set in H1(ℝn).
Study of Poligar Violence in Late 18th Century Tamil Country in South India
Authors: Seylon Raman N.
Published: December 2004

This paper is written in an effort to understand the nature and the causes behind the brutal acts of violence unleashed by the poligar military households of South India. It particularly focuses on the poligar rajah Kattabomma Nayakar, who has, since the early 1950s, assumed the role of an ancestor figure of Tamil nationalism. I have relied mainly on colonial archival materials and a few folkloric accounts as my sources and used the anthropological insights of F. G. Baily, Victor Turner, and Steward Gordon in their studies of the political conflicts. In this paper, I do not so much question the reliability and accuracy of the colonial materials. However, I examine their interpretations and the motivations that many historians seem to have overlooked. This is particularly so in the case of poligar led violence as its true causes are often misrepresented and misunderstood in colonial records. We could even say that there is a vested colonial interest in misunderstanding these acts of violence, which are often used as citations to justify the subsequent colonial policies directed not only against the poligars but also against the entire the civil population of the Tamil country. In this paper, I argue that the poligars such as Kattabomma Nayakar were rebels with a cause. They saw themselves indulging in most cases in activities that stood within the bounds of the poligars' traditional mode of conduct. Further, I will also demonstrate how the political violence is intimately linked with political mobility and state formation in pre modern South India. A wider applicability of the results of this study to other parts of South Asia is useful in illuminating the causes and the nature of the political conflicts in various cross cultural settings.
Comparative Investigation of the Pharmacokinetics of Bosentan in Caucasian and Japanese Healthy Subjects
Authors: van Giersbergen Paul L. M. , Dingemanse Jasper
Published: December 2004

Bosentan is a dual endothelin receptor antagonist in development for the treatment of pulmonary arterial hypertension in Japan, whereas it is registered for this indication in Europe and the United States. The present study was conducted to compare the pharmacokinetics of bosentan in Caucasian and Japanese subjects. In a double‐blind, placebo‐controlled, ascending single‐dose, 5‐way crossover study, 10 healthy Caucasian and 10 Japanese subjects (1:1 male/female ratio) received single doses of 31.25, 62.5, 125, and 250 mg of bosentan or placebo. Pharmacokinetic profiles of bosentan and its pharmacologically active hydroxy metabolite, Ro 48–5033, were determined after each dose of bosentan. The pharmacokinetics of bosentan were similar and dose proportional in both ethnic groups. However, peak plasma concentration values of Ro 48–5033 were significantly greater in Japanese subjects (P < .05). This difference could not be explained by the lower body weight of the Japanese subjects. Females in both groups tended to have higher exposure to both bosentan and Ro 48–5033 than males. The results suggest that, based on pharmacokinetic grounds, no dose adjustment of bosentan is necessary when used to treat Japanese patients in comparison to Caucasian patients.
CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma
Authors: Trudel Suzanne , Li Zhi Hua , Wei Ellen , Wiesmann Marion , Chang Hong , Chen Christine , Reece Donna , Heise Carla , Stewart A. Keith
Published: December 2004

The t(4;14) translocation that occurs uniquely in a subset (15%) of patients with multiple myeloma (MM) results in the ectopic expression of the receptor tyrosine kinase (RTK), fibroblast growth factor receptor 3 (FGFR3). Inhibition of activated FGFR3 in MM cells induces apoptosis, validating FGFR3 as a therapeutic target in t(4;14) MM and encouraging the clinical development of FGFR3 inhibitors for the treatment of these patients, who have a poor prognosis. We describe here the characterization of a novel, small-molecule inhibitor of class III, IV, and V RTKs, CHIR-258, as an inhibitor of FGFR3. CHIR-258 potently inhibits FGFR3 with an inhibitory concentration of 50% (IC50) of 5 nM in in vitro kinase assays and selectively inhibited the growth of B9 cells and human myeloma cell lines expressing wild-type (WT) or activated mutant FGFR3. In responsive cell lines, CHIR-258 induced cytostatic and cytotoxic effects. Importantly, addition of interleukin 6 (IL-6) or insulin growth factor 1 (IGF-1) or coculture on stroma did not confer resistance to CHIR-258. In primary myeloma cells from t(4;14) patients, CHIR-258 inhibited downstream extracellular signal-regulated kinase (ERK) 1/2 phosphorylation with an associated cytotoxic response. Finally, therapeutic efficacy of CHIR-258 was demonstrated in a xenograft mouse model of FGFR3 MM. These studies support the clinical evaluation of CHIR-258 in MM.
Decision-Making About Tamoxifen in Women at High Risk for Breast Cancer: Clinical and Psychological Factors
Authors: Bober Sharon L. , Hoke Lizbeth A. , Duda Rosemary B. , Regan Meredith M. , Tung Nadine M.
Published: December 2004

Purpose

To explore the health-related and psychological factors that influence decision making about tamoxifen (Nolvadex; AstraZeneca, Waltham, MA) chemoprevention in women at increased risk for developing breast cancer.

Methods

This study involves the assessment of 129 women eligible to take tamoxifen following cancer-risk counseling. Treatment decision and decision satisfaction were measured at 2 and 4 months following counseling. Health-related factors included physician recommendation, personal and family-related health history, and concern about side effects. Psychological factors included breast cancer–related anxiety, risk perception, and depression.

Results

At 2 months’ follow-up, 44% of participants declined tamoxifen treatment. This number increased to 49% at 4 months. Personal and family health history were not related to the decision, but history of abnormal biopsy did predict tamoxifen use. Physician recommendation was highly correlated with treatment decision. Concern about side effects was related to the decision to decline treatment. Breast cancer–related anxiety and heightened risk perception were associated with the decision to take tamoxifen. However, anxiety and psychological distress were also negatively related to treatment satisfaction.

Conclusion

Decision-making about tamoxifen is complex, and many eligible women decline treatment or remain undecided. Findings call for further educational follow-up with high-risk women after they undergo initial counseling. Factors related to misperceptions of risk and side effects, as well as psychological distress, may be particularly important targets for intervention.
Intratumoral Injection of Dendritic Cells Engineered to Secrete Interleukin-12 by Recombinant Adenovirus in Patients With Metastatic Gastrointestinal Carcinomas
Authors: Mazzolini Guillermo , Alfaro Carlos , Sangro Bruno , Feijoó Esperanza , Ruiz Juan , Benito Alberto , Tirapu Iñigo , Arina Ainhoa , Sola Josu , Herraiz Maite , Lucena Felipe , Olagüe Cristina , Subtil José , Quiroga Jorge , Herrero Ignacio , Sádaba Belén , Bendandi Maurizio , Qian Cheng , Prieto Jesús , Melero Ignacio
Published: December 2004

Purpose

To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity.

Patients and Methods

Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 × 106to 50 × 106cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals.

Results

Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment.

Conclusion

Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.
Silymarin Protects Pancreatic β-Cells against Cytokine-Mediated Toxicity: Implication of c-Jun NH2-Terminal Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Pathways
Authors: Matsuda Takeru , Ferreri Kevin , Todorov Ivan , Kuroda Yoshikazu , Smith Craig V. , Kandeel Fouad , Mullen Yoko
Published: December 2004

Silymarin is a polyphenolic flavonoid that has a strong antioxidant activity and exhibits anticarcinogenic, antiinflammatory, and cytoprotective effects. Although its hepatoprotective effect has been well documented, the effect of silymarin on pancreatic β-cells is largely unknown. In this study, the effect of silymarin on IL-1β and/or interferon (IFN)-γ-induced β-cell damage was investigated using RINm5F cells and human islets. IL-1β and/or IFN-γ induced cell death in a time-dependent manner in RINm5F cells. The time-dependent increase in cytokine-induced cell death appeared to correlate with the time-dependent nitric oxide (NO) production. Silymarin dose-dependently inhibited both cytokine-induced NO production and cell death in RINm5F cells. Treatment of human islets with a combination of IL-1β and IFN-γ (IL-1β+IFN-γ), for 48 h and 5 d, resulted in an increase of NO production and the impairment of glucose-stimulated insulin secretion, respectively. Silymarin prevented IL-1β+IFN-γ-induced NO production and β-cell dysfunction in human islets. These cytoprotective effects of silymarin appeared to be mediated through the suppression of c-Jun NH2-terminal kinase and Janus kinase/signal transducer and activator of transcription pathways. Our data show a direct cytoprotective effect of silymarin in pancreatic β-cells and suggest that silymarin may be therapeutically beneficial for type 1 diabetes.
Protective effect of propyl gallate against myocardial oxidative stress-induced injury in rat
Authors: Karthikeyan K , Bai B R Sarala , Gauthaman K , Devaraj S Niranjali
Published: December 2004

This study was designed to investigate the effect of chronic administration of propyl gallate on myocardial oxidative stress-induced injury. Propyl gallate was administered orally to Wistar albino rats (150–200 g) in three different doses, by gastric gavage (250 mg kg−1 (P1), 500 mg kg−1 (P2) and 750 mg kg−1 (P3)), 6 days a week for 5 weeks. At the end of this period, all the rats, except the normal untreated rats that served as the control group, were administered isoproterenol (ISO), 85 mg kg−1 subcutaneously, for 2 consecutive days to induce myocardial injury. After 48 h, rats (n = 6 per group) were anaesthetized with anaesthetic ether, sacrificed and the hearts were harvested for the estimation of thiobarbituric acid reactive substances (TBARS), endogenous antioxidants (reduced glutathione (GSH), superoxide dismutase (SOD) and catalase) and for the assessment of histological changes. In the P2 BL group (BL = baseline), there was a significant (P < 0.001) rise in baseline TBARS and SOD when compared with the saline-treated group, while no such changes were observed in the other baseline-treated groups. However, there was a significant (P < 0.001) increase in TBARS and endogenous anti-oxidants (GSH, SOD and catalase) in the P2 ISO and P3 ISO groups, when the hearts were subjected to in-vivo myocardial oxidative stress-induced injury. We observed no such changes in the P1 ISO group. This study showed that propyl gallate modulates the levels of endogenous antioxidants present at the myocardial site. Whether these modifications are a result of direct interference at this site or a remote effect is not immediately clear. In conclusion, from the results it could be stated that chronic administration of 500 mg kg−1 of propyl gallate offers significant protection against myocardial oxidative stress-induced injury.
Recombinant human lactoferrin prevents NSAID-induced intestinal bleeding in rodents
Authors: Dial Elizabeth J , Dohrman Amanda J , Romero Jim J , Lichtenberger Lenard M
Published: December 2004

Recombinant human lactoferrin (RHLF) was tested for its ability to prevent non-steroidal anti-inflammatory drug (NSAID)-induced intestinal injury in rats and mice. Acute and chronic models using indometacin, naproxen and diclofenac were used. Measurements were made of intestinal bleeding and inflammation. Orally administered RHLF was effective at preventing acute NSAID-induced increases in gut bleeding and myeloperoxidase activity. Oral RHLF was also effective at blocking some chronic manifestations of indometacin usage. Protection by RHLF of the intestinal tract from NSAIDs appears to be linked to attenuation of neutrophil migration to the intestine, and is independent of prostaglandins and nitric oxide. RHLF does not bind to the NSAID or interfere with the NSAID biological activity. We conclude that orally administered RHLF is effective at preventing NSAID-induced intestinal injury in rodents and should be investigated for this potential therapeutic use in man.
Protection of mitochondrial system by Hippophae rhamnoides L. against radiation-induced oxidative damage in mice
Authors: Goel Harish Chandra , Gupta Damodar , Gupta Shobha , Garg A P , Bala Madhu
Published: December 2004

The whole extract of the fresh berries of Hippophae rhamnoides L. (RH−3), which has been reported to provide protection to whole mice, various tissues, cells and cell organelles against lethal irradiation, was further investigated for its effects on mitochondria isolated from mouse liver. Superoxide anion, reduced (GSH) and oxidized glutathione (GSSG) levels, NADH-ubiquinone oxidoreductase (complex I), NADH-cytochrome c oxidoreductase (complex I/II), succinate-cytochrome c oxidoreductase (complex II/III), mitochondrial membrane potential (MMP), lipid peroxidation (LPx) and protein oxidation (PO) were determined for RH-3-mediated radioprotective manifestation. Pre-irradiation treatment of mice with RH-3 (30 mg kg−1, i.p.; single dose; −30 min) significantly inhibited the radiation-induced increase in superoxide anions, GSSG, thiobarbituric acid reactive substances (TBARS), complex I, complex I/III activity and MMP maximally at 4 h (P < 0.05). This treatment inhibited the oxidation of proteins (P < 0.05) at all the time periods studied here. This study suggests that pre-irradiation treatment of mice with RH-3 protects the functional integrity of mitochondria from radiation-induced oxidative stress.
Tympanal travelling waves in migratory locusts
Authors: Windmill James F. C. , Göpfert Martin C. , Robert Daniel
Published: December 2004

Hearing animals, including many vertebrates and insects, have the capacity to analyse the frequency composition of sound. In mammals, frequency analysis relies on the mechanical response of the basilar membrane in the cochlear duct. These vibrations take the form of a slow vibrational wave propagating along the basilar membrane from base to apex. Known as von Békésy's travelling wave, this wave displays amplitude maxima at frequency-specific locations along the basilar membrane, providing a spatial map of the frequency of sound - a tonotopy. In their structure, insect auditory systems may not be as sophisticated as those of mammals, yet some are known to perform sound frequency analysis. In the desert locust, this analysis arises from the mechanical properties of the tympanal membrane. In effect, the spatial decomposition of incident sound into discrete frequency components involves a tympanal travelling wave that funnels mechanical energy to specific tympanal locations, where distinct groups of mechanoreceptor neurones project. Notably, observed tympanal deflections differ from those predicted by drum theory. Although phenomenologically equivalent, von Békésy's and the locust's waves differ in their physical implementation. von Békésy's wave is born from interactions between the anisotropic basilar membrane and the surrounding incompressible fluids, whereas the locust's wave rides on an anisotropic membrane suspended in air. The locust's ear thus combines in one structure the functions of sound reception and frequency decomposition.
Extramuscular myofascial force transmission forin siturat medial gastrocnemius and plantaris muscles in progressive stages of dissection
Authors: Rijkelijkhuizen J. M. , Baan G. C. , de Haan A. , de Ruiter C. J. , Huijing P. A.
Published: December 2004

The aim of this study was to establish the extent of extramuscular myofascial force transmission for dissected rat medial gastrocnemius (GM) and plantaris (PL) muscles. Initially, this was done with GM still connected to extramuscular connective tissue (general fascia, neuro-vascular tract and compartmental fascia). Neighbouring muscles were also connected to these tissues. In a later stage, it was dissected progressively until finally a fully dissected in situ GM was obtained, for which the neuro-vascular tract (i.e. the nerves, bloodvessels and the surrounding connective tissue)was the only extramuscular tissue left intact. Force of GM was measured not only at its distal tendon in progressive stages of dissection, but also at its dissected proximal tendon. In the stage where GM was still connected to extramuscular tissues, the experiments showed that up to 40.5±5.9%(mean ± s.e.m.) of the force exerted by the neighbouring PL muscle was transmitted onto the calcaneal bone, even when the PL tendon was not connected to this bone. After distal PL-tenotomy, a difference between proximally and distally measured forces of GM constituted evidence for myofascial force transmission. In the fully dissected in situ GM muscle, no relevant myofascial force transmission occurred in the reference position (the position of the GM origin corresponding to a knee angle of 120°). However, some myofascial force transmission occurred when the relative position of the origin of the fully dissected GM muscle was changed with respect to the neuro-vascular tract.
Burrow air phase maintenance and respiration by the mudskipperScartelaos histophorus(Gobiidae: Oxudercinae)
Authors: Lee Heather J. , Martinez Callie A. , Hertzberg Katherine J. , Hamilton Amy L. , Graham Jeffrey B.
Published: December 2004

A laboratory burrow and mudflat system was used to examine aspects of burrow air-phase maintenance and utilization by the amphibious mudskipper Scartelaos histophorus. While confined to its burrow during simulated`high tide', this species respires both aquatically and aerially, in the latter case utilizing an air phase it had established by transporting air into the burrow during simulated `low tide'. Over the course of `high-tide'confinement, burrow-water PO2 declines, making the air phase more important for respiration; the burrow-water O2tension eliciting air-phase respiration is 4.8±0.2 kPa. At `low tide',when the fish has access to air, it deposits new air in the air phase by transporting gulps into the burrow and releasing them. Observed air-deposition rates for both males and females were 12.3±4.5 trips h-1. All of the fish tested (N=8 individuals + 2 pairs) deposited air and responded to experimental air-phase withdrawal by replacing the air (72 of 74 tests, 97.3%). Also, repeated tests with one fish showed that experimental reduction of the air-phase PO2 by mixing with N2 elicited a gas-expelling behavior at O2 levels less than 10.3 kPa. At O2 levels greater than 10.3 kPa, the fish left the air phase intact and added to it by depositing surface air.
Weak and strong priming cues in bumblebee contextual learning
Authors: Dale Kyran , Harland Duane P. , Manning-Jones Adam , Collett Thomas S.
Published: December 2004

Bees have the flexibility to modulate their response to a visual stimulus according to the context in which the visual stimulus is seen. They readily learn that in one context a yellow target, but not a blue one, should be approached to reach sucrose and that in another context blue, but not yellow,leads to sucrose. Here we contrast the bumblebee's ability to use two types of contextual or priming cue in deciding which of two coloured targets to approach. Bumblebees could perform this task well when the pairs of colours to be discriminated were in two different places, so that the cues associated with each place indicated whether the bees should select a blue or a yellow target. In this case the priming cues were presented concurrently with the rewarded stimuli. Priming cues, which occur a little earlier than a rewarded stimulus, seem less powerful in their ability to bias a bee's choice of rewarded stimulus.

We tried with a variety of methods to train bees to use a priming colour to indicate which of two colours should be approached a few seconds later. Our only success with such sequential priming cues was when each pair of rewarded and unrewarded colours could be distinguished by additional spatial cues. Bees were trained to choose a blue-black checkerboard over a yellow-black checkerboard, after viewing a yellow priming cue, and to choose a uniform yellow target over a uniform blue one, after viewing a blue priming cue. They performed this task almost without error. To see whether bees had associated each rewarded stimulus with the relevant sequential priming cue, bees were tested with a choice between the two rewarded stimuli (the yellow target and the blue-black checkerboard). The bees' choice was biased towards the blue-black checkerboard, when the preceding priming cue was yellow, and towards the yellow target, when the priming cue was blue. We suppose that the experiment works because the presence or absence of the checkerboard provides an additional distinguishing spatial cue that can be linked to and reinforce the sequential one. Under natural conditions, as when bees follow routes,there will normally be such a synergy between spatial and sequential cues.
Prevalence of oesophagitis in patients with persistent upper respiratory symptoms
Authors: Catalano F. , Terminella C. , Grillo C. , Biondi S. , Zappalà M. , Bentivegna C.
Published: December 2004

A growing body of evidence suggests that a variety of upper respiratory symptoms (URS) are associated with gastro-oesophageal reflux (GORD). The aim of this study was to determine the prevalence of endoscopic erosive, and non-erosive, oesophagitis among patients complaining of persistent URS, in the absence of typical GORD symptoms, and to compare them with a comparison group of similar age. A group of 110 patients aged 18–75, presenting with persistent URS with no suspicion of GORD symptoms, underwent upper flexible endoscopy, with biopsy sampling for histology, and was compared with a group of 117 patients of similar age undergoing endoscopy for reasons other than GORD. Patients affected with upper airway disorders, such as posterior laryngitis, chronic sinusitis and vocal fold nodules, had a significantly higher prevalence of oesophagitis of varying degrees (31 per cent) compared to the comparison population(15.4 per cent) (p < 0.01). These data suggest that in many patients with chronic URS occult gastro-oesophageal diseases are present.
Dual-probe 24-hour ambulatory pH monitoring for diagnosis of laryngopharyngeal reflux
Authors: Issing W.J. , Karkos P.D. , Perreas K. , Folwaczny C. , Reichel O.
Published: December 2004

Background: Patients with gastroesophageal reflux disease may suffer from a variety of symptoms from the upper aerodigestive tract. The objective of this study was to determine the impact of dual-probe 24-hr pH monitoring in the diagnosis of reflux-related otolaryngological disorders.

Methods: Twenty-two patients with symptoms such as chronic cough, globus pharyngeus, heartburn,dysphonia and burning sensation of the tongue underwent a complete ear, nose and throat examination, 24-hr dual-probe pH monitoring, and oesophago-gastro-duodenoscopy.

Results: pH monitoring revealed gastroesophageal (distal) reflux in all patients and pharyngeal (proximal) reflux in 21 patients. Treatment consisted of a proton pump inhibitor (esomeprazole). Within 4 weeks 68 per cent of patients had no laryngopharyngeal symptoms; within 8 weeks 95 per cent of patients were symptom-free.

Conclusions: Patients with atypical reflux symptoms such as hoarseness, globus sensation or throat-clearing responded well to anti-reflux treatment.
Efficacy and systemic tolerability of mometasone furoate and betamethasone sodium phosphate
Authors: Patel Rajan S. , Shaw Steve R. , Wallace A. Michael , McGarry Gerald W.
Published: December 2004

This study evaluates the efficacy and systemic tolerability of licensed doses of mometasone furoate (Nasonex®) and betamethasone sodium phosphate (Betnesol®) in allergic chronic rhinosinusitis patients. It also assesses the diagnostic accuracy of morning salivary cortisol (MSC) concentrations to screen for adrenal suppression inthese patients.

Forty-eight patients were prospectively randomized to two treatment limbs. Symptom scores and adrenal function assessments were performed immediately prior to commencement and at the end of treatment.

One (4 per cent) mometasone furoate and 14 (58 per cent) betamethasone sodium phosphate patients developed biochemical evidence of adrenal suppression. There were statistically significant (p < 0.005) reductions in symptom scores following treatment, but no significant difference (p > 0.05) between the drug groups regarding post-treatment symptom scores. As a screening tool for iatrogenic adrenal suppression, MSC had a sensitivity of 100 per cent and a specificity of 97 per cent.

This study demonstrates the high risk of developing adrenal suppression secondary to betamethasone sodium phosphate therapy. The salivary cortisol assay is an accurate tool for monitoringadrenal function and is ideally suited to the out-patient setting.
Spontaneous arteriovenous malformation of the external auditory meatus
Authors: Raghu Mallappa , De Ranit , Higgins Nicholas , Axon Patrick
Published: December 2004

Arteriovenous malformations (AVM) of the head and neck are rare. They usually occur intracranially and derive their vascular supply from the intracranial vessels. In the English literature there has not been any documented case of AVMs in and around the external auditory meatus (EAM). The authors present the first case, a spontaneous AVM deriving its vascular supply from the posterior auricular artery. The diagnostic difficulties and management strategies of spontaneous AVMs are discussed.
Aspirated stoma button: an unusual complication
Authors: Sanjeevan N. , Mathews J. , McCormick M.S.
Published: December 2004

The larynx functions as a protective valve of the upper airway. An end-tracheostomy represents a risk factor for foreign body aspiration. We describe a case of tracheostomy stoma button aspiration, leading to recurrent chest infection and irreversible lung damage, necessitating a pneumonectomy. This is the first reported case of this kind. This case also emphasizes the importance of patient education and of stoma button design.
Impaired Synaptic Function in the Microglial KARAP/DAP12-Deficient Mouse
Authors: Roumier Anne , Béchade Catherine , Poncer Jean-Christophe , Smalla Karl-Heinz , Tomasello Elena , Vivier Eric , Gundelfinger Eckart D. , Triller Antoine , Bessis Alain
Published: December 2004

Several proteins are expressed in both immune and nervous systems. However, their putative nonimmune functions in the brain remain poorly understood. KARAP/DAP12 is a transmembrane polypeptide associated with cell-surface receptors in hematopoeitic cells. Its mutation in humans induces Nasu-Hakola disease, characterized by presenile dementia and demyelinization. However, alteration of white matter occurs months after the onset of neuropsychiatric symptoms, suggesting that other neuronal alterations occur in the early phases of the disease. We hypothesized that KARAP/DAP12 may impact synaptic function. In mice deficient for KARAP/DAP12 function, long-term potentiation was enhanced and was partly NMDA receptor (NMDAR) independent. This effect was accompanied by changes in synaptic glutamate receptor content, as detected by the increased rectification of AMPA receptor EPSCs and increased sensitivity of NMDAR EPSCs to ifenprodil. Biochemical analysis of synaptic proteins confirmed these electrophysiological data. In mutants, the AMPA receptor GluR2 subunit expression was decreased only in the postsynaptic densities but not in the whole membrane fraction, demonstrating specific impairment of synaptic receptor accumulation. Alteration of the BNDF-tyrosine kinase receptor B (TrkB) signaling in the mutant was demonstrated by the dramatic decrease of synaptic TrkB with no change in other regulatory or scaffolding proteins. Finally, KARAP/DAP12 was detected only in microglia but not in neurons, astrocytes, or oligodendrocytes. KARAP/DAP12 may thus alter microglial physiology and subsequently synaptic function and plasticity through a novel microglia-neuron interaction.
Molecular Determinants Responsible for Differences in Desensitization Kinetics of AMPA Receptor Splice Variants
Authors: Quirk Jennifer C. , Siuda Edward R. , Nisenbaum Eric S.
Published: December 2004

Flip (i) and flop (o) alternatively spliced variants of the four glutamate AMPA receptor subunits (GluR1-4) are differentially expressed in the CNS and can display distinct rates of desensitization that contribute to the heterogeneity of native AMPA receptor-dependent synaptic responses. In the present study, we initially compared the kinetics of desensitization in response to fast application of glutamate (1 mm) for the eight different homomeric recombinant human AMPA receptors (hGluR1-4i and o) heterologously expressed in mammalian cells. Consistent with previous reports on recombinant rat AMPA receptors, the time constants of desensitization between human GluR1i and GluR1o receptors were the same, whereas the flip isoforms for GluR2-4 receptors exhibited significantly slower rates of desensitization compared with the flop isoforms. To identify the molecular determinants responsible for these functional differences, the effects of exchanging amino acid residues in the flip-flop cassette of GluR2i and GluR2o were investigated. Three amino acid residues in the flip-flop region (Thr765, Pro766, and Ser775 in flip and Asn765, Ala766, and Asn775 in flop) were identified that contribute to splice-variant differences in the rate of desensitization. Recent structural data show that these three residues are located on helix J, which forms part of the intradimer interface of AMPA receptor ligand-binding cores, and that the stability of this interface may regulate desensitization. The present results suggest that these three residues may confer differences in flip and flop receptor desensitization rates by directly and/or indirectly influencing the stability of the interface between adjacent subunits.