bluuebunny/crossref_metadata_2025_split huggingface dataset:
Histologic and Immunohistochemical Review of Splenic Fibrohistiocytic Nodules in Dogs
Authors: Moore A.S. , Frimberger A.E. , Sullivan N. , Moore P.F. 
Published: August 2012

BackgroundSplenic fibrohistiocytic nodules (SFHN) are commonly diagnosed. It is suspected that these represent a heterogeneous group of malignant and nonmalignant diseases, separation of which could improve the ability of clinicians to prognosticate for dogs.Hypothesis/ObjectivesImmunohistochemistry will differentiate histologic diagnoses within the group of SFHN; survival after splenectomy is associated with those histologic types.AnimalsThirty‐two dogs with SFHN treated by or under direction from veterinary oncologists.MethodsRetrospective case record analysis from dogs followed from splenectomy until death. Clinical, histopathologic, and immunohistochemistry data analyzed for an association with survival time.ResultsThirty‐two dogs had SFHN; grade 1 (2 dogs), grade 2 (9 dogs), and grade 3 (lymphoid percentage <40%; 21 dogs). Twenty‐two dogs died, 10 were censored (9 alive median of 883 days after splenectomy). Median overall survival was 387 days, and grade 3 SFHN was positively associated with survival time as previously reported (P < .001). Of 31 available samples, dogs had diseases reclassified as nodular hyperplasia (13; 8 complex, 5 lymphoid including 2 marginal zone), lymphoma (4; 2 marginal zone lymphoma, 1 high grade B‐cell lymphoma, and 1 marginal zone transitional to high grade B‐cell lymphoma), 8 stromal sarcomas, and 6 histiocytic sarcomas. Dogs with histiocytic sarcoma had worse survival (median 74 days) than dogs with other diseases.Conclusions and Clinical ImportanceSplenic histiocytic sarcoma is an aggressive disease; however, some dogs with stromal sarcomas had long survival times. The term SFHN is no longer warranted for this group of disorders.
Melatonin influences proliferation and differentiation of rat dental papilla cells in vitro and dentine formation in vivo by altering mitochondrial activity
Authors: Liu Jie , Zhou Hongyu , Fan Wenguo , Dong Weiguo , Fu Shenli , He Hongwen , Huang Fang 
Published: August 2012

AbstractMelatonin mediates a variety of biological processes ranging from the control of circadian rhythms to immune regulation. Melatonin also influences bone formation and osteointegration of dental implants. However, the effects of melatonin on dentine formation have not been examined. This study investigated the effects of melatonin on the proliferation and differentiation of rat dental papilla cells (rDPCs) in vitro and dentine formation in vivo. We found that melatonin (0, 10−12, 10−10,10−8 m) induced a dose‐dependent reduction in rDPCs proliferation, increased alkaline phosphatase (ALP) activity, the expression of dentine sialoprotein (DSP), and mineralized matrix formation in vitro. In vivo melatonin (50 mg/kg, BW, i.p.) inhibited dentine formation. Melatonin (10−8 m) suppressed the activity of complex I and IV in the basal medium (OS−) and enhanced the activity of complex I and complex IV in osteogenic medium (OS+). These results demonstrate that melatonin suppresses the proliferation and promotes differentiation of rDPCs, the mechanisms of which may be related to activity of mitochondrial complex I and complex IV.
A ring of threonines in the inner vestibule of the pore of CNGA1 channels constitutes a binding site for permeating ions
Authors: Marchesi Arin , Mazzolini Monica , Torre Vincent 
Published: August 2012

Key points
Cyclic nucleotide‐gated (CNG) channels are multi‐ion channels showing the anomalous mole fraction effect (AMFE) in the presence of Li+ and Cs+ mixtures.
We show that Cs+ ions at the intracellular side of the membrane block the entry of Na+ ions in a voltage dependent way.
The blockage is relieved when Thr359 and Thr360 at the intracellular entrance of the selectivity filter are replaced with an alanine. Moreover, the AMFE in the presence of intracellular mixtures of Li+ and Cs+ is abolished in T360A mutant channels.
We have identified a second binding site – composed by the ring of Thr360 at the intracellular vestibule – in the selectivity filter of CNG channels controlling monovalent cations selectivity and permeation.
These results help us understand fundamental similarities and differences between the pore of CNG channels and K+ channels.
Abstract  Cyclic nucleotide‐gated (CNG) channels and K+ channels have a significant sequence identity and are thought to share a similar 3D structure. K+ channels can accommodate simultaneously two or three permeating ions inside their pore and therefore are referred to as multi‐ion channels. Also CNGA1 channels are multi‐ion channels, as they exhibit an anomalous mole fraction effect (AMFE) in the presence of mixtures of 110 mm Li+ and Cs+ on the cytoplasmic side of the membrane. Several observations have identified the ring of Glu363 in the outer vestibule of the pore as one of the binding sites within the pore of CNGA1 channels. In the present work we identify a second binding site in the selectivity filter of CNGA1 channels controlling AMFE. Here, we show also that Cs+ ions at the intracellular side of the membrane block the entry of Na+ ions. This blockage is almost completely removed at high hyperpolarized voltages as expected if the Cs+ blocking site is located within the transmembrane electric field. Indeed, mutagenesis experiments show that the block is relieved when Thr359 and Thr360 at the intracellular entrance of the selectivity filter are replaced with an alanine. In T359A mutant channels AMFE in the presence of intracellular mixtures of Li+ and Cs+ is still present but is abolished in T360A mutant channels. These results suggest that the ring of Thr360 at the intracellular entrance of the selectivity filter forms another ion binding site in the CNGA1 channel. The two binding sites composed of the rings of Glu363 and Thr360 are not independent; in fact they mediate a powerful coupling between permeation and gating, a specific aspect of CNG channels.
Inhibition of micturition reflex by activation of somatic afferents in posterior femoral cutaneous nerve
Authors: Tai Changfeng , Shen Bing , Mally Abhijith D. , Zhang Fan , Zhao Shouguo , Wang Jicheng , Roppolo James R. , de Groat William C. 
Published: August 2012

Key points
Activation of afferents in the posterior femoral cutaneous nerve (PFCN) can reflexively induce efferent firing in the pudendal nerve and pudendal afferent firing via a motor–sensory coupling.
Activation of pudendal afferent nerves can inhibit the micturition reflex, suggesting PFCN stimulation might also inhibit the micturition reflex.
This study discovered a somato‐bladder inhibitory reflex elicited by electrical or tactile stimulation of cutaneous afferents in the PFCN, but excluded the involvement of pudendal nerves.
This PFCN‐bladder inhibitory reflex could be utilized to develop new neuromodulation therapies for lower urinary tract disorders.
Abstract  This study determined if activation of somatic afferents in posterior femoral cutaneous nerve (PFCN) could modulate the micturition reflex recorded under isovolumetric conditions in α‐chloralose anaesthetized cats. PFCN stimulation inhibited reflex bladder activity and significantly (P < 0.05) increased bladder capacity during slow infusion of saline or 0.25% acetic acid (AA). The optimal frequency for PFCN stimulation‐induced bladder inhibition was between 3 and 10 Hz, and a minimal stimulation intensity of half of the threshold for inducing anal twitching was required. Bilateral pudendal nerve transection eliminated PFCN stimulation‐induced anal twitching but did not change the stimulation‐induced bladder inhibition, excluding the involvement of pudendal afferent or efferent axons in PFCN afferent inhibition. Mechanical or electrical stimulation on the skin surface in the PFCN dermatome also inhibited bladder activity. Prolonged (2 × 30 min) PFCN stimulation induced a post‐stimulation inhibition that persists for at least 2 h. This study revealed a new cutaneous‐bladder reflex activated by PFCN afferents. Although the mechanisms and physiological functions of this cutaneous‐bladder reflex need to be further studied, our data raise the possibility that stimulation of PFCN afferents might be useful clinically for the treatment of overactive bladder symptoms.
Deletion of heart‐type cytochrome c oxidase subunit 7a1 impairs skeletal muscle angiogenesis and oxidative phosphorylation
Authors: Lee Icksoo , Hüttemann Maik , Liu Jenney , Grossman Lawrence I. , Malek Moh H. 
Published: August 2012

Key points
Cytochrome c oxidase (Cox) is the proposed rate‐limiting enzyme of aerobic metabolism in mammals.
This study examined a mouse model that has a heart/skeletal muscle‐specific isoform of Cox deleted and represents a mild form of mitochondrial myopathy.
The results indicated that endurance capacity was severely limited in the knockout animals compared with controls.
The observed exercise intolerance was accompanied by decreased capillarity in the hindlimb muscle as well as reduced energy production.
The results suggest that mild mitochondrial myopathy results in adverse structural and functions changes in muscle bioenergetics.
Abstract  Oxidative metabolism is needed for sustained skeletal muscle function. A key component of such metabolism is cytochrome c oxidase, the 13‐subunit terminal complex of the mitochondrial electron transport chain. We used mice null for one of the two isoforms of Cox subunit 7a, heart/skeletal muscle‐specific Cox7a1, to examine the cellular and functional responses of muscle adaptation in response to mitochondrial dysfunction. Specifically we determined if deletion of Cox7a1 would (1) limit exercise capacity, and (2) alter genes responsible for skeletal muscle capillarity and mitochondrial biogenesis. Sixteen male mice (Cox7a1 null mice, n= 8, and littermate controls, n= 8) performed incremental and run‐to‐exhaustion treadmill tests. The hindlimb muscles for both groups were analysed. The results indicated that capillary indices were reduced (by 30.7–44.9%) in the Cox7a1 null mice relative to controls. In addition, resting ATP levels and Cox specific activity were significantly reduced (>60%) in both glycolytic and oxidative muscle fibre types despite an increase in a major regulator of mitochondrial biogenesis, PGC‐1β. These changes in the skeletal muscle resulted in exercise intolerance for the Cox7a1 null mice. Thus, our data indicate that deletion of the Cox7a1 isoform results in reduced muscle bioenergetics and hindlimb capillarity, helping to explain the observed impairment of muscle structure and function.
Pharmacokinetics and Pharmacodynamics of Oral Artesunate Monotherapy in Patients with Uncomplicated Plasmodium falciparum Malaria in Western Cambodia
Authors: Saunders David , Khemawoot Phisit , Vanachayangkul Pattaraporn , Siripokasupkul Raveewan , Bethell Delia , Tyner Stuart , Se Youry , Rutvisuttinunt Wiriya , Sriwichai Sabaithip , Chanthap Lon , Lin Jessica , Timmermans Ans , Socheat Doung , Ringwald Pascal , Noedl Harald , Smith Bryan , Fukuda Mark , Teja-isavadharm Paktiya 
Published: August 2012

ABSTRACT

Artemisinin-resistant malaria along the Thailand-Cambodian border is an important public health concern, yet mechanisms of drug action and their contributions to the development of resistance are poorly understood. The pharmacokinetics and pharmacodynamics of oral artesunate monotherapy were explored in a dose-ranging trial in an area of emerging artesunate resistance in western Cambodia. We enrolled 143 evaluable subjects with uncomplicated
Plasmodium falciparum
malaria in an open label study of directly observed artesunate monotherapy at 3 dose levels (2, 4, and 6 mg/kg of body weight/day) for 7 days at Tasanh Health Center, Tasanh, Cambodia. Clinical outcomes were similar among the 3 groups. Wide variability in artesunate and dihydroartemisinin concentrations in plasma was observed. No significant dose-effect or concentration-effect relationships between pharmacokinetic (PK) and parasite clearance parameters were observed, though baseline parasitemia was modestly correlated with increased parasite clearance times. The overall parasite clearance times were prolonged compared with the clearance times in a previous study at this site in 2006 to 2007, but this did not persist when the evaluation was limited to subjects with a comparable artesunate dose (4 mg/kg/day) and baseline parasitemia from the two studies. Reduced plasma drug levels with higher presentation parasitemias, previously hypothesized to result from partitioning into infected red blood cells, was not observed in this population with uncomplicated malaria. Neither
in vitro
parasite susceptibility nor plasma drug concentrations appeared to have a direct relationship with the pharmacodynamic (PD) effects of oral artesunate on malaria parasites. While direct concentration-effect relationships were not found, it remains possible that a population PK modeling approach that allows modeling of greater dose separation might discern more-subtle relationships.
Antiparasitic Effect of Vitamin B
12
on Trypanosoma cruzi
Authors: Ciccarelli Alejandra B. , Frank Fernanda M. , Puente Vanesa , Malchiodi Emilio L. , Batlle Alcira , Lombardo Maria Elisa 
Published: August 2012

ABSTRACT

A nutritional characteristic of trypanosomatid protozoa is that they need a heme compound as a growth factor. Because of the cytotoxic activity of heme and its structural similarity to cobalamins, we have investigated the
in vitro
and
in vivo
effect of vitamin B
12
(or cyanocobalamin) on the different forms of
Trypanosoma cruzi
. Cyanocobalamin showed a marked antiparasitic activity against epimastigotes (50% inhibitory concentration [IC
50
], 2.42 μM), amastigotes (IC
50
, 10.69 μM), and trypomastigotes (IC
50
, 9.46 μM). Anti-epimastigote and -trypomastigote values were 1.7 to 4 times lower than those obtained with the reference drug benznidazole (Bnz). We also found that B
12
and hemin do not interact with each other in their modes of action. Our results show that B
12
increases intracellular oxidative activity and stimulates both superoxide dismutase (50%) and ascorbate peroxidase (20%) activities, while the activity of trypanothione reductase was not modified. In addition, we found that the antioxidants dithiothreitol and ascorbic acid increase the susceptibility of the parasite to the cytotoxic action of B
12
. We propose that vitamin B
12
exerts its growth-inhibitory effect through the generation of reactive oxygen species. In an
in vivo
assay, a significant reduction in the number of circulating parasites was found in
T. cruzi
-infected mice treated with cyanocobalamin and ascorbic acid. The reduction of parasitemia in benznidazole-treated mice was improved by the addition of these vitamins. According to our results, a combination of B
12
and Bnz should be further investigated due to its potential as a new therapeutic modality for the treatment of Chagas' disease.
Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen
Authors: Debnath Anjan , Tunac Josefino B. , Galindo-Gómez Silvia , Silva-Olivares Angélica , Shibayama Mineko , McKerrow James H. 
Published: August 2012

ABSTRACT

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba
Naegleria fowleri
. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species
Naegleria gruberi
. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against
Naegleria
than that of amphotericin B. Transmission electron microscopy of
N. fowleri
trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae.
In vivo
efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM.
TD-1792 versus Vancomycin for Treatment of Complicated Skin and Skin Structure Infections
Authors: Stryjewski Martin E. , Potgieter Peter D. , Li Yu-Ping , Barriere Steven L. , Churukian Allan , Kingsley Jeff , Corey G. Ralph ,   for the TD-1792 Investigators Group
Published: August 2012

ABSTRACTTD-1792 is a first-in-class glycopeptide-cephalosporin heterodimer that exhibits bactericidal activity against Gram-positive pathogens. We conducted a randomized, double-blind, active-control, phase II trial in patients with complicated skin and skin structure infections caused by suspected or confirmed Gram-positive organisms. Patients 18 to 65 years old were randomized to receive 7 to 14 days of either TD-1792 (2 mg/kg of body weight intravenously [i.v.] every 24 h [q24h]) or vancomycin (1 g i.v. q12h, with dosage regimens adjusted per site-specific procedures). A total of 197 patients were randomized and received at least one dose of study medication. Rates of clinical success at the test-of-cure evaluation were similar in all analysis populations. Among 170 clinically evaluable patients, cure rates were 91.7% and 90.7% in the TD-1792 and vancomycin groups, respectively (95% confidence interval [CI] of −7.9 to 9.7 for the difference). In microbiologically evaluable patients with methicillin-resistantStaphylococcus aureusat baseline (n= 75), cure rates were 94.7% in the TD-1792 group and 91.9% in the vancomycin group. Microbiological eradication of Gram-positive pathogens (n= 126) was achieved in 93.7% and 92.1% of patients in the TD-1792 and vancomycin groups, respectively. Seven patients were discontinued from study medication due to an adverse event (AE): 2 and 5 in the TD-1792 and vancomycin groups, respectively. AEs were of similar types and severities between the two groups, other than pruritus, which was more common in patients who received vancomycin. No patients in the TD-1792 group experienced a serious AE. This study supports further clinical development of TD-1792 in patients with Gram-positive infection.
Characterization of Resistance to the Protease Inhibitor GS-9451 in Hepatitis C Virus-Infected Patients
Authors: Dvory-Sobol Hadas , Wong Kelly A. , Ku Karin S. , Bae Andrew , Lawitz Eric J. , Pang Phillip S. , Harris Jeanette , Miller Michael D. , Mo Hongmei 
Published: August 2012

ABSTRACT
GS-9451, a novel hepatitis C virus (HCV) nonstructural 3/4a (NS3/4a) protease inhibitor, is highly active in patients infected with HCV genotype 1 (GT 1). The aim of this study is to characterize the clinical resistance profile of GS-9451 in GT 1 HCV-infected patients in a phase 1, 3-day monotherapy study. The full-length NS3/4A gene was population sequenced at baseline, on the final treatment day, and at follow-up time points. NS3 protease domains from patient isolates with emerging mutations were cloned into an NS3 shuttle vector, and their susceptibilities to GS-9451 and other HCV inhibitors were determined using a transient replication assay. No resistance mutations at NS3 position 155, 156, or 168 were detected in any of the baseline samples or in viruses from patients treated with 60 mg of GS-9451 once daily. Among patients who received 200 mg and 400 mg of GS-9451, viruses with mutations at position D168 (D168E/G/V) and R155 (R155K), which confer high-level resistance to GS-9451, were detected in those with GT 1b and GT 1a virus, respectively. Viruses with D168 mutations were no longer detected in any GT 1b patient at day 14 and subsequent time points. In GT 1a patients, R155K mutants were replaced by the wild type in 57% of patients at week 24. These NS3 clinical mutants were sensitive to NS5B and NS5A inhibitors, as well as alpha interferon (IFN-α) and ribavirin. The lack of cross-resistance between GS-9451 and other classes of HCV inhibitors supports the utility of combination therapy.
Addition of Ceftaroline to Daptomycin after Emergence of Daptomycin-Nonsusceptible Staphylococcus aureus during Therapy Improves Antibacterial Activity
Authors: Rose Warren E. , Schulz Lucas T. , Andes David , Striker Rob , Berti Andrew D. , Hutson Paul R. , Shukla Sanjay K. 
Published: August 2012

ABSTRACT

Antistaphylococcal beta-lactams enhance daptomycin activity and have been used successfully in combination for refractory methicillin-resistant
Staphylococcus aureus
(MRSA) infections. Ceftaroline possesses MRSA activity, but it is unknown if it improves the daptomycin potency comparably to other beta-lactams. We report a complex patient case of endocarditis who was treated with daptomycin in combination with ceftaroline, which resulted in clearance of a daptomycin-nonsusceptible strain. An
in vitro
pharmacokinetic/pharmacodynamic model of renal failure was used to simulate the development of daptomycin resistance and evaluate the microbiologic effects of daptomycin plus ceftaroline treatment. Combination therapy with daptomycin and ceftaroline restored daptomycin sensitivity
in vivo
and resulted in clearance of persistent blood cultures. Daptomycin susceptibility
in vitro
was increased in the presence of either ceftaroline or oxacillin. Daptomycin at 6 mg/kg of body weight every 48 h was bactericidal in the model but resulted in regrowth and daptomycin resistance (MIC, 2 to 4 μg/ml) with continued monotherapy. The addition of ceftaroline at 200 mg every 12 h after the emergence of daptomycin resistance enhanced bacterial killing. Importantly, daptomycin plus ceftaroline as the initial combination therapy produced rapid and sustained bactericidal activity and prevented daptomycin resistance. Both
in vivo
- and
in vitro
-derived daptomycin resistance resulted in bacteria with more fluid cell membranes. After ceftaroline was added in the model, fluidity was restored to the level of the initial
in vivo
isolate. Daptomycin-resistant isolates required high daptomycin exposures (at least 10 mg/kg) to optimize cell membrane damage with daptomycin alone. Ceftaroline combined with daptomycin was effective in eliminating daptomycin-resistant MRSA, and these results further justify the potential use of daptomycin plus beta-lactam therapy for these refractory infections.