bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal Death in Developmental Models: Possible Implications in Neuropathology
Authors: Johnson Eugene M. , Deckwerth Thomas L. , Deshmukh Mohanish
Published: January 2008

Extensive neuronal death occurs in the developing nervous system. Death of neurons during this process is apoptotic and appears to utilize a pathway that is conserved in various mammalian cells and organisms. Recent evidence suggests that neuronal death during trauma, stroke, or neurode‐generative diseases may also occur by a similar mechanism. This review discusses the molecular mechanism of developmental neuronal death by examining the biochemical and molecular events associated with neuronal death after trophic factor withdrawal. The ability to inhibit neuronal death by manipulating the Bcl‐2 or the ICE‐family proteins demonstrates the importance of these proteins in the neuronal apoptotic pathway. The utility of inhibiting neuronal death by blocking the apoptotic pathway as therapy in neuropathological situations is discussed.
Cell Death in C. elegans: Molecular insights into Mechanisms Conserved Between Nematodes and Mammals
Authors: Driscoll Monica
Published: January 2008

As is the case for most metazoans, C. elegans cells have the potential to undergo developmental cell death (programmed cell death) or a necrotic‐like death in response to cell injury. Analysis of mutations that disrupt the reproducible pattern of cell death that occurs during C. elegans development has defined a genetic pathway for programmed cell death. This program involves the activities of certain genes, such as ces‐1 and the ces‐2 bZIP transcription factor, which regulate the life/death decision in specific subsets of cells. ced‐9, a Bcl‐2 family member, acts globally to negatively regulate the activities of ced‐4S (which promotes cell death) and ced‐4L, which promotes cell life. ced‐3 encodes a member of the ICE cysteine protease family that is essential for execution of all programmed cell deaths. Once cells die, corpses are phagocytized and consumed in what appear to be at least two parallel pathways that require the activities of ced‐1 ced‐6, ced‐7 and ced‐2, ced‐5, ced‐10. Degradation of corpse DNA requires the product of the nuc‐1 gene. Degenerative cell death, characterized by cell swelling, can be induced by different cell injuries including that conferred by mutant degenerin ion channels (encoded by deg‐1, mec‐4, mec‐10 and unc‐8) and by expression of human β‐amyloid peptide. Remarkable parallels between nematode and mammalian death programs have advanced understanding of human cell death mechanisms.
Mechanisms of Neuronal Death in Alzheimer's Disease
Authors: Cotman Carl W. , Su Joseph H.
Published: January 2008

Recent data in cell culture has shown that brain neurons are particularly vulnerable to degeneration by apoptosis. Further the inducers that activate the program (e.g. β‐amyloid, oxidatative damage, low energy metabolism) correspond to conditions present in the Alzheimer's disease (AD) brain. This suggests the possibility that apoptosis may be one of the mechanisms contributing to neuronal loss in this disease. Indeed, some neurons in vulnerable regions of the AD brain show evidence of DNA damage, nuclear apoptotic bodies, chromatin condensation, and the induction of select genes characteristic of apoptosis in cell culture and animal models. This suggests the existence of apoptosis in the AD brain, a hypothesis also consistent with evolving research in one of the regulatory functions of the presenilin genes. On the other hand, DNA damage is present in the majority of neurons in vulnerable regions in early and mild cases. In most tissues, cells in fully activated apoptosis degenerate and are removed within hours to days and thus it seems all DNA damage is unlikely to signify terminal apoptosis. The presence of extensive DNA damage suggests an acceleration of damage, faulty repair process, loss of protective mechanisms, or an activation and arrest of aspects of the apoptotic program. DNA damage is unlikely to be an artifact of postmortem delay or agonal state. The existence of protective mechanisms for neurons may exist as these cells are nondividing and essential. In this context it is interesting that Bcl‐2 is upregulated in most neurons with DNA damage. Further, at least one DNA repair enzyme is also upregulated. Thus it appears as if neurons are in a struggle between degeneration and repair. As research advances it is critical to reduce the stimuli that cause the neuronal damage and discover the key intervention points to assist neurons in the repair processes.
Trinucleotide Repeat Instability: Genetic Features and Molecular Mechanisms
Authors: R. La Spada Albert
Published: January 2008

Trinucleotide repeat expansions are an important cause of inherited neurodegenerative disease. The expanded repeats are unstable, changing in size when transmitted from parents to offspring (inter‐generational instability, “meiotic instability”) and often showing size variation within the tissues of an affected individual (somatic mosaicism, “mitotic instability”). Repeat instability is a clinically important phenomenon, as increasing repeat lengths correlate with an earlier age of onset and a more severe disease phenotype. The tendency of expanded trinucleotide repeats to increase in length during their transmission from parent to offspring in these diseases provides a molecular explanation for anticipation (increasing disease severity in successive affected generations). In this review, I explore the genetic and molecular basis of trinucleotide repeat instability. Studies of patients and families with trinucleotide repeat disorders have revealed a number of factors that determine the rate and magnitude of trinucleotide repeat change. Analysis of trinucleotide repeat instability in bacteria, yeast, and mice has yielded additional insights. Despite these advances, the pathways and mechanisms underlying trinucleotide repeat instability in humans remain largely unknown. There are many reasons to suspect that this uniquely human phenomenon will significantly impact upon our understanding of development, differentiation and neurobiology.
Toward Understanding the Molecular Pathology of Huntington's Disease
Authors: Wellington Cheryl L. , Brinkman Ryan R. , O'Kusky John R. , Hayden Michael R.
Published: January 2008

Huntington's Disease (HD) is caused by expansion of a CAG trinucleotide beyond 35 repeats within the coding region of a novel gene. Recently, new insights into the relationship between CAG expansion in the HD gene and pathological mechanisms have emerged. Survival analysis of a large cohort of affected and at‐risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD symptoms and dying of HD by a certain age. Animals transgenic for the first exon of huntingtin with large CAG repeats lengths have been reported to have a complex neurological phenotype that bears interesting similarities and differences to HD. The repertoire of huntingtin‐inter‐acting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to interact with two of its four known protein partners appears to be influenced by CAG length. Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated to specifically cleave huntingtin in a CAG length‐dependent manner. Many of these features are combined in a model suggesting mechanisms by whi h the pathogenesis of HD may be initiated. The development of appropriate in vitro and animal models for HD will allow the validity of these models to be tested.
January 1997 ‐ 7 Year Old Girl with Seizures
Authors: Al‐Hindi Hindi , Subach Brian , Hamilton Ronald L.
Published: January 2008

Case Abstract

A seven year old girl presented with six month history of seizures. An MRI scan showed a cortical lesion in the left temporal lobe which was resected. Neuropathology examination demonstrated meningioangiomatosis, an unusual hamartomatous condition sometimes associated with neurofibromatosis 2. Approximately 50 cases of meningioangiomatosis have been reported in the literature. These are reviewed and compared to the current case.
February 1997‐9 Year Old Girl with Hydrocephalus
Authors: Hamilton Dr. Ronald L.
Published: January 2008

Case Abstract

A nine year old girl presented with nausea vomiting and hydrocephalus. Imaging studies demonstrated a large right thalamic mass with areas of cystic change or necrosis. Sections of resected material showed perivascular pseudorosettes, necrosis, endothelial proliferation, numerous mitoses, densely cellular areas and numerous foci with a clear‐cell morphology. This case is used to illustrate the features of anaplastic ependymomas and to discuss the relationship of the histologic features to prognosis.
Genetics of Glioma Progression and the Definition of Primary and Secondary Glioblastoma
Authors: Kleihues Paul , Ohgaki Hiroko
Published: January 2008

Glioblastoma multiforme, the most malignant human brain tumor, may develop de novo (primary glioblastoma) or through progression from low‐grade or anaplastic astrocytoma (secondary glioblastoma). We present evidence that these subtypes of glioblastoma constitute distinct disease entities which evolve through different genetic pathways, affect patients at different age and are likely to differ in prognosis and response to therapy. Primary glioblastomas develop in older patients (mean, 55 years) and typically show EGFR overexpres‐sion or, less frequently, MDM2 overexpression and pi6 deletion. Secondary glioblastomas develop in younger patients (mean, 40 years) and frequently contain TP53 mutations and, less consistently, loss of DCC expression. Although primary and secondary glioblastomas are considered to be histologically indistinguishable, we found that the pattern and pathogenesis of necrosis are different, large areas of ischaemic necrosis surrounded by Fas expressing tumor cells being a hallmark of primary glioblastomas. The giant cell glioblastoma occupies an intermediate position. Like the primary glioblastoma, it rapidly develops de novo but manifests in younger patients (including children) and has genetic alterations typical for secondary glioblastomas, i.e. frequent TP53 mutations and lack of EGFR overexpression.
A Confocal Microscopic Analysis of Galaninergic Hyperinnervation of Cholinergic Basal Forebrain Neurons in Alzheimer's Disease
Authors: Bowser Robert , Kordower Jeffrey H. , Mufson Elliott J.
Published: January 2008

The galanin (GAL) containing peptide fiber system innervates the basal forebrain and has been shown to hyperinnervate remaining cholinergic neurons in Alzheimer's disease (AD). GAL modulates the release of acetylcholine and, therefore, may depress this neurotransmitter in surviving cholinergic basal forebrain (CBF) neurons in AD. The aim of this study was to identify putative synaptic contacts between GAL immunoreactive processes and CBF neurons and evaluate whether these processes hypertrophy in AD patients. We observed by confocal laser microscopy a hyperinnervation of GAL‐containing fibers in both AD and Parkinson's disease patients with concurrent AD (PD/AD). Galaninergic fibers were often seen in direct apposition to remaining CBF neurons and enwrapped cholinergic cell soma and dendrites. Our results demonstrate that GAL‐containing fibers are in direct apposition to CBF neurons in normal‐aged humans and that this phenotype is enhanced in AD and PD/AD, suggesting that direct synaptic contacts occur between GAL‐containing fibers and CBF neurons. Because GAL can modulate acetylcholine release from cholinergic neurons, hyperinnervation of GAL fibers in AD and PD/AD patients may further decrease release of acetylcholine from remaining CBF neurons. We propose that therapies based solely on acetylcholinesterase inhibitors may be insufficient to effectively increase cortical levels of acetylcholine.
Characterization of Neural Cell Lines Derived from SV40 Large T‐Induced Primitive Neuroectodermal Tumors
Authors: Weggen Sascha , Bayer Thomas A. , Koch Anke , Salewski Holger , Scheidtmann Karl‐Heinz , Pietsch Torsten , Wiestler Otmar D.
Published: January 2008

We recently reported intriguing properties of neural tumors generated by retrovirus‐mediated transfer of the SV40 large T antigen into fetal rat brain transplants. Histopathologically, these neoplasms displayed characteristic features of primitive neuroectodermal tumors (PNET) and exhibited a striking potential for migration into the host brain. In the present study, four cell lines were derived from these PNETs and characterized. Two lines with an immature phenotype expressed the embryonal form of the neural cell adhesion molecule and nestin. They showed spheroid formation and delicate cell processes. The remaining cell lines had a flat, epitheloid appearance and were immunoreactive for synaptophysin, neurofilament proteins and glial fibrillary acidic protein. These cells constitute valuable tools to study the cellular origin(s) and molecular basis of PNETs, differentiation of neural progenitors and tumor cell migration in the brain.
A Molecular Genetic Model of Astrocytoma Histopathology
Authors: Louis David N.
Published: January 2008

As the molecular events responsible for astrocytoma formation and progression are being clarified, it is becoming possible to correlate these alterations with the specific histopathological and biological features of astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. In WHO grade II astrocytomas, autocrine stimulation by the platelet‐derived growth factor system coupled with inactiva‐tion of the p53 gene may lead to a growth stimulus in the face of decreased cell death with slow net growth ensuing. Such cells would also have defective responses to DNA damage and impaired DNA repair, setting the stage for future malignant change. Such biological scenarios recapitulate many of the clinicopathological features of WHO grade II astrocytomas. Anaplastic astrocytomas further display release of a critical cell cycle brake that involves the CDKN2/p16, RB and CDK4 genes. This results in mitoses seen histologically; clinically, there is more conspicuous, rapid growth. Finally, glioblastomas may emerge from the microenviron‐mental outgrowth of more malignant clones in a complex vicious cycle that involves necrosis, hypoxia, growth factor release, angiogenesis and clonal selection; growth signals mediated by activation of epidermal growth factor receptors may precipitate glioblastomas. It is clear as well that glioblastoma multiforme can arise via a number of independent genetic pathways, although the clinical significance of these distinctions remains unclear.
Classification and Grading of Low‐Grade Astrocytic Tumors in Children
Authors: Giannini Caterina , Scheithauer Bernd W.
Published: January 2008

This article reviews current perspectives in the classification and grading of astrocytomas in children and calls attention to several histologically distinct groups of low‐grade tumors that characteristically arise during childhood. Recognition of these tumors and the range of histological features that they may exhibit is essential for making rational assessments regarding their expected behavior and, more importantly, for guiding therapeutic intervention. For example, pleomorphic xanthoastrocytoma, which may exhibit “anaplastic” features, generally carries a relatively favorable prognosis and should not be classified with other high‐grade gliomas, such as anaplastic astrocytoma and glioblastoma multiforme. Similarly, the finding of anaplastic features, such as vascular proliferation or necrosis, in pilocytic astrocytomas does not automatically portend the unfavorable prognosis that such features would imply for “diffuse” astrocytomas. Increased appreciation of the morphological diversity of astrocytomas in children should help to improve the management of children with low‐grade astrocytic tumors by avoiding potentially dangerous overtreatment of otherwise indolent lesions.
Free‐living, Amphizoic and Opportunistic Amebas
Authors: Martinez Augusto Julio , Visvesvara Govinda S.
Published: January 2008

Amebas belonging to the generaNaegleria, AcanthamoebaandBalamuthiaare free‐living, amphizoic and opportunistic protozoa that are ubiquitous in nature. These amebas are found in soil, water and air samples from all over the world. Human infection due to these amebas involving brain, skin, lung and eyes has increased significantly during the last 10 years. The epidemiology, immunology, protozoology, pathology, and clinical features of the infections produced by these protozoa differ strikingly.

Infection by the pathogenicNaegleria fowleriis acquired by exposure to polluted water in ponds, swimming pools and man‐made lakes. Raised temperatures during the hot summer months or warm water from power plants facilitate the growth ofN. fowleri. N. fowleriis a thermophilic ameba that grows well in tropical and subtropical climates. The CNS infection, called Primary Amebic Meningoencephalitis (PAM), produced byN. fowleriis characterized by an acute fulminant meningoencephalitis leading to death 3–7 days after exposure. Victims are healthy, young individuals with a history of recent water‐related sport activities. The portal of entry is the olfactory neuroepithelium. The pathologic changes are an acute hemorrhagic necrotizing meningoencephalitis with modest purulent exudate, mainly at the base of the brain, brainstem and cerebellum. Trophozoites can be seen within the CNS lesions located mainly around blood vessels. Thus far 179 cases have been reported; 81 in the USA alone.

Balamuthia mandrillarisand several species ofAcanthamoebaare pathogenic “opportunistic” free‐living amebas which cause Granulomatous Amebic Encephalitis (GAE) in humans and animals. GAE is an infection, usually seen in debilitated, malnourished individuals, in patients undergoing immunosuppressive therapy for organ transplants and in Acquired Immunodeficiency Syndrome (AIDS). The granulomatous component is negligible, particularly in immunocompromised individuals. Pathologically these amebas produce a patchy, chronic or subacute granulomatous encephalitis with the presence of trophozoites and cysts. The portal of entry is probably through the respiratory tract or an ulceration of the skin reaching the CNS by hematogenous spread. As of October 1, 1996, 166 cases 1103 due toAcanthamoebaand 63 due to Balamothial of GAE have been reported from around the world. Of these 103 cases due toAcanthamoeba(72 have been reported in the USA alone, > 50 in AIDS). It is well known that several species ofAcanthamoebacan also produce, chronic sight threatening ulceration of the cornea calledAcanthamoebakeratitis (AK), mostly in contact lens wearers or in individuals with minor corneal abrasions. Hundreds of cases of AK have been documented world wide.
Trypanosomiasis
Authors: Chimelli Leila , Scaravilli Francesco
Published: January 2008

African (sleeping sickness) and American (Chagas' disease) trypanosomiasis, caused by protozoa of the family Trypanosomatidae, are diseases that are endemic in parts of Africa and Latin America, respectively. Physicians in developed countries may occasionally see cases because of extensive travel and immigration from endemic countries. Although neurological involvement is common in both, its incidence and clinical presentation differ considerably. African trypanosomiasis, caused by subspecies of Trypanosoma brucei (T b rhodesiense, T b gambiense), is transmitted by the tsetse fly and causes meningoencephalitis, in which somnolence is a prominent feature. Parasites may reach the brain parenchyma through the choroid plexus or the Virchow Robin spaces. American trypanosomiasis, caused by Trypanosoma cruzi is transmitted by reduviid bugs. While lesions in the central nervous system are not prominent, except in the reactivated forms which occur in immunodeficient patients, the peripheral nerve, mainly the autonomic nervous system, is frequently involved, leading to the cardiomegaly and the digestive megaviscera. Congenital infections may also occur.

In this paper we give an account of the epidemiology, clinical presentation and pathological features of these two protozoal infections based on human and experimental studies of both the central and peripheral nervous system.
Neuroschistosomiasis
Authors: Pittella José E. H.
Published: January 2008

Schistosomiasis is an infection caused by digenetic trematode platyhelminths of the genus Schistosoma. These blood flukes use man and other mammals as definitive hosts and aquatic and amphibious snails as intermediate hosts. Of the schistosomal species, S. mansoni, S haematobium and S. japonicum are the most important to man and the most widely distributed. The infection affects about 200 million individuals in 74 countries of Latin America, Africa and Asia. Far less commonly, schistosomes reach the central nervous system (CNS). This may occur at any time from the moment the worms have matured and the eggs have been laid. For this reason, CNS involvement may be observed with any of the clinical forms of schistosomal infection. The presence of eggs in the CNS induces a cell‐mediated periovular granulomatous reaction. When eggs reach the CNS during the early stages of the infection or during evolution of the disease to its chronic forms, large necrotic‐exudative granulomas are found. In‐situ egg deposition following the anomalous migration of adult worms appears to be the main, if not the only, mechanism by which Schistosoma may reach the CNS in these stages. The mass effect produced by the heavy concentration of eggs and the presence of large granulomas in circumscribed areas of the brain and spinal cord explains, respectively, 1) the signs and symptoms of increased intracranial pressure and focal neurological signs; and 2) the signs and symptoms of rapidly progressing transverse myelitis, usually affecting the lumbosacral segments of the spinal cord. Most of the cases of CNS involvement associated with the hepatosplenic and cardiopulmonary chronic forms, or with severe urinary schistosomiasis, though more frequent, are asymptomatic. In the patients with these clinical forms, the random and sparse distribution of eggs in the CNS indicates that the embolization of eggs from the portal mesenteric system to the brain and spinal cord constitutes the main route of CNS invasion by Schistosoma. The discrete inflammatory reaction elicited by the sparsely distributed eggs in the CNS explains the lack of neurological symptoms that could be produced by egg deposition.
Viruses and Rickettsiae
Authors: Esiri Margaret M.
Published: January 2008

In this review I shall try to provide a brief, up‐to‐date, account of the neuropathology of those viral and rickettsial diseases that are particularly prevalent in tropical regions. These diseases are not, however, exclusive to the tropics. Some, such as AIDS, are common in temperate regions as well, though others are closer to being exclusively tropical, such as some of the arthropod‐borne (ARBO) virus encephalides. The latter are dependent for their dissemination on an existence during part of their infectious cycle in insects which are, in turn, climatically and seasonally sensitive. This necessarily limits their geographical distribution. Factors that influence some of the other diseases are less closely dependent on climate and geography and reflect more the social or cultural conditions under which people live. Thus, diseases that depend for their spread on forms of human behavior such as promiscuity or drug abuse (AIDS), or poor hygiene and living conditions (polio, rickettsial diseases) or on contact with domestic and other animals (rabies) may occur in a more widespread distribution, for the tropics are not the only places that afford opportunities for these diseases to flourish.

I shall select for discussion aspects of the pathology of these diseases that are currently undergoing investigation but will aim to present these against the backdrop of more established aspects of their pathology. Recent reviews of the pathology of viral encephalitis can be found in Hamilton and Wiley (33) and Esiri and Kennedy (20) and of HIV‐1 infection in Price & Sidtis (78) and Scaravilli (85).
August 1996 — Frontal Lobe Tumor in 11 Year Old Girl
Authors: Hamilton Ronald
Published: January 2008

Case Abstract

An 11 year old girl presented with an 8 month history of left temporal headaches with new onset of nausea and vomiting with increased severity of headaches. An MRI scan showed a frontal lobe mass. The tumor was resected and histologic studies demonstrated a central neurocytoma. The clinical, radiologic and pathologic aspects (including immunohistochemistry and electron microscopy) of central neurocytomas are reviewed and the atypical features of this case described.
Discovery and Characterization of Substituted Diphenyl Heterocyclic Compounds as Potent and Selective Inhibitors of Hepatitis C Virus Replication
Authors: Huang Peiyong , Goff Dane A. , Huang Qi , Martinez Anthony , Xu Xiang , Crowder Scott , Issakani Sarkiz D. , Anderson Emily , Sheng Ning , Achacoso Philip , Yen Ann , Kinsella Todd , Darwish Ihab S. , Kolluri Rao , Hong Hui , Qu Kunbin , Stauffer Emily , Goldstein Eileen , Singh Rajinder , Payan Donald G. , Lu H. Henry
Published: January 2008

A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication as measured by real-time reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that was more potent and highly specific for HCV replication, with no significant inhibitory activity against a panel of HCV-related positive-stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-α) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-α/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection.
Killing of
Neisseria gonorrhoeae, Streptococcus agalactiae
(Group B Streptococcus),
Haemophilus ducreyi
, and Vaginal
Lactobacillus
by 3-
O
-Octyl-
sn
-Glycerol
Authors: Moncla B. J. , Pryke K. , Isaacs Charles E.
Published: January 2008

The microbicide candidate octylglycerol inactivates sexually transmitted bacterial pathogens at concentrations which spare normal vaginal flora (lactobacillus). Standard minimum microbicidal concentration assays and time-kill assays revealed the drug concentrations and times required for inactivation. Octylglycerol concentrations must exceed the binding capacity of any human serum albumin to be effective.
Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of
Staphylococcus aureus
Infection
Authors: MacGowan Alasdair P. , Bowker Karen E. , Noel Alan R.
Published: January 2008

The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven
Staphylococcus aureus
strains (methicillin-resistant
S. aureus
[MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillin-sensitive
S. aureus
[MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using
S. aureus
at a standard inoculum of 10
6
CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10
8
CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10
8
CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC
24
) and 48 h (
P
< 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ± 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ± 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC
24
as ABE was 24.9% ± 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2× and 4× the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against
S. aureus
is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.
In Vitro and In Vivo Antifungal Activities of T-2307, a Novel Arylamidine
Authors: Mitsuyama Junichi , Nomura Nobuhiko , Hashimoto Kyoko , Yamada Eio , Nishikawa Hiroshi , Kaeriyama Makoto , Kimura Akiko , Todo Yozo , Narita Hirokazu
Published: January 2008

The in vitro and in vivo antifungal activities of T-2307, a novel arylamidine, were evaluated and compared with those of fluconazole, voriconazole, micafungin, and amphotericin B. T-2307 exhibited broad-spectrum activity against clinically significant pathogens, including
Candida
species (MIC range, 0.00025 to 0.0078 μg/ml),
Cryptococcus neoformans
(MIC range, 0.0039 to 0.0625 μg/ml), and
Aspergillus
species (MIC range, 0.0156 to 4 μg/ml). Furthermore, T-2307 exhibited potent activity against fluconazole-resistant and fluconazole-susceptible-dose-dependent
Candida albicans
strains as well as against azole-susceptible strains. T-2307 exhibited fungicidal activity against some
Candida
and
Aspergillus
species and against
Cryptococcus neoformans
. In mouse models of disseminated candidiasis, cryptococcosis, and aspergillosis, the 50% effective doses of T-2307 were 0.00755, 0.117, and 0.391 mg·kg
−1
·dose
−1
, respectively. This agent was considerably more active than micafungin and amphotericin B against candidiasis and than amphotericin B against cryptococcosis, and its activity was comparable to the activities of micafungin and amphotericin B against aspergillosis. The results of preclinical in vitro and in vivo evaluations performed thus far indicate that T-2307 could represent a potent injectable agent for the treatment of candidiasis, cryptococcosis, and aspergillosis.
In Vitro Phenotypic Susceptibility of Human Immunodeficiency Virus Type 2 Clinical Isolates to Protease Inhibitors
Authors: Desbois Delphine , Roquebert Bénédicte , Peytavin Gilles , Damond Florence , Collin Gilles , Bénard Antoine , Campa Pauline , Matheron Sophie , Chêne Geneviève , Brun-Vézinet Françoise , Descamps Diane
Published: January 2008

We determine phenotypic susceptibility of human immunodeficiency virus type 2 (HIV-2) isolates to amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, saquinavir, and tipranavir. Saquinavir, lopinavir, and darunavir are potent against wild-type HIV-2 isolates and should be preferred as first-line options for HIV-2-infected patients. Other protease inhibitors are less active against HIV-2 than against HIV-1.
MyD88 Negatively Controls Hypergammaglobulinemia with Autoantibody Production during Bacterial Infection
Authors: Woods Anne , Soulas-Sprauel Pauline , Jaulhac Benoit , Arditi Bérénice , Knapp Anne-Marie , Pasquali Jean-Louis , Korganow Anne-Sophie , Martin Thierry
Published: January 2008

A large body of evidence has convincingly shown that Toll-like receptors are necessary sensors for infections with pathogens, but their activation was also suggested to generate autoimmunity. During experimental infections, the lack of these sensors or of their signaling molecules should lead to a deficient immune response. We found out that MyD88, the major adaptor of the Toll/interleukin-1 (Toll/IL-1) receptor signaling pathway, can actually act as a negative regulator of B-cell function in some settings. MyD88-deficient mice infected by
Borrelia burgdorferi
developed extreme hypergammaglobulinemia compared to wild-type animals, with high levels of immunoglobulin M (IgM) autoantibodies. In vivo, cell transfer experiments and cell blocking assays showed that this phenotype was not linked to the absence of MyD88 in B cells but rather to CD4 T-cell and likely dendritic cell dysfunctions leading to a Th1-to-Th2 cytokine switch. In addition, our results suggest a relative defect in the Ig class switch recombination process, since MyD88 knockout mice developed mostly IgM antibodies. Collectively, these data emphasize the complex role of the Toll/IL-1 receptor pathway in tuning the immune response against infection and avoiding autoimmunity.
Capsular Antigen Fraction 1 and Pla Modulate the Susceptibility of
Yersinia pestis
to Pulmonary Antimicrobial Peptides Such as Cathelicidin
Authors: Galván Estela M. , Lasaro Melissa A. S. , Schifferli Dieter M.
Published: January 2008

Inhaled
Yersinia pestis
produces a severe primary pneumonia known as pneumonic plague, which is contagious and highly lethal to humans and animals. In this study, we first determined the susceptibility of
Y. pestis
KIM6 to antimicrobial molecules of the airways. We found that (i) rat bronchoalveolar lavage fluid (rBALF) effectively killed KIM6 cells growing at 37°C; (ii) the antibacterial components of rBALF were small peptides (<10 kDa) that included two cationic antimicrobial peptides (CAMPs), the rat cathelicidin rCRAMP, and β-defensin RBD-1; (iii) the human cathelicidin LL-37 killed KIM6 cells as well as rBALF did; and (iv) the bactericidal property of LL-37 was synergistically amplified by human β-defensin 1, another constitutively expressed pulmonary CAMP. Second, the effects of three major surface proteins of
Y. pestis
, namely, the capsular antigen fraction 1 (F1), the pH 6 antigen (Psa fimbriae), and the outer membrane protease Pla, on the bactericidal effect of the antimicrobial rBALF peptides was determined with corresponding deletion mutants. We showed that (i) a
Y. pestis psa
mutant was only slightly more susceptible to rBALF than the parental KIM6 strain, (ii) a
caf
(F1 gene) mutant and a
caf psa
mutant were resistant to rBALF or LL-37, (iii) a
caf pla
mutant was as susceptible to the effect of rBALF or LL-37 as KIM6 was (
caf
+
pla
+
), and (iv) only the single
caf
mutant (
pla
+
), but not KIM6 or the
caf pla
double mutant, degraded LL-37. The activity of Pla toward LL-37 was confirmed with
pla
mutants carrying a single-residue substitution affecting plasminogen cleavage. Taken together, our data indicated that Pla might act as a virulence factor not only by processing plasminogen but also by inactivating CAMPs, particularly when F1 is not expressed.
Mining the
Moraxella catarrhalis
Genome: Identification of Potential Vaccine Antigens Expressed during Human Infection
Authors: Ruckdeschel Elizabeth A. , Kirkham Charmaine , Lesse Alan J. , Hu Zihua , Murphy Timothy F.
Published: January 2008

Moraxella catarrhalis
is an important cause of respiratory infections in adults and otitis media in children. Developing an effective vaccine would reduce the morbidity, mortality, and costs associated with such infections. An unfinished genome sequence of a strain of
M. catarrhalis
available in the GenBank database was analyzed, and open reading frames predicted to encode potential vaccine candidates were identified. Three genes encoding proteins having molecular masses of approximately 22, 75, and 78 kDa (designated Msp [
Moraxella s
urface
p
roteins]) (
msp22
,
msp75
, and
msp78
, respectively) were determined to be conserved by competitive hybridization using a microarray, PCR, and sequencing of the genes in clinical isolates of
M. catarrhalis
. The genes were transcribed when
M. catarrhalis
was grown in vitro. These genes were amplified by PCR and cloned into
Escherichia coli
expression vectors. Recombinant proteins were generated and then studied using enzyme-linked immunosorbent assays with preacquisition and postclearance serum and sputum samples from 31 adults with chronic obstructive pulmonary disease (COPD) who acquired and cleared
M. catarrhalis
. New antibody responses to the three proteins were observed for a small proportion of the patients with COPD, indicating that these proteins were expressed during human infection. These studies indicate that the Msp22, Msp75, and Msp78 proteins, whose genes were discovered using genome mining, are highly conserved among strains, are expressed during human infection with
M. catarrhalis
, and represent potential vaccine antigens.
αB-Crystallin Protects Retinal Tissue during
Staphylococcus aureus
- Induced Endophthalmitis
Authors: Whiston Emily A. , Sugi Norito , Kamradt Merideth C. , Sack Coralynn , Heimer Susan R. , Engelbert Michael , Wawrousek Eric F. , Gilmore Michael S. , Ksander Bruce R. , Gregory Meredith S.
Published: January 2008

Bacterial infections of the eye highlight a dilemma that is central to all immune-privileged sites. On the one hand, immune privilege limits inflammation to prevent bystander destruction of normal tissue and loss of vision. On the other hand, bacterial infections require a robust inflammatory response for rapid clearance of the pathogen. We demonstrate that the retina handles this dilemma, in part, by activation of a protective heat shock protein. During
Staphylococcus aureus
-induced endophthalmitis, the small heat shock protein αB-crystallin is upregulated in the retina and prevents apoptosis during immune clearance of the bacteria. In the absence of αB-crystallin, mice display increased retinal apoptosis and retinal damage. We found that
S. aureus
produces a protease capable of cleaving αB-crystallin to a form that coincides with increased retinal apoptosis and tissue destruction. We conclude that αB-crystallin is important in protecting sensitive retinal tissue during destructive inflammation that occurs during bacterial endophthalmitis.
Vibrio vulnificus
Biotype 2 Serovar E
gne
but Not
galE
Is Essential for Lipopolysaccharide Biosynthesis and Virulence
Authors: Valiente Esmeralda , Jiménez Natalia , Merino Susana , Tomás Juan M. , Amaro Carmen
Published: January 2008

This work aimed to establish the role of
gne
(encoding UDP-GalNAc 4-epimerase activity) and
galE
(encoding UDP-Gal-4-epimerase activity) in the biosynthesis of surface polysaccharides, as well as in the virulence for eels and humans of the zoonotic serovar of
Vibrio vulnificus
biotype 2, serovar E. DNA sequence data revealed that
gne
and
galE
are quite homologous within this species (≥90% homology). Mutation in
gne
of strain CECT4999 increased the surface hydrophobicity, produced deep alterations in the outer membrane architecture, and resulted in noticeable increases in the sensitivity to microcidal peptides (MP), to eel and human sera, and to phagocytosis/opsonophagocytosis. Furthermore, significant attenuation of virulence for eels and mice was observed. By contrast, mutation in
galE
did not alter the cellular surface, did not increase the sensitivity to MP, serum, or phagocytosis, and did not affect the virulence for fish and mice. The change in the attenuated-virulence phenotype produced by a mutation in
gne
was correlated with the loss of the O-antigen lipopolysaccharide (LPS), while the capsule was maintained. Complementation of a
gne
-deficient mutant restored the LPS structure together with the whole virulence phenotype. In conclusion,
gne
, but not
galE
, is essential for LPS biosynthesis and virulence in the zoonotic serovar of
V. vulnificus
biotype 2.
The Sho1 Sensor Regulates Growth, Morphology, and Oxidant Adaptation in
Aspergillus fumigatus
but Is Not Essential for Development of Invasive Pulmonary Aspergillosis
Authors: Ma Yan , Qiao Jianjun , Liu Wei , Wan Zhe , Wang Xiaohong , Calderone Richard , Li Ruoyu
Published: January 2008

Aspergillus fumigatus
is an important opportunistic fungal pathogen. This organism must be able to adapt to stress changes in the microenvironment during host invasion and systemic spread. The high-osmolarity-glycerol (HOG) mitogen-activated protein kinase (HOG-MAPK) signaling pathway plays an important role in regulating morphology, growth, and adaptation to stress and virulence in a number of fungal pathogens. The Sho1 adaptor protein is one important element of the two upstream branches of the HOG-MAPK pathway in
Saccharomyces cerevisiae
, a signal transduction cascade involved in adaptation to stress. We constructed a
sho1
mutant of
A. fumigatus
, MA21. Both the growth and germination rates of the mutant were reduced, and the MA21 strain had an irregular hyphal morphology characterized by reduced production of phialides and conidia. This gene deletion mutant was sensitive to 2.5 mM hydrogen peroxide and 15 μM menadione, but it appeared to be minimally sensitive to diamide compared to the wild-type strain. In an immunosuppressed mouse model, the mutant was as virulent as the wild-type or complemented strains. These data support the idea that the loss of
sho1
, a highly conserved gene among fungi, regulates radial hyphal growth and delays germination of
A. fumigatus
conidia. In addition, the
sho1
gene has a visible effect in the adaptation to oxidative stress in
A. fumigatus
similar to that in
S. cerevisiae
.
Braun Lipoprotein (Lpp) Contributes to Virulence of Yersiniae: Potential Role of Lpp in Inducing Bubonic and Pneumonic Plague
Authors: Sha Jian , Agar Stacy L. , Baze Wallace B. , Olano Juan P. , Fadl Amin A. , Erova Tatiana E. , Wang Shaofei , Foltz Sheri M. , Suarez Giovanni , Motin Vladimir L. , Chauhan Sadhana , Klimpel Gary R. , Peterson Johnny W. , Chopra Ashok K.
Published: January 2008

Yersinia pestisevolved fromY. pseudotuberculosisto become the causative agent of bubonic and pneumonic plague. We identified a homolog of theSalmonella entericaserovar Typhimurium lipoprotein (lpp) gene inYersiniaspecies and preparedlppgene deletion mutants ofY. pseudotuberculosisYPIII,Y. pestisKIM/D27 (pigmentation locus minus), andY. pestisCO92 with reduced virulence. Mice injected via the intraperitoneal route with 5 × 107CFU of the ΔlppKIM/D27 mutant survived a month, even though this would have constituted a lethal dose for the parental KIM/D27 strain. Subsequently, these ΔlppKIM/D27-injected mice were solidly protected against an intranasally administered, highly virulentY. pestisCO92 strain when it was given as five 50% lethal doses (LD50). In a parallel study with the pneumonic plague mouse model, after 72 h postinfection, the lungs of animals infected with wild-type (WT)Y. pestisCO92 and given a subinhibitory dose of levofloxacin had acute inflammation, edema, and masses of bacteria, while the lung tissue appeared essentially normal in mice inoculated with the Δlppmutant of CO92 and given the same dose of levofloxacin. Importantly, while WTY. pestisCO92 could be detected in the bloodstreams and spleens of infected mice at 72 h postinfection, the Δlppmutant of CO92 could not be detected in those organs. Furthermore, the levels of cytokines/chemokines detected in the sera were significantly lower in animals infected with the Δlppmutant than in those infected with WT CO92. Additionally, the Δlppmutant was more rapidly killed by macrophages than was the WT CO92 strain. These data provided evidence that the Δlppmutants of yersiniae were significantly attenuated and could be useful tools in the development of new vaccines.
High-power (80 W) potassium titanyl phosphate laser prostatectomy in 128 high-risk patients
Authors: Yuan J , Wang H , Wu G , Liu H , Zhang Y , Yang L
Published: January 2008

Objective

To evaluate the safety and merits of 80 W potassium titanyl phosphate (KTP) laser prostatectomy in men with high cardiovascular or pulmonary risk, receiving oral anticoagulant medication, or with bleeding disorders.

Methods

A prospective clinical trial was performed in 128 high-risk men with benign prostatic hyperplasia who underwent photoselective vaporisation of the prostate (PVP). The operation time, postoperative serum sodium and packed cell volume were recorded. The International Prostate Symptom Score (IPSS), maximal flow rate (Qmax) and post-void residual urine volume (PVR) were measured at every follow-up visit.

Results

In all patients, KTP laser prostatectomy was performed successfully. The mean (SD) operation time was 51.6 (22.8) min. No blood transfusions were required. No major complications occurred during surgery, and there was no mortality. The mean (SD) catheterisation time was 2.8 (1.6) days. IPSS decreased from 19.2 (6.1) before surgery to 11.5 (8.2), 7.8 (6.4), 6.7 (5.3) and 6.1 (4.6), respectively, at 1, 3, 6 and 12 months after. Qmax increased from 7.0 (2.8) ml/s to 14.5 (9.3), 20.2 (11.5), 21.3 (8.6) and 24.8 (8.0) ml/s, respectively. PVR decreased from 168 (89) ml to 35 (29), 30 (26), 27 (21) and 23 (34) ml, respectively.

Conclusions

80 W KTP laser prostatectomy is a virtually bloodless, safe and effective procedure for men with high cardiovascular or pulmonary risk or bleeding disorders or taking oral anticoagulant medication.
Multiple physical urticarias
Authors: Torchia D , Francalanci S , Bellandi S , Fabbri P
Published: January 2008

Physical urticarias are a group of mucocutaneous disorders characterised by the appearance of whealing and/or angioedema and induced by physical stimuli. A 24-year-old Caucasian male affected by ultraviolet A-induced solar urticaria, specific food-dependent exercise-induced anaphylaxis, symptomatic dermographism and allergic rhinoconjunctivitis is described.
Sleep-disordered breathing and cardiovascular disease
Authors: Amit Benjamin J , Lewis K E
Published: January 2008

Sleep-disordered breathing (SDB) describes a group of disorders characterised by abnormalities in the frequency and/or depth of breathing while asleep. The most common type is the obstructive sleep apnoea/hypopnoea syndrome (OSAHS); it affects 2–4% of the adult population and is an independent risk factor for hypertension. Another type is central sleep apnoea (CSA), which includes Cheyne–Stokes respiration; it is most commonly seen in patients with congestive heart failure and other critical illnesses including cerebrovascular accidents. There is accumulating evidence that both these types of SDB are associated with cardiac failure, arrhythmias and coronary artery disease. Treatment of OSAHS with continuous positive airway pressure (CPAP) has lowered blood pressure, reduced the frequency and severity of some arrhythmias, and improved markers of endovascular inflammation. CPAP has had a mild positive effect on left ventricular function in chronic heart failure by treating co-existent SDB, but it has not improved mortality, possibly because it does not fully treat associated CSA. Clinicians need to be aware of the increasing associations of SDB, especially OSAHS, with cardiovascular dysfunction, as treatment of co-existent SDB will not only improve sleepiness, quality of life, and driving risk, but there is growing evidence that it may also improve cardiovascular risk itself, even in non-sleepy subjects.