Etching kinetics of a self-etching primer

Self-etching primers are thought to offer significant advantages over total-etch adhesive systems. The hypothesis tested in this study was that there was no difference in etching characteristics between a self-etching primer and a phosphoric acid solution at the same pH. Etching was assessed using atomic force microscopy (AFM) evaluation of site-specific changes in the height of the peritubular and intertubular dentin as a function of exposure time. Human dentin disks (n = 6/group), prepared with an acid-resistant glass reference layer, were etched with a self-etching primer and with 0.0134 M phosphoric acid (both pH approximately egual to 1.94). Depth changes relative to the reference layer were measured with the AFM after each etching interval, at 15 different locations, each in the peritubular and intertubular dentin. The total demineralization depth was measured in a scanning electron microscope. Peritubular dentin etching rate was linear while it could be measured (up to 15 s) and was greater for the self-etching primer (p < 0.0001). Intertubular dentin displayed a similar demineralization pattern with both acids, ultimately reaching a plateau in the majority of specimens. The self-etching primer attained a plateau after less recession than phosphoric acid (p < 0.0001). Dentin demineralization appears to be affected by other factors in addition to the pH of the etchant solutions.     

GABAA receptors and benzodiazepines: a role for dendritic resident subunit mRNAs

This review is designed to describe the evolution of the seminal observation made simultaneously in 1975 by Dr. W. Haefely's laboratory (Hoffman La Roche, Basel, Switzerland) and in the Laboratory of Preclinical Pharmacology (NIH, St. Elizabeths Hospital, Washington DC), that benzodiazepine action was mediated by a modulation of GABA action at GABA(A) receptors. In fact, our suggestion was that the benzodiazepine receptor was "a receptor on a receptor" and that this receptor was GABA(A). Needless to say, this suggestion created opposition, but we did not abandon the original idea, in fact, as shown in this review, there is now universal agreement with our hypothesis on the mode of action of benzodiazepines. Hence, this review deals with the allosteric modulation of GABA(A) receptors by benzodiazepines, the role of GABA(A) receptors and benzodiazepine structure diversities in this modulation, and describes the results of our attempts to establish a benzodiazepine (imidazenil) devoid of tolerance, withdrawal symptoms, and changes in the expression of GABA(A) receptor subunits during tolerance. It also deals with the idea that the synthesis of GABA(A) receptor subunits triggered by tolerance resides in dendrites and spines where mRNAs and the apparatus for this translation is located. New analytic procedures may foster progress in the understanding of tolerance to and withdrawal from benzodiazepines.     

Salmon GnRH and its analogues bind the human placental receptor

OBJECTIVE: The presence of GnRH receptors in the human placenta has been recognized for a number of years. However, mammalian GnRH, which is expressed in placental tissues, has limited affinity for the chorionic receptor. On the basis of immunological and bioactivity data, we have previously proposed that the chorionic GnRH may differ from mammalian GnRH. METHODS: We have studied the affinity of another isoform of GnRH (ie, salmon GnRH and stable analogues of this GnRH isoform), and compared their receptor affinity to that of mammalian GnRH and its analogues. RESULTS: Using our receptor assay method with the labeled mammalian GnRH analogue Buserelin, salmon GnRH had a twofold greater affinity for the placental GnRH receptor than did mammalian GnRH and for the stable salmon GnRH analogue the affinity was increased tenfold. Using a homologous receptor assay method with a stable salmon GnRH analogue as label, the affinity for this salmon GnRH analogue had a K(d) of 101 nmol/L. CONCLUSION: The presence of these higher affinity receptors for non-mammalian GnRH in the human placenta has led us to propose that the chorionic tissues may express more than one isoform of GnRH and that non-mammalian GnRH, such as salmon GnRH, may be potent regulators of placental functions.     

Carcinosarcoma of the uterine cervix: a report of eight cases with immunohistochemical analysis and evaluation of human papillomavirus status

Carcinosarcomas (malignant Müllerian mixed tumors [MMMTs]) of the uterine cervix are rare neoplasms. This report describes the morphology, immunohistochemical profiles, and human papillomavirus (HPV) status of eight cervical MMMTs. Patients' ages ranged from 32 to 93 years (mean, 61 years). Seven cases showed in situ squamous cell carcinoma (SCC). The invasive epithelial component (EC) was composed of combined adenoid basal carcinoma, basaloid SCC, and adenoid cystic carcinoma (ACC) in two cases. Keratinizing SCC, large cell nonkeratinizing SCC, undifferentiated carcinoma, and basaloid SCC predominated in the remaining tumors, one of which had admixed ACC. The sarcomatous component (SC) was homologous and spindled with admixed myxoid areas in three lesions. The ECs and SCs in six MMMTs showed dual immunostaining with epithelial membrane antigen and the pan-keratin marker, MNF116. The SC was vimentin-positive in seven cases. Five tumors had a vimentin-positive EC. The SC was positive for muscle specific actin and/or smooth muscle actin in seven lesions, of which four were desmin-positive. Polymerase chain reaction (PCR) using GP5+/GP6+ L1 consensus primers detected HPV DNA in all eight cases. Nonisotopic in situ hybridization with digoxigenin-labeled probes to HPV types 6, 11, 16, 18, 31 and 33 demonstrated integrated HPV 16 in three cases, not only in the EC, but also in nuclei of the SC. This is the first study to implicate HPV in the evolution of cervical MMMTs. The above observations lend support to a metaplastic theory of histogenesis.     

The Impact of Neurodegenerative Disorders on Ageing: an Overview of the Sydney Older Persons Study

Abstract . This paper reviews the Sydney Older Persons Study, a longitudinal study following an initial cohort of 630 subjects aged 75 and over, community living in the inner west region of Sydney, carried out over seven years in four waves from 1991. We discuss the epidemiology of neurodegenerative disorders (NDDs) in relation to: each other, systemic disorders, death, lifestyle, risk factors and their impact on quality of life, service use and carers.     

Clinical Diagnosis and Disability Among Community Dwellers Aged 75 and Over: The Sydney Older Persons Study

Objectives : Disability is an important predictor of health and community service utilisation. Understanding its pathogenesis has implications for planning of future health services. The aim of our study was to examine the contribution of systemic, psychiatric and neurodegenerative diseases to disability in an “old‐old” population. Methods : 647 men and women over the age of 75 participated in the Sydney Older Person's Study. Disability in activities of daily living (ADL), instrumental activities of daily living (IADL) and mobility was assessed using self report, informant and clinician assessments. Diagnoses of systemic, psychiatric, neurodegenerative diseases were made by clinicians. Individual disease contribution to disability was assessed using multiple regression analysis. Contribution to disability by the groups of systemic, neurodegenerative and psychiatric diagnoses was assessed, using hierarchical regression. Results : Neurodegenerative diseases were the major contributors to ADL impairment. Systemic and psychiatric diseases played a role in IADL and mobility impairment, as did the neurodegenerative diseases. Of the neurodegenerative diseases, dementia/cognitive impairment and Parkinsonism/gait slowing particularly contributed to disability. Self‐report under‐identified the role of the neurodegenerative diseases in disability. It also introduced a gender effect, that the clinical measures did not share to the same extent. Conclusions : Neurodegenerative diseases are important contributors to disability and assessments and diagnosis of neurodegenerative diseases should be included in disability assessments. Self report under‐identifies the importance of these conditions.     

Antiperspirants and the hyperhidrosis patient

Hyperhidrosis is the production of excess sweat of the armpits, hands, feet, or face. The sweating can be simply unsightly or a true impairment to the optimal functioning of children and adults. This dermatologic problem can be treated with topical antiperspirants, oral medications, or by injections of botulinum toxin. This article examines the physiology of sweat reduction and the efficacy of various therapies, and presents a practical approach for the treatment of this condition.     

New insights into tumor microstructure using temporal diffusion spectroscopy

Magnetic resonance images (MRI) that depict rates of water diffusion in tissues can be used to characterize the cellularity of tumors and are valuable in assessing their early response to treatment. Water diffusion rates are sensitive to the cellular and molecular content of tissues and are affected by local microstructural changes associated with tumor development. However, conventional maps of water diffusion reflect the integrated effects of restrictions to free diffusion at multiple scales up to a specific limiting spatial dimension, typically several micrometers. Such measurements cannot distinguish effects caused by structural variations at a smaller scale. Variations in diffusion rates then largely reflect variations in the density of cells, and no information is available about changes on a subcellular scale. We report here our experiences using a new approach based on Oscillating Gradient Spin-Echo (OGSE) MRI methods that can differentiate the influence on water diffusion of structural changes on scales much smaller than the diameter of a single cell. MRIs of glioblastomas in rat brain in vivo show an increased contrast and spatial heterogeneity when diffusion measurements are selectively sensitized to shorter distance scales. These results show the benefit of OGSE methods for revealing microscopic variations in tumors in vivo and confirm that diffusion measurements depend on factors other than cellularity.     

Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine in healthy premature infants

BACKGROUND: Premature infants seem to be at greater risk of hospitalization from rotavirus gastroenteritis than term infants. Safety and efficacy of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine were assessed in premature infants enrolled in the large-scale, blinded, placebo-controlled rotavirus efficacy and safety trial (REST). METHODS: Healthy infants 6-12 weeks of chronologic age at study entry were randomized to receive 3 oral doses of pentavalent rotavirus vaccine or placebo at 4- to 10-week intervals. Infants born at < or =36 weeks of gestational age were eligible if thriving at the time of enrollment. Safety and efficacy were retrospectively assessed in these premature infants comparing vaccine with placebo recipients. Cases of rotavirus gastroenteritis were defined as forceful vomiting and/or > or =3 watery or looser-than-normal stools within a 24-hour period, accompanied by detection of rotavirus antigen in the stool. RESULTS: A total of 2070 infants between 25 and 36 gestational weeks received at least 1 dose of vaccine or placebo; 1005 vaccine recipients and 1061 placebo recipients were evaluable for safety. Serious adverse events occurred in 55 vaccine recipients (5.5%) and 62 placebo recipients (5.8%). In a nested substudy of 308 premature infants evaluable for detailed safety (154 in each group), the frequencies of fever, diarrhea, vomiting, and irritability were comparable between vaccine and placebo recipients. Overall, 3 doses of the pentavalent vaccine reduced the rate of hospitalizations and emergency department visits in premature infants due to rotavirus gastroenteritis by 100% (95% CI: 82.2-100) compared with placebo. The vaccine also prevented 73.0% (95% CI: -2.2-95.2) of rotavirus gastroenteritis cases of any severity. CONCLUSIONS: In this post hoc analysis of healthy premature infants, the pentavalent rotavirus vaccine was generally well-tolerated and substantially reduced rotavirus-attributable hospitalizations and emergency department visits compared with placebo. Overall, vaccine safety and efficacy seemed to be generally comparable to the results in the REST study population as a whole. These results support vaccinating healthy premature infants on the same schedule as term infants.     

Low-dose rectal inoculation of rhesus macaques by SIVsmE660 or SIVmac251 recapitulates human mucosal infection by HIV-1

We recently developed a novel strategy to identify transmitted HIV-1 genomes in acutely infected humans using single-genome amplification and a model of random virus evolution. Here, we used this approach to determine the molecular features of simian immunodeficiency virus (SIV) transmission in 18 experimentally infected Indian rhesus macaques. Animals were inoculated intrarectally (i.r.) or intravenously (i.v.) with stocks of SIVmac251 or SIVsmE660 that exhibited sequence diversity typical of early-chronic HIV-1 infection. 987 full-length SIV env sequences (median of 48 per animal) were determined from plasma virion RNA 1–5 wk after infection. i.r. inoculation was followed by productive infection by one or a few viruses (median 1; range 1–5) that diversified randomly with near starlike phylogeny and a Poisson distribution of mutations. Consensus viral sequences from ramp-up and peak viremia were identical to viruses found in the inocula or differed from them by only one or a few nucleotides, providing direct evidence that early plasma viral sequences coalesce to transmitted/founder viruses. i.v. infection was >2,000-fold more efficient than i.r. infection, and viruses transmitted by either route represented the full genetic spectra of the inocula. These findings identify key similarities in mucosal transmission and early diversification between SIV and HIV-1, and thus validate the SIV–macaque mucosal infection model for HIV-1 vaccine and microbicide research.An effective HIV-1 vaccine, microbicide, or other pre- or post-exposure prophylactic must interdict virus at or near the moment of mucosal transmission or in the early period preceding the establishment of viral latency and disseminated infection (1–4). In humans, it has been difficult to study these earliest viral host events in vivo (2, 5–13), and in tissue explant cultures or in Indian rhesus macaques the HIV-1 or simian immunodeficiency virus (SIV) inocula have typically been high to achieve uniform infection of controls or to visualize infection events in situ (14–20), thus prompting concerns about the physiological relevance of the model systems (21–24). Further complicating the analysis of early infection events in vivo is the viral “eclipse” period during which virus replicates in mucosal and locoregional lymphoreticular tissues but is not yet detectable in the circulating plasma (25). In SIV-infected macaques, the eclipse period is generally ∼4–7 d in duration, and in HIV-1–infected humans, it is ∼7–21 d (5, 18, 25–27).Previously, we observed that in the early stages of HIV-1 infection preceding antibody seroconversion (eclipse phase and Fiebig stages I and II [25]), virus diversification follows a pattern of random evolution with an almost starlike phylogeny and a Poisson distribution of nucleotide substitutions (5). We thus hypothesized that the genetic identity of transmitted or early founder viruses could be inferred unambiguously by phylogenetic analysis of discrete low-diversity viral lineages that emanate from them. This hypothesis was supported by an analysis of 3,449 full-length env genes from 102 human subjects with acute HIV-1 subtype B infection, where we found that (a) acute viral sequences sampled before the development of measurable adaptive immune responses conformed to a pattern of random virus evolution; (b) viral sequence diversity resulted in model estimates of time to a most recent common ancestor (MRCA) that was consistent with clinical histories and Fiebig stage classifications; and (c) in most subjects (78 of 102) there was evidence of productive infection by only a single virus, whereas in 24 other subjects infection resulted from transmission of at least 2 to 5 viruses, each recognizable as a discrete virus lineage (5). These findings have since been corroborated in seven additional patient cohorts infected by HIV-1 subtypes A, B, C, or D (28–35). A key innovation common to these studies was the use of singe-genome amplification (SGA) of plasma viral RNA, followed by direct amplicon sequencing to characterize the virus quasispecies (5, 35–39). This method provides proportional representation of plasma viral RNA (vRNA) and precludes Taq polymerase-induced template switching (recombination), Taq polymerase-associated nucleotide substitutions in finished sequences, template resampling, and cloning bias (5, 35, 37, 38, 40).In this study, we sought to directly test our strategy for identifying transmitted/founder viruses in the Indian rhesus macaque SIV infection model where we could define essential experimental parameters, including the route of SIV infection, genetic composition of the inoculum, and the duration between virus inoculation and sampling of plasma vRNA. The primary study objectives were twofold: first, to determine if, as our hypothesis and model predict, plasma SIV sequences sampled at or near peak viremia coalesce to sequences of viruses responsible for transmission and productive clinical infection weeks earlier; and second, to determine how closely a low-dose SIV rectal transmission model in Indian rhesus macaques recapitulates features of human infection by HIV-1, including the extent of the mucosal barrier to virus transmission, the number of transmitted/founder viruses leading to productive infection, and the molecular patterns of early virus diversification.