Pituitary hypoplasia and respiratory distress syndrome in Prop1 knockout mice.

Mutations in Prophet of PIT1 (Prop1), one of several homeodomain transcription factors that are required for the development of the anterior pituitary gland, are the predominant cause of MPHD (multiple pituitary hormone deficiency) in humans. We show that deletion of Prop1 in mice causes severe pituitary hypoplasia with failure of the entire Pit1 lineage and delayed gonadotrope development. The pituitary hormone deficiencies cause secondary endocrine problems and a high rate of perinatal mortality due to respiratory distress.

Fatal multifocal metastasis of Clostridium septicum: a case report.

Clostridium septicum infection produces rapidly spreading tissue necrosis, often, but not exclusively, associated with trauma or large bowel malignancy. We present a unique case of atraumatic infection leading to multifocal metastatic spread in a neutropenic patient, emphasising the devastating potential of this disease.

Scc2 couples replication licensing to sister chromatid cohesion in Xenopus egg extracts.

The cohesin complex is a central player in sister chromatid cohesion, a process that ensures the faithful segregation of chromosomes in mitosis and meiosis. Previous genetic studies in yeast show that Scc2/Mis4, a HEAT-repeat-containing protein, is required for the loading of cohesin onto chromatin. In this study, we have identified two isoforms of Scc2 in humans and Xenopus (termed Scc2A and Scc2B), which are encoded by a single gene but have different carboxyl termini created by alternative splicing.

Cadherin 23 is a component of the tip link in hair-cell stereocilia.

Mechanoelectrical transduction, the conversion of mechanical force into electrochemical signals, underlies a range of sensory phenomena, including touch, hearing and balance. Hair cells of the vertebrate inner ear are specialized mechanosensors that transduce mechanical forces arising from sound waves and head movement to provide our senses of hearing and balance; however, the mechanotransduction channel of hair cells and the molecules that regulate channel activity have remained elusive. One molecule that might participate in mechanoelectrical transduction is cadherin 23 (CDH23), as mutations in its gene cause deafness and age-related hearing loss.

Quantification of T(2) relaxation changes in articular cartilage with in situ mechanical loading of the knee.

Purpose: To devise a method for producing in vivo MRI images of the knee under physiologically significant loading, and to compare and evaluate the changes in cartilage characteristics before and during in situ compression of the knee.

Material And Methods: A total of 26 asymptomatic subjects were imaged on a 1.5 Tesla Philips Intera scanner using a commercially available knee coil.

Myosin-1c, the hair cell's adaptation motor.

Given their prominent actin-rich subcellular specializations, it is no surprise that mechanosensitive hair cells of the inner ear exploit myosin molecules-the only known actin-dependent molecular motors-to carry out exotic but essential tasks. Recent experiments have confirmed that an unconventional myosin isozyme, myosin-1c, is a component of the hair cell's adaptation-motor complex. This complex carries out slow adaptation, provides tension to sensitize transduction channels, and may participate in assembly of the transduction apparatus.

Chemical-genetic inhibition of a sensitized mutant myosin Vb demonstrates a role in peripheral-pericentriolar membrane traffic.

Selective, in situ inhibition of individual unconventional myosins is a powerful approach to determine their specific physiological functions. Here, we report the engineering of a myosin Vb mutant that still hydrolyzes ATP, yet is selectively sensitized to an N(6)-substituted ADP analog that inhibits its activity, causing it to remain tightly bound to actin. Inhibition of the sensitized mutant causes inhibition of accumulation of transferrin in the cytoplasm and increases levels of plasma-membrane transferrin receptor, suggesting that myosin Vb functions in traffic between peripheral and pericentrosomal compartments.

Developmental assembly of transduction apparatus in chick basilar papilla.

Hair cells, the sensory receptors of auditory and vestibular systems, use a transducer apparatus that renders them remarkably sensitive to mechanical displacement as minute as 1 nm. To study the embryonic development of the transducer apparatus in hair cells of the chick auditory papilla, we examined hair cells that have been labeled with N-(3-triethylammoniumpropyl)-4-(4-(dibutylamino)styryl) pyridiniumdibromide, which has been shown to permeate the transducer channels. In addition, mechanotransduction currents were recorded directly using whole-cell patch-clamp techniques.

A prospective trial of variable stiffness pediatric vs. standard instrument colonoscopy.

Background: The pediatric variable stiffness colonoscope is believed to have theoretical advantages over the standard colonoscope, however a systematic evaluation of this instrument in routine clinical practice involving adult patients is lacking.

Methods: Consecutive patients (blinded) undergoing colonoscopy in an outpatient endoscopy center by one of 4 experienced colonoscopists had the procedure performed with a standard colonoscope (n=384) or pediatric variable stiffness colonoscope (n=413). Failure to negotiate the sigmoid colon within 10 minutes was regarded as a failure and, if suitable, the patient was crossed over to colonoscopy with the alternative instrument.

Accessing wound-care information on the Internet: the implications for patients.

The Internet and the World Wide Web have revolutionised communication and provide a unique forum for the exchange of information. It has been proposed that the Internet has given the public more access to medical information resources and improved patient education. This study assessed the impact of the Internet on the availability of information on wound care management.

A critical review of vascular endothelial growth factor (VEGF) analysis in peripheral blood: is the current literature meaningful?

Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor with a key role in many physiological and pathological processes. Investigation into the implications of circulating levels of this cytokine is progressing at an exponential rate. However, there are important inconsistencies between reports ranging from method of sample collection, processing, software manipulation and data interpretation and controversy as to whether plasma, serum or whole blood will provide the best prognostic information.

Myosin-I isozymes in neonatal rodent auditory and vestibular epithelia.

Myosin isozymes are essential for hair cells, the sensory cells of the inner ear. Because a myosin-I subfamily member may mediate adaptation of mechanoelectrical transduction, we examined expression of all eight myosin-I isozymes in rodent auditory and vestibular epithelia. Using RT-PCR, we found prominent expression of three isozymes, Myo1b (also known as myosin-Ia or myr 1).

Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits.

Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons.

Calmodulin binding to recombinant myosin-1c and myosin-1c IQ peptides.

Background: Bullfrog myosin-1c contains three previously recognized calmodulin-binding IQ domains (IQ1, IQ2, and IQ3) in its neck region; we identified a fourth IQ domain (IQ4), located immediately adjacent to IQ3. How calmodulin binds to these IQ domains is the subject of this report.

Results: In the presence of EGTA, calmodulin bound to synthetic peptides corresponding to IQ1, IQ2, and IQ3 with Kd values of 2-4 microM at normal ionic strength; the interaction with an IQ4 peptide was much weaker.

Simulation of the passive infrared spectral signatures of bioaerosol and natural fog clouds immersed in the background atmosphere.

At first glance, an examination of the bulk refractive indices for the 8-12 microm waveband of various bioaerosols suggests differentiation with respect to common background aerosols based upon the spectral characteristics of the absorption. The question of whether there is a spectral signature of bioaerosol clouds when those clouds are immersed in a typical atmosphere, including the boundary layer background aerosols, has been addressed in a simulation using the Weather and Atmospheric Visualization Effects for Simulation (WAVES) suite of codes. Using measured values of the refractive index for common bacterial spores, and their typical size distributions, the single-scattering, ensemble-averaged optical properties such as extinction/absorption coefficients, albedo, and the scattering phase function was computed for bioaerosol clouds at a resolution of 1 cm-1.

The hair cell's transduction channel.

The elusive transduction channel is the key player in mechanical transduction by the sensory hair cells of the inner ear. Multiple factors have thwarted molecular identification of this channel, including the lack of a definitive pharmacological signature, the paucity of hair cells, and the uniqueness of their transduction mechanism. At present, we are forced to speculate as to the transduction channel's identity; functional characteristics suggest, however, that it may well belong to transient receptor potential superfamily of ion channels.

A novel form of the RelA nuclear factor kappaB subunit is induced by and forms a complex with the proto-oncogene c-Myc.

Members of both Myc and nuclear factor kappaB (NF-kappaB) families of transcription factors are found overexpressed or inappropriately activated in many forms of human cancer. Furthermore, NF-kappaB can induce c-Myc gene expression, suggesting that the activities of these factors are functionally linked. We have discovered that both c-Myc and v-Myc can induce a previously undescribed, truncated form of the RelA(p65) NF-kappaB subunit, RelA(p37).

Myosin-1c interacts with hair-cell receptors through its calmodulin-binding IQ domains.

Myosin-1c plays an essential role in adaptation of hair-cell mechanoelectrical transduction. To mediate adaptation, myosin-1c must interact directly or indirectly with other components of the transduction apparatus, including the mechanically gated transduction channel. As a first step toward identifying myosin-1c receptors, we used recombinant myosin-1c fragments to identify specific binding sites in hair cells and to biochemically characterize their interaction with myosin-1c.

A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells.

Myosin-1c (also known as myosin-Ibeta) has been proposed to mediate the slow component of adaptation by hair cells, the sensory cells of the inner ear. To test this hypothesis, we mutated tyrosine-61 of myosin-1c to glycine, conferring susceptibility to inhibition by N(6)-modified ADP analogs. We expressed the mutant myosin-1c in utricular hair cells of transgenic mice, delivered an ADP analog through a whole-cell recording pipette, and found that the analog rapidly blocked adaptation to positive and negative deflections in transgenic cells but not in wild-type cells.

Development of a virtual screening method for identification of "frequent hitters" in compound libraries.

A computer-based method was developed for rapid and automatic identification of potential "frequent hitters". These compounds show up as hits in many different biological assays covering a wide range of targets. A scoring scheme was elaborated from substructure analysis, multivariate linear and nonlinear statistical methods applied to several sets of one and two-dimensional molecular descriptors.