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Introduction and hypothesis Stress urinary incontinence (SUI) and pelvic organ prolapse (POP) are common pelvic floor disorders (PFDs). Owing to significant adverse events associated with mesh-related pelvic floor procedures (PFPs) in a proportion of the surgically treated population, and deficits in collection and reporting of these events, the Australian Government identified an urgent need for a tracking mechanism to improve safety and quality of care. The Australasian Pelvic Floor Procedure Registry (APFPR) was recently established following the 2018 Senate Committee Inquiry with the aim of tracking outcomes of PFP involving the use of devices and/or prostheses, with the objective of improving the health outcomes of women who undergo these procedures. This paper will describe the APFPR’s aims, development, implementation and possible challenges on the way to its establishment. Methods The APFPR has been developed and implemented in accordance with the national operating principles of clinical quality registries (CQRs). The minimum datasets (MDS) for the registry’s database have been developed using a modified Delphi process, and data are primarily being collected from participating surgeons. Patient recruitment is based on an opt-out approach or a waiver of consent. Patient-reported outcome measures (PROMs) providing additional health and outcome information will be obtained from participating women to support safety monitoring of mesh-related adverse events. Results Currently in the Australasian Pelvic Floor Procedure Registry (APFPR) there are 32 sites from various jurisdictions across Australia, that have obtained relevant ethics and governance approvals to start patient recruitment and data collection as of January 2023. Additionally, there are two sites that are awaiting governance review and five sites that are having documentation compiled for submission. Seventeen sites have commenced patient registration and have entered data into the database. Thus far, we have 308 patients registered in the APFPR database. The registry also published its first status report and a consumer-friendly public report in 2022. Conclusions The registry will act as a systematic tracking mechanism by collecting outcomes on PFP, especially those involving devices and/or prostheses to improve safety and quality of care.

The cochlea uses two types of mechanosensory cell to detect sounds. A single row of inner hair cells (IHCs) synapse onto neurons to transmit sensory information to the brain, and three rows of outer hair cells (OHCs) selectively amplify auditory inputs(1). So far, two transcription factors have been implicated in the specific differentiation of OHCs, whereas, to our knowledge, none has been identified in the differentiation of IHCs(2–4). One such transcription factor for OHCs, INSM1, acts during a crucial embryonic period to consolidate the OHC fate, preventing OHCs from transdifferentiating into IHCs(2). In the absence of INSM1, embryonic OHCs misexpress a core set of IHC-specific genes, which we predict are involved in IHC differentiation. Here we find that one of these genes, Tbx2, is a master regulator of IHC versus OHC differentiation in mice. Ablation of Tbx2 in embryonic IHCs results in their development as OHCs, expressing early OHC markers such as Insm1 and eventually becoming completely mature OHCs in the position of IHCs. Furthermore, Tbx2 is epistatic to Insm1: in the absence of both genes, cochleae generate only OHCs, which suggests that TBX2 is necessary for the abnormal transdifferentiation of INSM1-deficient OHCs into IHCs, as well as for normal IHC differentiation. Ablation of Tbx2 in postnatal, largely differentiated IHCs makes them transdifferentiate directly into OHCs, replacing IHC features with those of mature and not embryonic OHCs. Finally, ectopic expression of Tbx2 in OHCs results in their transdifferentiation into IHCs. Hence, Tbx2 is both necessary and sufficient to make IHCs distinct from OHCs and maintain this difference throughout development.

Maternal risks such as poor mental health, partner violence, and substance misuse can undermine child health and development. Maternal and early childhood home visiting programs address these risks primarily through referral and coordination with community-based services, yet effects on these outcomes have been small. This study assessed the strengths of local home visiting sites' systems to support coordination of mental health, partner violence, and substance use services. Investigators recruited home visiting sites (N = 88) representing diverse models from a national practice-based research network, the Home Visiting Applied Research Collaborative (HARC). Web-based surveys assessed five implementation system supports for coordination and nine coordination activities drawn from the Measurement Framework for Coordination developed earlier in the project. Surveys also assessed seven coordination barriers identified in previous research. Sites varied in their implementation supports and coordination activities; on average, sites had stronger systems in place to support screening and referring families than to support linkage and follow-up. Implementation supports and activity scores were higher for mental health and partner violence than for substance use. Across all service needs, scores were highest for offering a referral and documenting the caregiver's agreement for exchange of information between providers. Scores were lowest for offering a warm handoff. Lack of open slots and lack of transportation were major barriers to successful coordination for all three services. Results suggest that home visiting coordination could be strengthened by focusing on infrastructure for linkage and follow-up with services in the broader system of care.

The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death—most often of OHCs—is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1–3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC-specific differentiation. Conditional deletion of Insm1 in mice demonstrates that INSM1 is the key switch that causes the maturation of outer hair cells in the cochlea, with its absence resulting in an increase in inner hair cells instead.

The mammalian cochlea contains two types of mechanosensory hair cells (HCs) that play different and critical roles in hearing. Inner hair cells (IHCs), with an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, enabling enhanced sensitivity to sound and sharp tuning. Cochlear HCs are solely generated during development and their death, most often of OHCs, is the main cause of deafness. OHCs and IHCs, together with supporting cells, originate embryonically from the prosensory region of the otocyst, but how HCs differentiate into two different types is unknown1–3. Here we show that Insm1, which encodes a zinc finger protein transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1 many HCs born embryonically as OHCs switch fates to become mature IHCs. In order to identify the genetic mechanisms by which Insm1 operates, we compared transcriptomes of immature IHCs vs OHCs, as well as OHCs with and without INSM1. OHCs lacking INSM1 upregulate a set of genes, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals for the first time a mechanism by which these neighboring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs upregulating these few IHC-enriched transcripts trans-differentiate into IHCs, revealing the first candidate genes for IHC-specific differentiation.

INSM1 is a zinc-finger protein expressed throughout the developing nervous system in late neuronal progenitors and nascent neurons. In the embryonic cortex and olfactory epithelium, Insm1 may promote the transition of progenitors from apical, proliferative, and uncommitted to basal, terminally-dividing and neuron producing. In the otocyst, delaminating and delaminated progenitors express Insm1, whereas apically-dividing progenitors do not. This expression pattern is analogous to that in embryonic olfactory epithelium and cortex (basal/subventricular progenitors). Lineage analysis confirms that auditory and vestibular neurons originate from Insm1-expressing cells. In the absence of Insm1, otic ganglia are smaller, with 40% fewer neurons. Accounting for the decrease in neurons, delaminated progenitors undergo fewer mitoses, but there is no change in apoptosis. We conclude that in the embryonic inner ear, Insm1 promotes proliferation of delaminated neuronal progenitors and hence the production of neurons, a similar function to that in other embryonic neural epithelia. Unexpectedly, we also found that differentiating, but not mature, outer hair cells express Insm1, whereas inner hair cells do not. Insm1 is the earliest known gene expressed in outer versus inner hair cells, demonstrating that nascent outer hair cells initiate a unique differentiation program in the embryo, much earlier than previously believed.

Elected pope in the wake of a rebellion, Eugenius III came to power as a relative unknown during a time of crisis. This book examines the controversial developments in papal justice and theological debate during his pontificate, his treatment of Cistercian monasteries, his relationships with France, Spain, and Rome, his work in the papal states, and the crusades. It offers a new view of an under-appreciated pope and the place of the church in a rapidly changing European society.

This study evaluated discharge documentation for people with dementia who were discharged home, against expected discharge criteria and determined relationships between compliance scores and outcomes. This cross-sectional study audited discharge documentation and conducted a post discharge survey of carers. There were 73 eligible discharges and clinically significant documentation deficits for people with dementia included: risk assessments of confusion (48%), falls and pressure injury (56%); provision of medication dose-decision aids (53%), provision of contact information for patient support groups (6%) and advance care planning (9%). There was no significant relationship between compliance scores and outcomes. Carer strain was reported to be high for many carers. People with dementia and their carers are more vulnerable and at higher risk of poor outcomes after discharge. There are opportunities for improved provision of medications and risk assessment for people with dementia, provision of information for patient support groups and advanced care planning.

The purpose of this study was to provide evidence for the internal structure of the domain-general and context-specific components of future time perspective (FTP) and to provide support for a top-down structure of FTP theory. The participants included 546 engineering students from a large university in the southwest of the USA. The students responded to the Future Time Perspective Scale, the Perceptions of Instrumentality Scale, and the Student Perceptions of Classroom Knowledge-building Scale. Analyses present evidence for: (a) the structural fidelity of student responses to the respective theoretical constructs, and (b) the top down, domain-general to context-sensitive relation between FTP variables and student learning behavior. The results also indicate that students' use of knowledge building strategies may be influenced by both domain-general aspects of FTP and the perceived endogenous instrumentality of coursework. Implications include support for use of valid FTP measures and the recognition of the relation between FTP and value of present school activities.

Other Spaces is a collaborative creative arts exhibition project that explores visual and material expressions of cultural identity with a particular focus on museum collections. This project aims to provide a rich examination – visual, emotional and intellectual – of the multiple cultural narratives that contribute to the social fabric of Australia through a unique marriage of contemporary photomedia and creative writing practice. This project explores the ways that migrants and refugees have found to express their cultural identity through the material objects they have brought with them to Australia. Many of these objects are not only of great personal value but often of cultural, historical and religious significance. Some are very ordinary everyday objects but they can be highly evocative and symbolic of the relationship between culture and identity, and between the places of origin and an individual's present home in Australia. This article, through a combination of photography, creative text and scholarly discussion, will focus specifically on Italo-Australian migrants and on some of the material objects that they have donated to museum collections, and use these objects to explore notions of cultural belonging and identity.

Background The adverse effect of haemorrhagic complications after percutaneous coronary intervention (PCI) on outcome is well established with Helicobacter pylori infection known to be an important precipitant of peptic ulcer disease in patients receiving non-steroidal anti-inflammatory drug therapy. The prevalence of H. pylori positivity in patients undergoing PCI and receiving subsequent antiplatelet therapy is unknown. Aims: We sought to determine the prevalence and features associated with H. pylori positivity in patients undergoing PCI. Methods: All patients undergoing PCI between August 2008 and April 2009 were identified and assessed for H. pylori positivity with serological status determined by using a commercially supplied enzyme-linked immunosorbent assay. Results: A total of 245 patients undergoing PCI during the study period had samples obtained for H. pylori serology. Of these, 91 were positive for H. pylori serology (37%) and 148 were negative (60%) with six samples being equivocal (3%). Of those patients positive for H. pylori, 75% were on agents at admission known to promote or precipitate gastrointestinal haemorrhage. Patients positive for H. pylori tended to be older, with increased creatinine and more likely to be receiving proton pump inhibitor therapy. Conclusions: In an unselected cohort of patients undergoing PCI in a single centre, we detected a prevalence of H. pylori positivity in 37% of patients; this denotes a potentially treatable precipitant of haemorrhage in a considerable portion of patients receiving dual antiplatelet therapy after PCI. Further prospective study is required to determine if the presence of H. pylori positivity is associated with adverse events in terms of gastrointestinal and cardiac outcomes.

This article outlines what we have identified as ‘invisible psychology’ – the elements of our practice as applied psychologists that tend not to get noticed. We suggest that there are at least three manifestations of invisible psychology: it can be invisible to us; it can be invisible to those that might not receive a direct service but who have a stake or interest in our profession; it can be invisible to those who receive a direct service. We also consider ways in which our practice of psychology can become more visible.

Mechanosensory channels of sensory cells mediate the sensations of hearing, touch, and some forms of pain. The TRPA1 (a member of the TRP family of ion channel proteins) channel is activated by pain-producing chemicals, and its inhibition impairs hair cell mechanotransduction. As shown here and previously, TRPA1 is expressed by hair cells as well as by most nociceptors (small neurons of dorsal root, trigeminal, and nodose ganglia) and localizes to their sensory terminals (mechanosensory stereocilia and peripheral free nerves, respectively). Thus, TRPA1 channels are proposed to mediate transduction in both hair cells and nociceptors. Accordingly, we find that heterologously expressed TRPA1 display channel behaviors expected for both auditory and nociceptive transducers. First, TRPA1 and the hair cell transducer share a unique set of pore properties not described for any other channel (block by gadolinium, amiloride, gentamicin, and ruthenium red, a ranging conductance of ∼100 pS that is reduced to 54% by calcium, permeating calcium-induced potentiation followed by closure, and reopening by depolarization), supporting a direct role of TRPA1 as a pore-forming subunit of the hair cell transducer. Second, TRPA1 channels inactivate in hyperpolarized cells but remain open in depolarized cells. This property provides a mechanism for the lack of desensitization, coincidence detection, and allodynia that characterize pain by allowing a sensory neuron to respond constantly to sustained stimulation that is suprathreshold (i.e., noxious) and yet permitting the same cell to ignore sustained stimulation that is subthreshold (i.e., innocuous). Our results support a TRPA1 role in both nociceptor and hair cell transduction.

Growth cone motility is regulated by both fast voltage-dependent Ca2+ channels and by unknown receptor-operated Ca2+ entry mechanisms. Transient receptor potential (TRP) homomeric TRPC5 ion channels are receptor-operated, Ca2+-permeable channels predominantly expressed in the brain. Here we show that TRPC5 is expressed in growth cones of young rat hippocampal neurons. Our results indicate that TRPC5 channel subunits interact with the growth cone-enriched protein stathmin 2, are packaged into vesicles and are carried to newly forming growth cones and synapses. Once in the growth cone, TRPC5 channels regulate neurite extension and growth-cone morphology. Dominant-negative TRPC5 expression allowed significantly longer neurites and filopodia to form. We conclude that TRPC5 channels are important components of the mechanism controlling neurite extension and growth cone morphology.

Throughout their careers, teachers continue to be learners of the craft of teaching. Like their students, motivation is a critical component of the learning process for teachers. We argue that inservice teachers’ motivation is influenced by their temporal context. To understand this motivational construct, we turn to future time perspective (FTP), which has been defined as “the degree to which and the way in which the chronological future is integrated into the present life-space of an individual through motivational goal setting processes” (Husman & Lens, 1999, p. 114). Students who lack such a connection to the future sometimes are merely “doing school” or going through the motions of learning with the least amount of effort necessary (Moyer & Husman, 2006). Teachers without a strong connection to their teaching futures can also engage in the same type of superficial professional learning. In this chapter, we examine dispositional and situational factors that promote the development of a broader and extended FTP, one that enables teachers to connect professional learning experiences in the present to increased teaching efficacy in the future.

In wild-type Caenorhabditis elegans, six cells develop as receptors for gentle touch. In egl-44 and egl-46mutants, two other neurons, the FLP cells, express touch receptor-like features. egl-44 and egl-46 also affect the differentiation of other neurons including the HSN neurons, two cells needed for egg laying. egl-44 encodes a member of the transcription enhancer factor family. The product of the egl-46gene, two Drosophila proteins, and two proteins in human and mice define a new family of zinc finger proteins. Both egl-44and egl-46 are expressed in FLP and HSN neurons (and other cells); expression of egl-46 is dependent on egl-44 in the FLP cells but not in the HSN cells. Wild-type touch cells expressegl-46 but not egl-44. Moreover, ectopic expression ofegl-44 in the touch cells prevents touch cell differentiation in an egl-46-dependent manner. The sequences of these genes and their nuclear location as seen with GFP fusions indicate that they repress transcription of touch cell characteristics in the FLP cells.

Objective.To describe family identification, family engagement, and service delivery in a statewide home visiting program for at-risk families of newborns.Setting.Six target communities of Hawaii's Healthy Start Program (HSP), which incorporates 1) early identification of at-risk families of newborns via population-based screening and assessment, and 2) paraprofessionalhome visiting to improve family functioning, promote child health and development, and prevent child maltreatment.Design.Cross-sectional study: describes early identification process and family characteristics associated with initial enrollment. Longitudinal study: describes home visiting process and characteristics associated with continued participation.Subjects.Cross-sectional study: civilian births in 6 communities (n = 6553). Longitudinal study: at-risk families in the intervention group of a randomized trial of the HSP (n = 373).Measures.Process: completeness and timeliness of early identification and home visiting activities; family characteristics: sociodemographics, child abuse risk factors, infant biologic risk.Results.Early identification staff determined risk status for 84% of target families. Families with higher risk scores, young mothers with limited schooling, and families with infants at biologic risk were more likely to enroll in home visiting. Half of those who enrolled were active at 1 year with an average of 22 visits. Families where the father had multiple risk factors and where the mother was substance abusing were more likely to have ≥12 visits; mothers who were unilaterally violent toward the father were less likely. Most families were linked with a medical home; linkage rates for other community resources varied widely by type of service. Half of families overall, but ≥80% of those active at 1 year, received core home visiting services. Performance varied by program site.Conclusions.It is challenging to engage and retain at-risk families in home visiting. Service monitoring must be an integral part of operations.

The nematode Caenorhabditis elegans possesses six morphologically similar neurons that are responsible for sensing gentle touch to the body. Previous genetic studies identified genes that are necessary for the production and differentiation of these touch cells. In particular, unc-86 encodes a POU-type homeodomain protein needed for the production of the touch cells, while mec-3 encodes a LIM-type homeodomain protein needed for the differentiation of the touch cells. Molecular studies showed that MEC-3 and UNC-86 bind cooperatively to sites in the mec-3 promoter and can synergistically activate transcription from it in vitro. Here we show that UNC-86::MEC-3 hetero-oligomer-binding sites are also found in the promoters of two presumed targets of mec-3, the mec-4 and mec-7 genes, that are necessary for the function of the touch cells. These sites, which are well-conserved in the related nematode C. briggsae, are required for promoter activity. When one of the binding sites is cloned into a heterologous promoter, expression is found in the touch cells and two to four other cells that express mec-3 and unc-86. These data support a model in which touch-cell differentiation is specified, in part, by the UNC-86::MEC-3 hetero-oligomer and not by MEC-3 alone. Ectopic expression of mec-3, driven by a heat-shock promoter, also supports this hypothesis: the acquisition of touch-cell characteristics by several additional cells under these conditions required unc-86. Since the touch-cell lineages express UNC-86 before MEC-3, MEC-3 appears to modify the activity of UNC-86, leading to touch-cell-specific gene expression. Because both UNC-86 and MEC-3 have activation domains, the formation of the hetero-oligomer may create a strong activator. In the modification of UNC-86 function by MEC-3 in the touch cells, these studies provide an example of how the sequential activation of transcription factors can determine cell fate within particular cell lineages.

Home visiting programs in the United States seek to improve maternal and child health, child development, and family economic self-sufficiency by supporting and educating families with young children. Today, home visiting is seen as an important strategy for high-risk families who may be difficult to engage in other services. The Patient Protection and Affordable Care Act (ACA) of 2010 included $1.5 billion over five years for states to operate the Maternal, Infant, and Early Childhood Home Visiting (MIECHV) program. It also required a national evaluation of the programs. This document describes the design of that evaluation — the Mother and Infant Home Visiting Program Evaluation (MIHOPE). MIHOPE was launched in 2011 by the Administration for Children and Families and the Health Resources and Services Administration within the U.S. Department of Health and Human Services. The evaluation is being conducted by MDRC in partnership with Mathematica Policy Research, James Bell Associates, Johns Hopkins University, the University of Georgia, and Columbia University.MIHOPE will include the following components:-An analysis of state needs assessments will describe the communities that states chose to target with MIECHV program services.-An implementation study will collect information on the services provided by local programs as well as the factors that helped shape those programs.-An impact analysis will estimate the effects of home visiting programs on family outcomes, both overall and for key subgroups of families.-An economic analysis will assess program costs and savings.The study will include approximately 5,100 families with a pregnant woman or a child under 6 months old. Families who enroll in the study will be randomly assigned to a home visiting group or to a comparison group that can use other services available in their community. Families will be spread across about 85 local programs in about 12 states. Sites must be operating one of four national models of home visiting: Early Head Start-Home Visiting Option, Healthy Families America, Nurse-Family Partnership, or Parents as Teachers. These four models were chosen because they are being implemented using MIECHV program funds in at least 10 states.Data for the implementation and impact studies will be collected from a variety of sources, including interviews with parents; observations of the home environment; observed interactions of parents and children; direct assessments of children’s development; observations of home visitors in their work with families during home visits; logs, observations, and interviews with home visitors, supervisors, and program administrators; program model documentation from program developers, grantees, and local sites; and administrative data on child abuse, health care use, maternal health, birth outcomes, and employment and earnings.The study will produce a report to Congress in 2015 that includes information on families and sites included in the evaluation as well as information on how states made decisions about how to spend home visiting funds. Later reports will provide more information on program implementation, the effects of home visiting programs for families, and the features of programs that are associated with larger effects.

Recent research into the development of the nervous system of the nematode Caenorhabditis elegans indicates the importance of multiple cell interactions and combinatorial gene expression. As many of the genes needed for C. elegans neuronal development have counterparts with similar activities in Drosophila melanogaster, the mechanisms of cell specification may be broadly conserved.

Mechanical deflection of the sensory hair bundles of receptor cells in the inner ear causes ion channels located at the tips of the bundle to open, thereby initiating the perception of sound. Although some protein constituents of the transduction apparatus are known, the mechanically gated transduction channels have not been identified in higher vertebrates. Here, we investigate TRP (transient receptor potential) ion channels as candidates and find one, TRPA1 (also known as ANKTM1), that meets criteria for the transduction channel. The appearance of TRPA1 messenger RNA expression in hair cell epithelia coincides developmentally with the onset of mechanosensitivity. Antibodies to TRPA1 label hair bundles, especially at their tips, and tip labelling disappears when the transduction apparatus is chemically disrupted. Inhibition of TRPA1 protein expression in zebrafish and mouse inner ears inhibits receptor cell function, as assessed with electrical recording and with accumulation of a channel-permeant fluorescent dye. TRPA1 is probably a component of the transduction channel itself.

We describe a novel mechanism for vital fluorescent dye entry into sensory cells and neurons: permeation through ion channels. In addition to the slow conventional uptake of styryl dyes by endocytosis, small styryl dyes such as FM1-43 rapidly and specifically label hair cells in the inner ear by entering through open mechanotransduction channels. This labeling can be blocked by pharmacological or mechanical closing of the channels. This phenomenon is not limited to hair cell transduction channels, because human embryonic kidney 293T cells expressing the vanilloid receptor (TRPV1) or a purinergic receptor (P2X2) rapidly take up FM1-43 when those receptor channels are opened and not when they are pharmacologically blocked. This channel permeation mechanism can also be used to label many sensory cell typesin vivo. A single subcutaneous injection of FM1-43 (3 mg/kg body weight) in mice brightly labels hair cells, Merkel cells, muscle spindles, taste buds, enteric neurons, and primary sensory neurons within the cranial and dorsal root ganglia, persisting for several weeks. The pattern of labeling is specific; nonsensory cells and neurons remain unlabeled. The labeling of the sensory neurons requires dye entry through the sensory terminal, consistent with permeation through the sensory channels. This suggests that organic cationic dyes are able to pass through a number of different sensory channels. The bright and specific labeling with styryl dyes provides a novel way to study sensory cells and neuronsin vivoandin vitro,and it offers new opportunities for visually assaying sensory channel function.

Members of the BNaC/ASIC family of ion channels have been implicated in mechanotransduction and nociception mediated by dorsal root ganglion (DRG) neurons. These ion channels are also expressed in the CNS. We identified the PDZ domain protein PICK1 as an interactor of BNaC1(ASIC2) in a yeast two-hybrid screen. We show by two-hybrid assays, glutathione S-transferase pull-down assays, and coimmunoprecipitations that the BNaC1-PICK1 interaction is specific, and that coexpression of both proteins leads to their clustering in intracellular compartments. The interaction between BNaC1 and PICK1 requires the PDZ domain of PICK1 and the last four amino acids of BNaC1. BNaC1 is similar to two other BNaC/ASIC family members, BNaC2 (ASIC1) and ASIC4, at its extreme C terminus, and we show that PICK1 also interacts with BNaC2. We found that PICK1, like BNaC1 and BNaC2, is expressed by DRG neurons and, like the BNaC1alpha isoform, is present at their peripheral mechanosensory endings. Both PICK1 and BNaC1alpha are also coexpressed by some pyramidal neurons of the cortex, by pyramidal neurons of the CA3 region of hippocampus, and by cerebellar Purkinje neurons, localizing to their dendrites and cell bodies. Therefore, PICK1 interacts with BNaC/ASIC channels and may regulate their subcellular distribution or function in both peripheral and central neurons.

The present study investigates clinical factors associated with decreased survival following Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS). Sixty-seven patients underwent TIPSS for bleeding related to portal hypertension, 42 (63%) on an urgent basis. TIPSS was successfully placed in 65 (97%) patients with no fatal procedural complications. Thirty day mortality was 21%, there being several predictive factors: transfer from another institution, urgency of procedure, sepsis, encephalopathy, higher mean serum bilirubin and low serum albumin. However, using regression analysis, 30 day mortality was predicted independently only by severe liver disease (Child-Pugh C, P= 0.003) and older age (P= 0.003). When stratified by Child-Pugh class, cumulative survival rates at 1 year for class A, B and C were 100, 90 and 34%, respectively. Only three of 25 patient deaths were due to variceal rebleeding. Thirty (46%) patients had a total of 41 rebleeding episodes, with mean time to first rebleed of 4.8 months (range, 3 days-38 months). Cumulative rebleeding rate at 1 year was 25%. Log-rank analysis did not reveal a significant difference in overall survival between rebleeders and non-rebleeders (P= 0.125). When investigated, shunt abnormalities (stenosis, occlusion) were identified in all cases of rebleeding. Our findings confirm TIPSS can be safe and effective in the control of refractory variceal haemorrhage. However, prognosis remains poor for patients with advanced liver disease, particularly if older and in the emergency setting. Vigilant surveillance and high rate of intervention is necessary to maintain shunt patency. Consideration could be given to elective shunt surgery instead of TIPSS for patients with recurrent bleeding and good prognosis liver disease.

SummaryIntense noise damages the cochlear organ of Corti, particularly the outer hair cells (OHCs) [1]; however, this epithelium is not innervated by nociceptors of somatosensory ganglia, which detect damage elsewhere in the body. The only sensory neurons innervating the organ of Corti originate from the spiral ganglion, roughly 95% of which innervate exclusively inner hair cells (IHCs) [2–4]. Upon sound stimulation, IHCs release glutamate to activate AMPA-type receptors on these myelinated type-I neurons, which carry the neuronal signals to the cochlear nucleus. The remaining spiral ganglion cells (type IIs) are unmyelinated and contact OHCs [2–4]. Their function is unknown. Using immunoreactivity to cFos, we documented neuronal activation in the brainstem of Vglut3−/− mice, in which the canonical auditory pathway (activation of type-I afferents by glutamate released from inner hair cells) is silenced [5, 6]. In these deaf mice, we found responses to noxious noise, which damages hair cells, but not to innocuous noise, in neurons of the cochlear nucleus, but not in the vestibular or trigeminal nuclei. This response originates in the cochlea and not in other areas also stimulated by intense noise (middle ear and vestibule) as it was absent in CD1 mice with selective cochlear degeneration but normal vestibular and somatosensory function. These data imply the existence of an alternative neuronal pathway from cochlea to brainstem that is activated by tissue-damaging noise and does not require glutamate release from IHCs. This detection of noise-induced tissue damage, possibly by type-II cochlear afferents, represents a novel form of sensation that we term auditory nociception.

Insect bristles are model mechanosensory organs. An ion channel of the TRP superfamily has recently been identified which is required for production of mechano-receptor currents by insect bristles, and seems likely to represent a new kind of mechanically gated channel.

This study was designed to determine the effect of the phenothiazine chlorpromazine (CPZ) on the activation of human thymocytes. We provide evidence that CPZ inhibits the accumulation of mRNA specific for the lymphokines, interleukin 2, interferon-gamma, tumor necrosis factor alpha and the proto-oncogene c-myc; by contrast, the accumulation of mRNA specific for the alpha chain of the interleukin 2 receptor and the subsequent early expression of Tac antigen on the cell surface is not inhibited by CPZ. The inhibition of the expression of lymphokine-specific mRNA results in a decrease in interferon-gamma synthesis and in inhibition of thymocyte proliferation as determined by the incorporation of [3H]thymidine. In addition, we show that activation of protein kinase C (PKC) in human thymocytes by 12-O-tetradecanoyl phorbol 13-acetate (TPA) causes the phosphorylation of a protein of a molecular mass of approximately 75 kDa. The function of this protein is as yet not defined, but it is possible that it plays a role in the transduction of the signals to the nucleus which in turn elicit the expression of the genes coding for c-myc and for the lymphokines required for thymocyte activation. We also demonstrate that CPZ, like the immunosuppressant drug cyclosporin A does not inhibit the phosphorylation of the 75-kDa protein which is induced by the activation of PKC by TPA and does not affect phosphoinositide breakdown, indicating that it exerts its effect at a site distal to the activation of PKC. These observations demonstrate that CPZ has an immunoregulatory function in addition to its psychotropic activity.

Background Insm1 is a zinc-finger transcription factor transiently expressed throughout the developing nervous system in late progenitors and nascent neurons. Insm1 is also highly expressed in medulloblastomas and other neuroendocrine tumors. Results We generated mice lacking the Insm1 gene and used them to elucidate its role in neurogenic proliferation of the embryonic olfactory epithelium. We found that deletion of Insm1 results in more apical cells and fewer nascent and mature neurons. In the embryonic olfactory epithelium of Insm1 mutants we detect fewer basal progenitors, which produce neurons, and more apical progenitors, which at this stage produce additional progenitors. Furthermore, in the mutants we detect fewer progenitors expressing NEUROD1, a marker of terminally dividing, neuronogenic (neuron-producing) progenitors (immediate neuronal precursors), and more progenitors expressing ASCL1, a marker of the transit amplifying progenitors that migrate from the apical to the basal edges of the epithelium while dividing to generate the terminal, neuronogenic progenitors. Finally, with timed administration of nucleoside analogs we demonstrate that the Insm1 mutants contain fewer terminally dividing progenitors at embryonic day 12.5. Conclusions Altogether, these results suggest a role for Insm1 in promoting the transition of progenitors from apical and proliferative to basal, terminal and neuronogenic. This role appears partially conserved with that of its nematode ortholog, egl-46. The similar effects of Insm1 deletion on progenitors of embryonic olfactory epithelium and cortex point to striking parallels in the development of these neuroepithelia, and particularly between the basal progenitors of olfactory epithelium and the subventricular zone progenitors of cortex.