How do gender and military sexual trauma impact PTSD symptoms in cognitive processing therapy and prolonged exposure?

OBJECTIVE: Effectiveness of evidence-based psychotherapy (EBP) for PTSD can vary based on gender and trauma type, with poorer outcomes for men and sexual traumas. Among veterans receiving EBPs for PTSD, the effects of the interaction between gender and military sexual trauma (MST) on treatment outcome are unclear. This study examined how gender and MST impact PTSD symptoms following cognitive processing therapy (CPT) and prolonged exposure (PE). METHOD: We conducted a national, retrospective cohort study of all post 9/11 veterans who had a PTSD diagnosis from 10/2001-9/2017 at VHA facilities and >1 psychotherapy visit. Inclusion criteria included completion of ≥8 CPT/PE sessions and pre- and post-treatment PCL (N = 9711). Mixed-effects linear regression models were conducted, separately by treatment, to examine associations between changes in PTSD symptoms and gender, MST, and their interactions with time. RESULTS: For both treatments, there were no significant differences in pre-treatment PCL by gender or MST, and PCL decreased significantly over time. In adjusted models, only the gender by time interaction on pre-to-post-CPT change was significant (p < .001); the decrease in women's PCL was 2.67 points greater, compared to men. CONCLUSIONS: Women veterans demonstrated greater reductions in PTSD symptoms from CPT. There were no differences by gender for PE, suggesting men and women veterans benefit similarly. Results suggest outcomes may be impacted by gender socialization when utilizing certain cognitive behavioral techniques. MST, regardless of gender, did not impact PTSD outcomes for either treatment. Both CPT and PE may thus be effective for veterans irrespective of MST history.

Regulatory gene expression boundaries demarcate sites of neuronal differentiation in the embryonic zebrafish forebrain.

During development of the zebrafish forebrain, a simple scaffold of axon pathways is pioneered by a small number of neurons. We show that boundaries of expression domains of members of the eph, forkhead, pax, and wnt gene families correlate with the positions at which these neurons differentiate and extend axons. Analysis of genetically or experimentally altered forebrains indicates that if a boundary is maintained, there is appropriate neural differentiation with respect to the boundary. Conversely, in the absence of a boundary, there is concomitant disruption of neural patterning. We also show that a strip of cells within the dorsal diencephalon shares features with ventral midline cells. This strip of cells fails to develop in mutant fish in which specification of the ventral CNS is disrupted, suggesting that its development may be regulated by the same inductive pathways that pattern the ventral midline.

The zebrafish homologue of the ret receptor and its pattern of expression during embryogenesis.

The c-ret proto-oncogene, a member of the receptor tyrosine kinase gene superfamily, plays a critical role in the development of the excretory system and the enteric and autonomic nervous systems of mammalian embryos. To study the potential function of the c-ret locus in lower vertebrates, we have isolated its zebrafish homologue, ret1 and established its expression pattern during embryogenesis. Ret1 mRNA first appears during early somitogenesis in the presumptive brain, spinal cord and excretory system. Within the CNS, expression of ret1 is detected in primary motor and sensory (Rohon-Beard) neurons. Ret1 transcripts are also expressed in subsets of neural crest cells and cranial ganglia as well as in the enteric nervous system. In the excretory system, expression is detected in the developing nephric duct and the pronephros. Our findings reveal a remarkable similarity in the expression pattern of c-ret between higher and lower vertebrates, suggesting that the function of this locus has been conserved throughout vertebrate evolution. Furthermore, the conservation of ret1 expression in cell types which remain unaffected by the mammalian c-ret mutations, such as motor and sensory neurons, suggests a function of this receptor in these cell lineages.

A graded response to BMP-4 spatially coordinates patterning of the mesoderm and ectoderm in the zebrafish.

The effects of signal perturbation on expression domains of molecular markers for the mesoderm and ectoderm have been analysed across the dorso-ventral axis in zebrafish embryos. Injection of RNA encoding bone morphogenetic protein-4 (BMP-4) ventralised the embryo, expanding the intermediate mesoderm and non-neural ectoderm at the expense of the dorso-anterior mesoderm and neural plate. A dose-dependent response was observed both morphologically and in expression of gta3, MyoD and pax2. Conversely, increases in dorso-anterior mesoderm and neurectoderm were generated by injection of RNA encoding either a dominant-negative BMP receptor (delta BMPR) or noggin, as demonstrated by goosecoid and pax2 expression. Ventral BMP-4 expression was also inhibited. Thus, patterning of both the mesoderm and the ectoderm during gastrulation appears to depend, directly or indirectly, on the level of BMP activity. Consistent with their locations prior to formation of the neural tube, elevated BMP-4 increased the number of dorsal spinal cord neurons whilst sonic hedgehog and islet1 expression in the ventral spinal cord were reduced. However, the ectopic neurons were not positioned more ventrally, implicating a prepattern in the dorsal neural tube that is independent of the ventral central nervous system.

Exogenous retinoic acid causes specific alterations in the development of the midbrain and hindbrain of the zebrafish embryo including positional respecification of the Mauthner neuron.

Exogenously applied retinoic acid given at the early stages of gastrulation causes abnormal development of the caudal midbrain and anterior hindbrain in vertebrate embryos. We describe the limits of the brain regions that are affected using neuroanatomical criteria in the zebrafish embryo. Analysis of the reticulospinal complex shows that the Mauthner cell, which normally differentiates in rhombomere 4, is duplicated either in this rhombomere or in rhombomere 2. Using probes for zebrafish krx20 and pax2, it is demonstrated that retinoic acid affects the expression domains of these regulatory genes in a manner that is consistent with the neuroanatomical data. Expression of the goosecoid gene, which expressed in the prospective anterior mesoderm from the onset of gastrulation, is unaffected by the doses of retinoic acid used in this study, reflecting the normal development of the anterior end of the embryo.

Expression of zebrafish GATA 3 (gta3) during gastrulation and neurulation suggests a role in the specification of cell fate.

In order to understand the role of the transcription factor GATA 3 in vertebrate development, we have examined its expression and some aspects of its regulation during gastrulation and neurulation in the zebrafish. The complete coding sequence of the cDNA encoding the zebrafish GATA 3 homologue, termed gta3, is described. Analysis of expression patterns by in situ hybridisation shows the gene to be expressed during gastrulation in the ventral region of the embryo which includes tissue fated to form the non-neural ectoderm. By the end of gastrulation, there is a clear border to the gta3 expression domain that is close to the edge of the neural plate. Subsequently, gta3 expresses in the pronephric duct and in defined regions of the central nervous system which include specific cells in each segment of the spinal cord and nuclei in the brain. Double labelling embryos with a probe for gta3 and antibodies which identify differentiated neurons suggest that gta3 is dynamically expressed during the early differentiation phase of a subset of neurons but not in the terminal phase. Analysis of gta3 expression in dorsalised embryos and in cyc and spt mutant embryos indicates that the neural expression of the gene is subject to control by signals from the mesoderm, including both the notochord and the somites, which influence the segmental organisation of expression in the spinal cord.

An early developmental role for eph-ephrin interaction during vertebrate gastrulation.

Eph receptor tyrosine kinases (RTK) and their ephrin ligands are involved in the transmission of signals which regulate cytoskeletal organisation and cell migration, and are expressed in spatially restricted patterns at discrete phases during embryogenesis. Loss of function mutants of Eph RTK or ephrin genes result in defects in neuronal pathfinding or cell migration. In this report we show that soluble forms of human EphA3 and ephrin-A5, acting as dominant negative inhibitors, interfere with early events in zebrafish embryogenesis. Exogenous expression of both proteins results in dose-dependent defects in somite development and organisation of the midbrain-hindbrain boundary and hindbrain. The nature of the defects as well as the distribution and timing of expression of endogenous ligands/receptors for both proteins suggest that Eph-ephrin interaction is required for the organisation of embryonic structures by coordinating the cellular movements of convergence during gastrulation.

Evidence for non-axial A/P patterning in the nonneural ectoderm of Xenopus and zebrafish pregastrula embryos.

Recent studies in early Xenopus and zebrafish embryos have demonstrated that posteriorizing, non-axial signals arising from outside the organizer (or shield) contribute to A/P patterning of the neural axis, in contradiction to the classical Spemann model in which such signals were proposed to be solely organizer derived. Our studies on the early expression of the transcription factors GATA-2 and 3 in both Xenopus and zebrafish nonneural ectoderm lend support to the existence of such non-axial signaling in the A/P axis. Thus we find that the earliest expression of GATA-2 and 3 is located in nonneural ectoderm and is strongly patterned in a graded manner along the A/P axis, being high anteriorly and absent from the most posterior regions. This results by early neurula stages in three broad zones: an anterior region which is positive for both GATA-2 and 3, a middle region which is positive for GATA-2 alone and a posterior region in which neither gene is expressed. These regions correspond to head, trunk and tail ectoderm and may represent the beginnings of functional segmentation of nonneural ectoderm, as suggested in the concept of the 'ectomere'. We find that A/P patterning of GATA expression in nonneural ectoderm may occur as early as late blastula/early gastrula stages. We investigate which posteriorizing signals might contribute to such distinct non axial ectodermal patterning in the A/P axis and provide evidence that both FGF and a Wnt family member contribute towards the final A/P pattern of GATA expression in nonneural ectoderm.

Characterisation of five novel zebrafish Eph-related receptor tyrosine kinases suggests roles in patterning the neural plate.

Eph-related receptor tyrosine kinases (RTKs) are the largest known subfamily of RTKs, comprising at least a dozen members. Expression studies suggest roles for these genes in patterning and differentiation of the nervous system, the neural crest, developing limbs and somites. Some of the recently isolated family of ligands for Eph-related RTKs have been shown to function as positional identifiers in the retinotectal system. We have previously characterised three Eph-related RTKs in the zebrafish (rtk1-3). Here we report the identification of five new zebrafish Eph-related RTKs (rtk4, rtk5, rtk6, rtk7 and rtk8) and describe their dynamic expression patterns. Based on these expression patterns, we propose that rtk4-8 play various roles in establishing territories within the developing central nervous system (CNS) and in the subsequent differentiation of defined neuronal populations.

Organization of motor units in the axolotl: a continuously growing animal.

The characteristics of motor units in the iliotibialis posterior muscle of the axolotl hindlimb are described. Tension recording and intracellular electrophysiological methods demonstrate that the physiological properties of the population of motor units are continuously distributed rather than grouped into a series of discrete types. Overlap between motor units occurs and this is positively correlated with motor unit size but negatively correlated with differences in time to peak tension. Immunocytochemical staining with antimyosin antibodies combined with histochemical demonstration of actomyosin ATPase activity revealed at least four types of muscle fibre which were distributed asymmetrically within iliotibialis posterior. The results are discussed in terms of the continuous growth of the muscle and the interactions between muscle and nerve in the formation of the axolotl motor system.

Continuous growth of the motor system in the axolotl.

During growth of the axolotl, motor neurons, and muscle fibres are added to the motor system. By double labelling neurons with tritiated thymidine and retrogradely transported HRP, we show that some motor neurons are born at postembryonic stages. Further analysis of motor neurons with the aid of HRP reveals this population of newly born cells relatively frequently in small (5-7 cm long) axolotls, but only rarely in large (7-13 cm long) axolotls. Evidence is presented that suggests that these immature cells are in the process of migrating from close to the ependyma out to the ventral horn. HRP transport also reveals growth cones of advancing axons within spinal nerves in animals up to 6 cm in length. Cell counts by light and electron microscopic methods show that muscle fibres are generated throughout larval life in the iliotibialis, a typical limb muscle. This analysis provides data consistent with the notion that new muscle fibres are added from a localised growth zone situated at the superficial edge of the muscle. These results are discussed in terms of the correlation between continuous growth of the motor system and the ability of the axolotl to functionally repair lesions to the peripheral nervous system.

In vitro regulation of HGF-SF expression by epithelial-mesenchymal interactions.

Studies of parameters which affect cellular proliferation, cellular differentiation together with studies of cell-cell interactions which affect cell behavior are particularly interesting in that they can be used to identify and characterise molecules which through changes in gene expression induce/inhibit cell proliferation, differentiation and movement. Such studies are crucial not only in the context of understanding growth and development, but also in understanding the processes of wound healing and regeneration as well as tumor invasion and metastasis. Here we present a summary of some cell culture models which we have developed for the study of the above-mentioned phenomenon, together with their application to the studies of regulation of HGF-SF expression.

Regeneration of descending axons in the spinal cord of the axolotl.

Horseradish peroxidase was used to describe the positions and approximate numbers of neurones with axons that descend to the lumbar spinal cord in normal axolotls and axolotls whose spinal cord had been transected 3-23 months previously. Three to 4 months after the transection approximately 10% of the axons had grown across the cut and returned to the lumbar spinal cord whereas 23 months after the transection the number and distribution of these cells were approaching those of the controls.

Cell turnover in neuromasts of zebrafish larvae.

The numbers and positions of cells undergoing cell death and proliferation in the neuromasts of 10 day old zebrafish larvae were assessed to investigate the ability of supporting cells to differentiate into hair cells. Evaluations of cell death and proliferation showed that a subpopulation of cells located in the centre of the neuromast undergo cell death, and a different subpopulation located at the periphery proliferate. This suggests that cell death of hair cells and proliferation of mantle supporting cells occurs as part of normal development, creating constant turnover of hair cells. We show that the caspase inhibitor zVADfmk reduces cell death while the aminoglycoside neomycin specifically induces an increased amount of cell death in the central population of cells. Both of these treatments affect the rate of proliferation of the peripheral subpopulation of cells in the neuromast suggesting that a feedback mechanism occurs regulating cell death and proliferation. We propose that the dying population of cells are hair cells and the proliferating cells are 'mantle' supporting cells, which is in agreement with previous observations suggesting that supporting cells can give rise to hair cells following hair cell death.

Cause, prevalence, and response to occupational musculoskeletal injuries reported by physical therapists and physical therapist assistants.

BACKGROUND AND PURPOSE: Physical therapists (PTs) and physical therapist assistants (PTAs) are susceptible to occupational musculoskeletal injuries. The purpose of this study was to examine the reported causes and prevalence of occupational musculoskeletal injuries to PTs and PTAs during a 2-year period. SUBJECTS: A questionnaire was mailed to 500 PTs and 500 PTAs randomly selected from the American Physical Therapy Association 1996 active membership list. Six hundred sixty-seven questionnaires were returned, giving a response rate of 67%. METHOD: Based on a literature review and a pilot study, an occupational injury questionnaire was constructed and mailed. Self-reports of injuries were obtained. RESULTS: Thirty-two percent of the PTs and 35% of the PTAs reported sustaining a musculoskeletal injury. The highest prevalence of injury was to the low back (62% of injured PTs and 56% of injured PTAs). The PTs reported the upper back and the wrist and hand as having the second highest prevalence (23%). The PTAs reported the upper back as having the second highest prevalence (28%). The PTs and PTAs reported making changes in their work habits of improved body mechanics, increased use of other personnel, and frequent change of work position. The majority of PTs and PTAs reported they did not limit patient contact time or area of practice after sustaining an injury. CONCLUSION AND DISCUSSION: Although PTs and PTAs are recognized to be knowledgeable in prevention and treatment of musculoskeletal injuries, they are susceptible to sustaining occupational musculoskeletal injuries because of performing labor-intensive tasks.