Gender data gap in military research: a review of the participation of men and women in military musculoskeletal injury studies.

Servicewomen are at increased risk of musculoskeletal injuries compared with their male counterparts, but women are under-represented in sports medicine research. The aim of this review was to assess the representation of women in military musculoskeletal injury studies. PubMed was searched for human original research studies using the terms Military OR Army OR Navy OR 'Air Force' AND 'musculoskeletal injury' Each study was categorised as epidemiology (basic training), epidemiology (trained personnel), risk factors, interventions and other. The number of male and female participants was retrieved from each study. A total of 262 studies were included: 98 (37%) studies only included men, 17 (6%) studies only included women and 147 (56%) studies included both men and women. A total of 8 051 778 participants were included in these studies (men: 6 711 082, 83%; women: 1 340 696, 17%). The study theme with the greatest proportion of women was musculoskeletal injury epidemiology studies in a basic training population (20% of participants) with the lowest proportion of women in intervention trials (6% of participants). These data suggest women are not under-represented in military musculoskeletal injury studies when considering the gender representation of most militaries. Our data are, however, biased by large epidemiological trials and women were under-represented in intervention trials. The under-representation of women in intervention trials could be due to difficulties in controlling for the effects of female sex steroids on musculoskeletal outcomes, or a focus on interventions in the most arduous military roles where injury risk is highest and women have been previously excluded.

Macrophages Promote Growth of Squamous Cancer Independent of T cells.

Oral cancers, primarily squamous cell carcinomas (SCCs), progress either slowly or aggressively. Here we assessed the role of macrophages in SCC behavior. We used mouse SCC cells derived from tumors harboring a KrasG12D activation mutation and Smad4 deletion in keratin 15-positive stem cells and a human oral SCC cell line, FaDu, which has NRAS amplification and SMAD4 deletion. SCC cells were transplanted into immune-compromised or immune-competent (syngeneic) recipients. After tumors were established, we used clodronate liposomes to ablate macrophages. We found that the number of tumor-associated macrophages (TAMs) was not affected by the presence of T cells but differed considerably among tumors derived from different SCC lines. Clodronate significantly reduced TAMs and splenic macrophages, resulting in reduced SCC volumes. Tumors with clodronate treatment did not show decreased proliferation but did exhibit increased apoptosis and reduced vascular density. FLIP (Fas-associated via death domain-like interleukin 1ß-converting enzyme inhibitory protein), an apoptosis inhibitor abundantly produced in tumor cells and TAMs, was reduced in tumor cells of clodronate-treated mice. Reduced FLIP levels correlated with reductions in phosphorylated nuclear NFκB p65 and NFκB inhibitor attenuated FLIP protein levels in SCC cells. Furthermore, TGFß1 serum levels and pSmad3 were reduced in clodronate-treated mice, but their reductions were insufficient to reverse epithelial-mesenchymal transition or TGFß-mediated angiogenesis in endothelial cells. Consequently, metastasis was not significantly reduced by macrophage reduction. However, reduced pSmad3 correlated with reduction of its transcriptional target, vascular endothelial growth factor A, in clodronate-treated tumor cells, which correlated with reduced vascular density in clodronate-treated tumors. Taken together, our study revealed that macrophages contribute to SCC expansion through interactions with tumor cells but are dispensable for SCC metastasis. Our study provides novel insights into understanding the contributions and limitations of TAMs in SCC progression.

Mouse Models for Studying Oral Cancer: Impact in the Era of Cancer Immunotherapy.

Model systems for oral cancer research have progressed from tumor epithelial cell cultures to in vivo systems that mimic oral cancer genetics, pathological characteristics, and tumor-stroma interactions of oral cancer patients. In the era of cancer immunotherapy, it is imperative to use model systems to test oral cancer prevention and therapeutic interventions in the presence of an immune system and to discover mechanisms of stromal contributions to oral cancer carcinogenesis. Here, we review in vivo mouse model systems commonly used for studying oral cancer and discuss the impact these models are having in advancing basic mechanisms, chemoprevention, and therapeutic intervention of oral cancer while highlighting recent discoveries concerning the role of immune cells in oral cancer. Improvements to in vivo model systems that highly recapitulate human oral cancer hold the key to identifying features of oral cancer initiation, progression, and invasion as well as molecular and cellular targets for prevention, therapeutic response, and immunotherapy development.

Global strain field mapping of a particle-laden interface using digital image correlation.

HYPOTHESIS: The ability to identify the stress-strain relations correctly is critical to understanding and modeling any rheological responses of an interface. Langmuir-Pockels (LP) trough is one of the most commonly used tools for studying an interface. Most, if not all, existing studies assume a 1D uniaxial compression during a LP-trough compression experiment. It is hypothesized that the deformation field is far more complex than what is typically assumed. EXPERIMENTS: To examine this hypothesis, we custom-built a glass-bottomed LP trough equipped with a camera to capture a series of optical images asa carbon nanotube (CNT)-laden interface is compressed. A digital image correlation (DIC) technique was then applied to the images to evaluate the global strain field during compression of the CNT laden interface. The DIC-corrected strain data were subsequently analyzed with the surface stress data to quantify the surface shear and dilatational moduli of the CNT-laden interface. FINDINGS: Our experimental findings clearly show, for the first time, the development of a non-uniform and complex 2D strain field during compression. The local strains were further quantified and compared with the usual assumption of 1D uniaxial compression. Although the compressive strain averaged over the whole trough area closely resembles the 1D uniaxial compression strain, the 1D compression assumption underestimates the local strain by about 36% at the center of the trough, where the surface stresses are measured. This is the first study in applying the DIC technique to map out the global strain field asa particle-laden interface is compressed. The method may also be applicable to other systems with similar optical texture, allowing the correct identification of stress-strain relationship of an interface.

Short communication: A reproductive tract scoring system to manage fertility in lactating dairy cows.

We developed a reproductive tract size and position score (SPS) system as a reproductive management tool to identify lactating dairy cows with decreased fertility. This system, relying solely on transrectal palpation, considers the size (cervical and uterine) and position of the reproductive tract relative to the pelvis. Cows undergoing pre-breeding exams were identified as having reproductive tracts that were small (SPS1), medium (SPS2), or large (SPS3). Cows designated SPS1 had small and compact uterine horns that rested within the pelvic cavity; SPS2 cows had reproductive tracts that were intermediate in cervical and uterine horn diameter, with longer uterine horns resting partially outside the pelvic cavity; and SPS3 cows had reproductive tracts that were larger and rested mostly outside the pelvic cavity. Cows that were SPS1 had a higher rate of pregnancy per artificial insemination (43.3 ± 3.7%) than cows that were SPS2 (36.9 ± 3.6%) or SPS3 (27.7 ± 4.3%). The percentage of cows with an SPS2 score differed in pregnancies per artificial insemination compared with SPS3 cows. The average days in milk was similar for SPS1, SPS2, and SPS3 cows (104.3 ± 3.5, 98.4 ± 3.4, and 94.7 ± 7.7, respectively). Ultrasound measurements of the uterine horn and cervical diameter, and length measurements of the uterine horns, cervix, and vagina confirmed differences among the SPS groups derived by transrectal palpation. The ease with which transrectal palpation can be used to determine the size and position of the reproductive tract attests to the relevance and usefulness of this scoring system to identify less fertile lactating dairy cows. The ability to do so with ease provides an opportunity to make economically relevant management decisions and maximize reproductive efficiency in a given herd.

Extragenic suppressors of the nimX2(cdc2) mutation of Aspergillus nidulans affect nuclear division, septation and conidiation.

The Aspergillus nidulans NIMX(CDC2) protein kinase has been shown to be required for both the G(2)/M and G(1)/S transitions, and recent evidence has implicated a role for NIMX(CDC2) in septation and conidiation. While much is understood of its G(2)/M function, little is known about the functions of NIMX(CDC2) during G(1)/S, septation, and conidiophore development. In an attempt to better understand how NIMX(CDC2) is involved in these processes, we have isolated four extragenic suppressors of the A. nidulans nimX2(cdc2) temperature-sensitive mutation. Mutation of these suppressor genes, designated snxA-snxD for suppressor of nimX, affects nuclear division, septation, and conidiation. The cold-sensitive snxA1 mutation leads to arrest of nuclear division during G(1) or early S. snxB1 causes hyperseptation in the hyphae and sensitivity to hydroxyurea, while snxC1 causes septation in the conidiophore stalk and aberrant conidiophore structure. snxD1 leads to slight septation defects and hydroxyurea sensitivity. The additional phenotypes that result from the suppressor mutations provide genetic evidence that NIMX(CDC2) affects septation and conidiation in addition to nuclear division, and cloning and biochemical analysis of these will allow a better understanding of the role of NIMX(CDC2) in these processes.

The impact of race on freedom from prostate-specific antigen failure in prostate cancer patients treated with definitive radiation therapy.

Many studies have reported that African-American men have the highest incidence and mortality rates for prostate cancer in the United States. A retrospective analysis of 607 patients treated with definitive radiation therapy was performed at the University of California San Francisco and its affiliated hospitals between 1987 and 1995. The patient population analyzed included African-American, Caucasian, and Asian men with AJCC T1-T3 disease. Race, Gleason score, pretreatment prostate-specific antigen levels, stage, and treatment delivery were all evaluated. The percent free from PSA failure at 48 months for African-American, Caucasian, and Asian men were 53%, 59%, and 53%, respectively. There was no difference among the three races or for any of the pairwise comparisons. Gleason score and stage of disease were each independent predictors of outcome, but race was not associated with remaining free from PSA failure. These results are similar to those recently reported in the literature from centers of excellence across the United States.

The distribution and origin of the calretinin-containing innervation of the nucleus accumbens of the rat.

The nucleus accumbens of the rat consists of several subregions that can be distinguished on the basis of histochemical markers. For example, the calcium-binding protein calbindin D28k is a useful marker of the core compartment of the nucleus accumbens. Calretinin, another calcium-binding protein, is found in a dense fibre plexus in the accumbal shell and septal pole regions. The source of the accumbal calretinin innervation is not known. We examined the distribution of calretinin in the nucleus accumbens and used tract-tracing and lesion methods to determine the source of this calretinin innervation. Intense calretinin immunoreactivity was present in the medial shell, but the density of calretinin axons diminished sharply in the ventrolateral shell. Regions of dense calretinin immunostaining and those areas with calbindin-like immunoreactive cell bodies were generally segregated in the nucleus accumbens, although some overlap in the transition region between the core and shell was seen. Small clusters of calretinin-immunoreactive fibres were seen in the core, where they were restricted to calbindin-negative patches. Injections of the anterograde tracer biotinylated dextran amine into the paraventricular thalamic nucleus labelled fibres in calretinin-rich regions of the accumbens. Conversely, injections of Fluoro-gold into the accumbal shell retrogradely labelled numerous cells in the paraventricular thalamic nucleus that were calretinin-immunoreactive. Electrolytic lesions of the paraventricular thalamic nucleus reduced calretinin levels in the shell by approximately 80%. These data indicate that the calretinin innervation of the nucleus accumbens is derived primarily from the thalamic paraventricular nucleus, and marks accumbal territories that are largely complementary to those defined by calbindin.

Clozapine pretreatment modifies haloperidol-elicited forebrain Fos induction: a regionally-specific double dissociation.

RATIONALE: Acute administration of typical antipsychotic drugs, such as haloperidol, results in the induction of the immediate-early gene c-fos in the dorsolateral striatum. In contrast, the atypical antipsychotic drug clozapine, which lacks significant extrapyramidal side effect liability, does not induce Fos protein in the dorsal striatum. Several studies have attempted to define the mechanisms through which typical antipsychotic drugs induce striatal Fos, often by pretreating animals with specific receptor antagonists. Despite the broad receptor profile of clozapine, there has been no study of the effect of clozapine pretreatment on haloperidol-elicited striatal Fos expression. METHODS: We examined the effects of clozapine pretreatment of rats on haloperidol-elicited forebrain Fos expression, using both immunoblot and immunohistochemical methods. The effects of clozapine pretreatment were assessed in the dorsal striatum and in the different nucleus accumbens compartments, the septum, and the prefrontal cortex. RESULTS: Clozapine pretreatment markedly decreased haloperidol-elicited striatal Fos induction and blocked haloperidol-induced catalepsy. Clozapine also attenuated haloperidol-elicited Fos expression in the nucleus accumbens, but in the prefrontal cortex and ventrolateral septum the effects of haloperidol and clozapine were additive. CONCLUSIONS: An emerging body of literature suggests a high incidence of rapid relapse in schizophrenic patients when clozapine treatment is discontinued. This psychosis is relatively resistant to haloperidol and other neuroleptics, even in patients who had previously responded well to neuroleptics. The present data may shed light on the central sites associated with and perhaps model certain aspects of the relapse associated with clozapine discontinuation.

High-strength, ultra-thin and fiber-reinforced pHEMA artificial skin.

Membranes of pHEMA-based composites were manufactured by adding various kinds of weaved and knitted fabrics and fibers into a deionized water solution of HEMA monomer, EGDMA cross-linker and BIE initiator, and followed by polymerization under ultraviolet radiation. By varying the amount of initial water addition (IWA), the dimensional change of pHEMA matrix from the newly fabricated state to the eventually swollen state could be adjusted to reduce the swellability mismatch with the fabrics and the possibility of the swollen membranes becoming folded and curled was avoided. Mechanical properties of the fiber-reinforced pHEMA composites, including yielding strength, maximum strength, Young's modulus and elongation at break, are improved evidently depending on the mechanical characteristics of additives applied. The involvement of fabrics and fibers in the soft pHEMA matrix also provides an alternative of making the ultra-thin membranes to overcome the problem of easily being torn during handling. In addition, some of these membranes also exhibit an improvement in water transmission rate.

Psychostimulant-induced Fos protein expression in the thalamic paraventricular nucleus.

Lesions of glutamatergic afferents to the nucleus accumbens have been reported to block psychostimulant-induced behavioral sensitization. However, thalamic glutamatergic projections to the nucleus accumbens have received little attention in the context of psychostimulant actions. We examined the effects of acute amphetamine and cocaine administration on expression of Fos protein in the thalamic paraventricular nucleus (PVT), which provides glutamatergic inputs to the nucleus accumbens and also receives dopaminergic afferents. Immunoblot and immunohistochemical studies revealed that both psychostimulants dose-dependently increased PVT Fos expression. PVT neurons retrogradely labeled from the nucleus accumbens were among the PVT cells that showed a Fos response to amphetamine. D2 family dopamine agonists, including low doses of the D3-preferring agonist 7-OH-DPAT, increased the numbers of Fos-like-immunoreactive neurons in the PVT. Conversely, the effects of cocaine and amphetamine on PVT Fos expression were blocked by pretreatment with the dopamine D2/3 antagonist raclopride. Because PVT neurons express D3 but not other dopamine receptor transcripts, it appears that psychostimulants induce Fos in PVT neurons through a D3 dopamine receptor. We suggest that the PVT may be an important part of an extended circuit subserving both the arousing properties and reinforcing aspects of psychostimulants.

The effects of thalamic paraventricular nucleus lesions on cocaine-induced locomotor activity and sensitization.

The brain circuitry that subserves the augmented locomotor response to repeated psychostimulant administration has been the subject of intense scrutiny. The dopaminergic innervation of the nucleus accumbens is critically involved in psychostimulant-elicited behavioral sensitization, and recent studies suggest that lesions of structures that send glutamatergic projections to the nucleus accumbens alter the acquisition or expression of psychostimulant-elicited sensitization. Although certain thalamic nuclei provide a major glutamatergic input to the striatum, the involvement of the thalamus in psychostimulant-elicited sensitization has not been investigated. We therefore examined the effects of lesions of the thalamic paraventricular nucleus, which projects to the shell of the nucleus accumbens, on cocaine-elicited locomotor sensitization. Lesions of the paraventricular nucleus did not alter basal locomotor activity, but significantly enhanced the acute locomotor response to cocaine. In contrast, repeated cocaine administration did not progressively augment locomotor activity in lesioned rats, but did so in sham-lesioned animals. The thalamic lesions also blocked the conditioned locomotor response to the environment in which the cocaine injections took place. These data suggest that the thalamic paraventricular nucleus may be an integral part of extended circuitry that subserves both the conditioned and nonconditioned components of psychostimulant-induced behavioral sensitization.

Effects of desmethylclozapine on Fos protein expression in the forebrain: in vivo biological activity of the clozapine metabolite.

Several products of the hepatic metabolism of clozapine are found in high concentrations in the plasma of schizophrenic patients treated with this atypical antipsychotic drug. One of these metabolites, N-desmethylclozapine, has substantially different affinities for dopamine and serotonin metabolites than does the parent compound. However, it is not known if this metabolite is active in vivo. We examined the effect of acute administration of desmethylclozapine to rats on forebrain Fos protein expression. Clozapine induces expression of this immediate-early gene in a distinct regional pattern in the brain. Desmethylclozapine significantly increased Fos protein expression in the medial prefrontal cortex and nucleus accumbens, but not in the dorsolateral striatum, thus mirroring the effects of the parent compound. These data indicate that the desmethyl metabolite of clozapine has in vivo biological activity.

Simultaneous determination of amoxycillin and clavulanic acid in pharmaceutical products by HPLC with beta-cyclodextrin stationary phase.

A simple, rapid and accurate method for simultaneous determination of amoxycillin and clavulanic acid using HPLC with beta-cyclodextrin stationary phase was developed. It involves the use of tetraethylammonium acetate (TEAA) as an additive reagent, methanol-buffer solution (pH 4.5) (35:65; v/v) as the mobile phase, detection at 225 mm and chromatogram within 12 min. Linearity and precision of the internal standard method have been obtained. Recoveries ranged from 99.25 to 105.63% for amoxycillin in the synthetic mixture. For clavulanic acid it was from 99.50 to 101.64%. This method is convenient and reproducible for analyses of these two components in different dosage forms.

A note on the early history of electrical stimulation of the human brain.

We address inconsistencies in two areas concerning who was first to electrically stimulate a human's brain. First, Boring (1950) and others attributed priority to Eduard Hitzig based on information mentioned somewhat incidentally in Fritsch and Hitzig's (1870) classic work using dogs. Others cited Fritsch and Hitzig but attributed priority to Roberts Bartholow (1874). Second, our examination of translations of Fritsch and Hitzig, especially of footnote 16 in Hitzig's report (1870) of a human case, revealed errors, omissions, and inconsistencies. To aid our inquiry, we requested and received new translations of footnote 16 and of Hitzig's report.

Circadian rhythm in the visual system of the lizard Anolis carolinensis.

The electroretinogram (ERG) was recorded from free-moving Anolis lizards once per hour for 5 days. As in our previous work, the b-wave, but not the a-wave, showed a reliable circadian rhythm (CR) in amplitude, with an acrophase near projected noon. Both the a- and b-waves showed a CR in peak time (implicit time, or IT), with the a-wave IT being longest near midnight, and the b-wave IT at midday. Acrophases were shifted when animals were housed on a phase-shifted light-dark cycle. The ERG CR was unaffected by removal of the parietal organ, but it was virtually abolished by removal of the pineal gland, thus suggesting that pineal output (probably melatonin) modulates retinal responses. In addition to the ERG, the tectal light-evoked potential exhibited a CR--a finding compatible with a circadian variation in retinal output. Lastly, the amplitude of the ERG component waveforms showed a seasonal variation, but the ERG CR was constant across the year.