Diagnostic and therapeutic value of intracellular biomarker testing in chronic pain.

Aim: Micronutrient and metabolic compound supplementation as a method of treating chronic pain is not well understood. Case: A 58 year-old woman presented with refractory painful neuropathy. She did not respond to conservative treatment and was seeking spinal cord stimulator implantation. She underwent a biomarker panel that revealed low intracellular levels of multiple compounds. As she supplemented her deficiencies, her symptoms fully resolved, and the implant was no longer indicated. Discussion: Micronutrient and metabolic compound testing could potentially expand non-invasive treatment options for patients with refractory chronic pain. Caution should be exercised given limited regulatory oversight in the supplement industry and actively ongoing nutritional research. Conclusion: Biomarker testing panels may be a useful adjunct in the management of refractory neuropathic pain.

Pelvic Floor Therapy and Initial Interventions for Pelvic Floor Dysfunction in Gynecologic Malignancies.

PURPOSE OF REVIEW: This review provides evidence-based updates for the first-line management approaches for pelvic floor disorders in patients with gynecologic malignancies, as well as important provider considerations when referring for pelvic floor physical therapy. RECENT FINDINGS: Currently, there is strong evidence to recommend pelvic floor muscle training as initial treatment for urinary incontinence and for pelvic organ prolapse; some evidence to recommend a more targeted pelvic floor muscle training program for fecal incontinence; and mostly expertise-based evidence to recommend vaginal gels or estrogen to aid with dyspareunia causing sexual dysfunction. More research is greatly needed to understand the role of overactive pelvic floor muscles in survivors with chronic pelvic pain and the treatment of post-radiation pelvic complications such as vaginal stenosis and cystitis. While pelvic floor disorders are common concerns in gynecologic cancer survivors, there are evidence-based initial noninvasive treatment approaches that can provide relief for many individuals.

Physical medicine & rehabilitation residents' perspectives on women's musculoskeletal health.

INTRODUCTION: Women are either disproportionately or uniquely affected by certain musculoskeletal conditions but have limited access to providers of sex-specific musculoskeletal care. Few physical medicine & rehabilitation (PM&R) residencies offer women's musculoskeletal health training, and it is unknown whether PM&R residents feel prepared to care for women's musculoskeletal health concerns. OBJECTIVE: To examine PM&R residents' perspectives and experiences in women's musculoskeletal health. DESIGN: Cross-sectional survey developed through clinical expertise and consistent with sports medicine guidelines. SETTING: Electronic survey sent to all accredited PM&R residency programs within the United States, distributed through program coordinators and resident representatives. PARTICIPANTS: PM&R residents. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The primary outcome was residents' perspective of comfort with women's musculoskeletal health. Secondary outcomes were exposure to formal education on women's musculoskeletal health topics, exposure to various learning formats for these topics; and residents' perspectives on desire for further education, access to field-specific mentors, and interest in incorporating women's musculoskeletal health into future practice. RESULTS: Two hundred eighty-eight responses were included for analysis (20% response rate, 55% female sex residents). Only 19% of residents self-reported feeling comfortable providing care for women's musculoskeletal health conditions. Comfort did not significantly differ by postgraduate year, program region, or sex. However, with regression modeling, the number of topics learned formally in their curriculum had an increased odds of residents self-reporting comfort (odds ratio [OR] 1.18, confidence interval [CI] 1.08-1.30, adjusted p value .01). The majority of residents viewed learning women's musculoskeletal health as important (94%) and requested more exposure to the field (89%). CONCLUSIONS: Many PM&R residents do not feel comfortable in caring for women's musculoskeletal health conditions despite their interest in the field. To improve health care access for patients seeking care for these sex-predominant or sex-specific conditions, residency programs may want to consider increasing exposure to women's musculoskeletal health for residents.

Evaluating Disability-Related Quality of Life in Women With Chronic Pelvic Pain.

OBJECTIVES: The primary aim of this study was to describe quality of life (QOL) in women with chronic pelvic pain using the Pain Disability Index (PDI). A secondary goal was to assess the measurement properties and validity of the PDI for this population. METHODS: This study was a cross-sectional retrospective chart review. In the setting of an outpatient female pelvic pain clinic, we included data from an initial evaluation of patients 16 years and older with chronic pelvic pain (N = 317) from 2012 to 2017. Quality of life was measured using the PDI and previously validated measures for depression and anxiety. RESULTS: The mean PDI score across all patients was similar to previously reported means for similar chronic pain populations. Patients experienced the most disability in their sexual activities. The most common cause of chronic pelvic pain was pelvic floor myofascial pain. Common diagnostic categories covered gynecologic, urologic, gastrointestinal, musculoskeletal, and neurological causes. The PDI was unable to discriminate between diagnoses. On average, patients qualified for mild depression and anxiety diagnoses. Results from a confirmatory factor analysis revealed the original factor structure for the PDI fits this population. CONCLUSIONS: The PDI shows promise as a questionnaire for QOL and could be a valuable clinician tool for tracking QOL in the chronic pelvic pain population. Additional research should be focused on assessing its ability to measure minimum clinically significant change over time.

1550-nm Nonablative Fractional Laser Versus 10,600-nm Ablative Fractional Laser in the Treatment of Surgical and Traumatic Scars: A Comparison Study on Efficacy and Treatment Regimen.

BACKGROUND: The appearance and symptoms of scars can cause significant distress to patients. OBJECTIVE: To assess and compare efficacy of the 1,500-nm nonablative fractional laser (NAFL) and 10,600-nm ablative fractional laser (AFL) in reducing symptoms and improving the appearance of traumatic or surgical scars. MATERIALS AND METHODS: Single-center prospective, randomized, blinded, split-scar study was conducted on 100 patients with a scar obtained through trauma or surgery. Three treatments of NAFL or AFL were administered to each half of the scar at 4-week intervals. Scars were self-rated by the patient using the Patient and Observer Scar Assessment Scale and a satisfaction score and objectively evaluated by blinded dermatologists using the Manchester Scar Scale and visual analog scale. RESULTS: Blinded observers found no statistically significant difference in scar appearance. Patient rating showed improvement of scar appearance (p < .0001). Pain was worse after treatment with AFL (p = .0492). Overall, there was no statistically significant evidence of one laser being superior or inferior to the other for patient and blinded observer scores (p = .3173 and p = .2513, respectively). CONCLUSION: Scar treatment with AFL or NAFL is associated with high patient satisfaction. Objective evaluation of scars did not identify improvement in scar appearance.

Durable multitransgene expression in vivo using systemic, nonviral DNA delivery.

Recombinant adeno-associated virus (AAV) vectors are transforming therapies for rare human monogenic deficiency diseases. However, adaptive immune responses to AAV and its limited DNA insert capacity, restrict their therapeutic potential. HEDGES (high-level extended duration gene expression system), a nonviral DNA- and liposome-based gene delivery platform, overcomes these limitations in immunocompetent mice. Specifically, one systemic HEDGES injection durably produces therapeutic levels of transgene-encoded human proteins, including FDA-approved cytokines and monoclonal antibodies, without detectable integration into genomic DNA. HEDGES also controls protein production duration from <3 weeks to >1.5 years, does not induce anti-vector immune responses, is reexpressed for prolonged periods following reinjection, and produces only transient minimal toxicity. HEDGES can produce extended therapeutic levels of multiple transgene-encoded therapeutic human proteins from DNA inserts >1.5-fold larger than AAV-based therapeutics, thus creating combinatorial interventions to effectively treat common polygenic diseases driven by multigenic abnormalities.

Differential regulation of germline apoptosis in response to meiotic checkpoint activation.

In Caenorhabditis elegans, germline apoptosis is promoted by egl-1 and ced-13 in response to meiotic checkpoint activation. We report that the requirement for these two factors depends on which checkpoints are active. We also identify a regulatory region of egl-1 required to inhibit germline apoptosis in response to DNA damage incurred during meiotic recombination.

A quality control mechanism coordinates meiotic prophase events to promote crossover assurance.

Meiotic chromosome segregation relies on homologous chromosomes being linked by at least one crossover, the obligate crossover. Homolog pairing, synapsis and meiosis specific DNA repair mechanisms are required for crossovers but how they are coordinated to promote the obligate crossover is not well understood. PCH-2 is a highly conserved meiotic AAA+-ATPase that has been assigned a variety of functions; whether these functions reflect its conserved role has been difficult to determine. We show that PCH-2 restrains pairing, synapsis and recombination in C. elegans. Loss of pch-2 results in the acceleration of synapsis and homolog-dependent meiotic DNA repair, producing a subtle increase in meiotic defects, and suppresses pairing, synapsis and recombination defects in some mutant backgrounds. Some defects in pch-2 mutants can be suppressed by incubation at lower temperature and these defects increase in frequency in wildtype worms grown at higher temperature, suggesting that PCH-2 introduces a kinetic barrier to the formation of intermediates that support pairing, synapsis or crossover recombination. We hypothesize that this kinetic barrier contributes to quality control during meiotic prophase. Consistent with this possibility, defects in pch-2 mutants become more severe when another quality control mechanism, germline apoptosis, is abrogated or meiotic DNA repair is mildly disrupted. PCH-2 is expressed in germline nuclei immediately preceding the onset of stable homolog pairing and synapsis. Once chromosomes are synapsed, PCH-2 localizes to the SC and is removed in late pachytene, prior to SC disassembly, correlating with when homolog-dependent DNA repair mechanisms predominate in the germline. Indeed, loss of pch-2 results in premature loss of homolog access. Altogether, our data indicate that PCH-2 coordinates pairing, synapsis and recombination to promote crossover assurance. Specifically, we propose that the conserved function of PCH-2 is to destabilize pairing and/or recombination intermediates to slow their progression and ensure their fidelity during meiotic prophase.

Reproductive aging: insights from model organisms.

Aging was once thought to be the result of a general deterioration of tissues as opposed to their being under regulatory control. However, investigations in a number of model organisms have illustrated that aspects of aging are controlled by genetic mechanisms and are potentially manipulable, suggesting the possibility of treatment for age-related disorders. Reproductive decline is one aspect of aging. In model organisms and humans of both sexes, increasing age is associated with both a decline in the number of progeny and an increased incidence of defects. The cellular mechanisms of reproductive aging are not well understood, although a number of factors, both intrinsic and extrinsic to an organism's germline, may contribute to aging phenotypes. Recent work in a variety of organisms suggests that nuclear organization and nuclear envelope proteins may play a role in these processes.

Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity.

Acetyl-CoA carboxylase (ACC) is a key enzyme of fatty acid metabolism with multiple isozymes often expressed in different eukaryotic cellular compartments. ACC-made malonyl-CoA serves as a precursor for fatty acids; it also regulates fatty acid oxidation and feeding behavior in animals. ACC provides an important target for new drugs to treat human diseases. We have developed an inexpensive nonradioactive high-throughput screening system to identify new ACC inhibitors. The screen uses yeast gene-replacement strains depending for growth on cloned human ACC1 and ACC2. In "proof of concept" experiments, growth of such strains was inhibited by compounds known to target human ACCs. The screen is sensitive and robust. Medium-size chemical libraries yielded new specific inhibitors of human ACC2. The target of the best of these inhibitors was confirmed with in vitro enzymatic assays. This compound is a new drug chemotype inhibiting human ACC2 with 2.8 muM IC(50) and having no effect on human ACC1 at 100 muM.

CD18 is required for intestinal T cell responses at multiple immune checkpoints.

The intestinal immune response to oral Ags involves a complex multistep process. The requirements for optimal intestinal T cell responses in this process are unclear. LFA-1 plays a critical role in peripheral T cell trafficking and activation, however, its role in intestinal immune responses has not been precisely defined. To dissect the role of LFA-1 in intestinal immune responses, we used a system that allows for segregation of T cell migration and activation through the adoptive transfer of LFA-1-deficient (CD18(-/-)) CD4(+) T cells from DO11.10 TCR transgenic mice into wild-type BALB/c mice. We find that wild-type mice adoptively transferred with CD18(-/-) DO11.10 CD4(+) T cells demonstrate decreases in the numbers of Ag-specific T cells in the intestinal lamina propria after oral Ag administration. We also find that in addition to its role in trafficking to intestinal secondary lymphoid organs, LFA-1 is required for optimal CD4(+) T cell proliferation in vivo upon oral Ag immunization. Furthermore, CD18(-/-) DO11.10 CD4(+) T cells primed in the intestinal secondary lymphoid organs demonstrate defects in up-regulation of the intestinal-specific trafficking molecules, alpha(4)beta(7) and CCR9. Interestingly, the defect in trafficking of CD18(-/-) DO11.10 CD4(+) T cells to the intestinal lamina propria persists even under conditions of equivalent activation and intestinal-tropic differentiation, implicating a role for CD18 in the trafficking of activated T cells into intestinal tissues independent of the earlier defects in the intestinal immune response. This argues for a complex role for CD18 in the early priming checkpoints and ultimately in the trafficking of T cells to the intestinal tissues during an intestinal immune response.