Mesenchymal stem cell extracellular vesicles mitigate vascular permeability and injury in the small intestine and lung in a mouse model of hemorrhagic shock and trauma.

BACKGROUND: Hemorrhagic shock and trauma (HS/T)-induced gut injury may play a critical role in the development of multi-organ failure. Novel therapies that target gut injury and vascular permeability early after HS/T could have substantial impacts on trauma patients. In this study, we investigate the therapeutic potential of human mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) in vivo in HS/T in mice and in vitro in Caco-2 human intestinal epithelial cells. METHODS: In vivo, using a mouse model of HS/T, vascular permeability to a 10-kDa dextran dye and histopathologic injury in the small intestine and lungs were measured among mice. Groups were (1) sham, (2) HS/T + lactated Ringer's (LR), (3) HS/T + MSCs, and (4) HS/T + MSC EVs. In vitro, Caco-2 cell monolayer integrity was evaluated by an epithelial cell impedance assay. Caco-2 cells were pretreated with control media, MSC conditioned media (CM), or MSC EVs, then challenged with hydrogen peroxide (H2O2). RESULTS: In vivo, both MSCs and MSC EVs significantly reduced vascular permeability in the small intestine (fluorescence units: sham, 456 ± 88; LR, 1067 ± 295; MSC, 765 ± 258; MSC EV, 715 ± 200) and lung (sham, 297 ± 155; LR, 791 ± 331; MSC, 331 ± 172; MSC EV, 303 ± 88). Histopathologic injury in the small intestine and lung was also attenuated by MSCs and MSC EVs. In vitro, MSC CM but not MSC EVs attenuated the increased permeability among Caco-2 cell monolayers challenged with H2O2. CONCLUSION: Mesenchymal stem cell EVs recapitulate the effects of MSCs in reducing vascular permeability and injury in the small intestine and lungs in vivo, suggesting MSC EVs may be a potential cell-free therapy targeting multi-organ dysfunction in HS/T. This is the first study to demonstrate that MSC EVs improve both gut and lung injury in an animal model of HS/T.

Altered germline cyst formation and oogenesis in Tex14 mutant mice.

During oocyte differentiation in mouse fetal ovaries, sister germ cells are connected by intercellular bridges, forming germline cysts. Within the cyst, primary oocytes form via gaining cytoplasm and organelles from sister germ cells through germ cell connectivity. To uncover the role of intercellular bridges in oocyte differentiation, we analyzed mutant female mice lacking testis-expressed 14 (TEX14), a protein involved in intercellular bridge formation and stabilization. In Tex14 homozygous mutant fetal ovaries, germ cells divide to form a reduced number of cysts in which germ cells remained connected via syncytia or fragmented cell membranes, rather than normal intercellular bridges. Compared with wild-type cysts, homozygous mutant cysts fragmented at a higher frequency and produced a greatly reduced number of primary oocytes with precocious cytoplasmic enrichment and enlarged volume. By contrast, Tex14 heterozygous mutant germline cysts were less fragmented and generate primary oocytes at a reduced size. Moreover, enlarged primary oocytes in homozygous mutants were used more efficiently to sustain folliculogenesis than undersized heterozygous mutant primary oocytes. Our observations directly link the nature of fetal germline cysts to oocyte differentiation and development.

New directions in necrotizing enterocolitis with early-stage investigators.

The 2019 Necrotizing Enterocolitis (NEC) Symposium expanded upon the NEC Society's goals of bringing stakeholders together to discuss cutting-edge science, potential therapeutics and preventative measures, as well as the patient-family perspectives of NEC. The Symposium facilitated discussions and shared knowledge with the overarching goal of creating "A World Without NEC." To accomplish this goal, new research to advance the state of the science is necessary. Over the last decade, several established investigators have significantly improved our understanding of the pathophysiology of NEC and they have paved the way for the next generation of clinician-scientists funded to perform NEC research. This article will serve to highlight the contributions of these young clinician-scientists that seek to elucidate how immune, microbial and nervous system dysregulation contributes to the pathophysiology of NEC.

In vivo histological evaluation of a novel ablative fractional resurfacing device.

BACKGROUND AND OBJECTIVES: A novel carbon dioxide (CO(2)) laser device employing ablative fractional resurfacing was tested on human skin in vivo for the first time. STUDY DESIGN/MATERIALS AND METHODS: An investigational 30 W, 10.6 microm CO(2) laser system was focused to a 1/e(2) spot size of 120 microm to generate an array of microscopic treatment zones (MTZ) in human forearm skin. A range of pulse energies between 5 and 40 mJ was tested and lesion dimensions were assessed histologically using hematoxylin and eosin. Wound healing of the MTZ's was assessed immediately-, 2-day, 7-day, 1-month, and 3-month post treatment. The role of heat shock proteins was examined by immunohistochemistry. RESULTS: The investigational CO(2) laser system created a microscopic pattern of ablative and thermal injury in human skin. The epidermis and part of the dermis demonstrated columns of thermal coagulation that surrounded tapering ablative zones lined by a thin eschar layer. Changing the pulse energy from 5 to 30 mJ resulted in a greater than threefold increase in lesion depth and twofold increase in width. Expression of heat shock protein (hsp)72 was detected as early as 2 days post-treatment and diminished significantly by 3 months. In contrast, increased expression of hsp47 was first detected at 7 days and persisted at 3 months post-treatment. CONCLUSION: The thermal effects of a novel investigational ablative CO(2) laser system utilizing fractional resurfacing were characterized in human forearm skin. We confirmed our previous ex vivo findings and show for the first time in-vivo, that a controlled array of microscopic treatment zones of ablation and coagulation could be deposited in human skin by varying treatment pulse energy. Immunohistochemical studies of heat shock proteins revealed a persistent collagen remodeling response lasting at least 3 months. We successfully demonstrated the first in-vivo use of ablative fractional resurfacing (AFR) treatment on human skin.

Reducing the risk for distal forearm fracture: preserve bone mass, slow down, and don't fall!

A case-control study of 1,150 female and male distal forearm cases and 2,331 controls of age 45 years and older was undertaken from 1996-2001 in five Northern California Kaiser Permanente Medical Centers. Most information on possible risk factors was obtained by an interviewer-administered questionnaire, supplemented by a few tests of lower extremity neurological function. Previous fractures since 45 years of age, a rough marker of osteoporosis, were associated with an increased risk (adjusted odds ratio [OR] [95% confidence interval] = 1.48 [1.20-1.84 ] per previous fracture). Several factors thought to protect against low bone mass were associated with a reduced risk, including current use of menopausal hormone therapy (adjusted OR = 0.60 [0.49-0.74]), ever used thiazide diuretics or water pills for at least 1 year (adjusted OR = 0.79 [0.64-0.97]), high body mass index (weight in kg/height in m2) (adjusted OR = 0.96 [0.89-1.04] per 5 unit increase), and high dietary calcium intake (adjusted OR = 0.88 [0.75-1.03] per 500 mg/day). Falls in the past year and conditions associated with falling, such as epilepsy and/or use of seizure medication (adjusted OR = 2.07 [1.35-3.17]) and a history of practitioner-diagnosed depression (adjusted OR = 1.40 [1.13-1.73]), were associated with increased risks. Having difficulty performing physical functions and all lower-extremity problems measured in this study were associated with reduced risks. The results from this and other studies indicate that distal forearm fractures tend to occur in people with low bone mass who are otherwise in relatively good health and are physically active, but who are somewhat prone to falling (particularly on an outstretched hand), and whose movements are not slowed by lower extremity problems and other debilities. Thus, measures to decrease fall frequency and to slow down the pace of relatively healthy people with low bone mass should lead to a lower frequency of distal forearm fracture.

Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury.

BACKGROUND AND OBJECTIVES: We introduce and clinically examine a new concept of skin treatment called fractional photothermolysis (FP), achieved by applying an array of microscopic treatment zones (MTZ) of thermal injury to the skin. STUDY DESIGN/MATERIALS AND METHODS: Two prototype devices emitting at 1.5 microm wavelength provided a pattern of micro-exposures with variable MTZ density. Effects of different MTZ densities were tested on the forearms of 15 subjects. Clinical effects and histology were assessed up to 3 months after exposure. Treatment of photoaged skin on the periorbital area in an additional 30 subjects receiving four treatments over a period of 2-3 weeks was also tested. Tissue shrinkage and clinical effects were assessed up to 3 months after treatment. RESULTS: Pattern densities with spacing of 250 microm or more were well tolerated. Typical MTZ had a diameter of 100 microm and penetrated 300 microm into the skin. Reepithelialization was complete within 1 day. Clinical effects were assessed over a 3-month period. Histology at 3 months revealed enhanced undulating rete ridges and increased mucin deposition within the superficial dermis. Periorbital treatments were well tolerated with minimal erythema and edema. Linear shrinkage of 2.1% was measured 3 months after the last treatment. The wrinkle score improved 18% (P < 0.001) 3 months after the last treatment. CONCLUSIONS: FP is a new concept for skin restoration treatment. Safety and efficacy were demonstrated with a prototype device. Further clinical studies are necessary to refine the optimum parameters and to explore further dermatological applications.

Disordered eating, menstrual irregularity, and bone mineral density in female runners.

PURPOSE: To examine the relationships between disordered eating, menstrual irregularity, and low bone mineral density (BMD) in young female runners. METHODS: Subjects were 91 competitive female distance runners aged 18-26 yr. Disordered eating was measured by the Eating Disorder Inventory (EDI). Menstrual irregularity was defined as oligo/amenorrhea (0-9 menses per year). BMD was measured by dual x-ray absorptiometry. RESULTS: An elevated score on the EDI (highest quartile) was associated with oligo/amenorrhea, after adjusting for percent body fat, age, miles run per week, age at menarche, and dietary fat, (OR [95% CI]: 4.6 [1.1-18.6]). Oligo/amenorrheic runners had lower BMD than eumenorrheic runners at the spine (-5%), hip (-6%), and whole body (-3%), even after accounting for weight, percent body fat, EDI score, and age at menarche. Eumenorrheic runners with elevated EDI scores had lower BMD than eumenorrheic runners with normal EDI scores at the spine (-11%), with trends at the hip (-5%), and whole body (-5%), after adjusting for differences in weight and percent body fat. Runners with both an elevated EDI score and oligo/amenorrhea had no further reduction in BMD than runners with only one of these risk factors. CONCLUSION: In young competitive female distance runners, (i) disordered eating is strongly related to menstrual irregularity, (ii) menstrual irregularity is associated with low BMD, and (iii) disordered eating is associated with low BMD in the absence of menstrual irregularity.