The pathophysiology and treatment of musculoskeletal fibrosis.

Fibrosis continues to challenge the regeneration and repair of the Orthopaedic tissues in states of injury or disease. The mechanism behind developmental fibrosis has been widely investigated in the last few decades. However, the current efficacy of treatment for existing fibrous scars remains insufficient from both basic research and clinical perspectives. Scarred fibrotic tissue impedes the physical function of affected local tissues and organs and may also be associated with abnormal pain conduction or tissue reinjury. It is necessary to discover the functional treatment for fibrous scars as this pathology is medically demanding to effected patients. The current article will review the mechanisms behind fibrosis formation and the treatment potential in the field of the musculoskeletal system, especially in the pathology and treatment of injured skeletal muscle and the development of osteoarthritis.

Is the age of cervical cancer diagnosis changing over time?

OBJECTIVES: The objective of this study was to determine if there has been an increase in the age of diagnosis of cervical cancer over time, specifically in the proportion of patients over 65 years old, given decreasing rates of hysterectomy. MATERIALS AND METHODS: A retrospective review of a single institution was conducted including cervical cancer patients seen between 1986 and 2016. Data included demographic variables including age of diagnosis, last cervical cancer screening, and cancer information. Cochran-Armitage test was used to assess temporal trends in the proportion of patients diagnosed over 65. RESULTS: A total of 1,019 patients with cervical cancer were reviewed, of whom 116 were over the age of 65. The age of diagnosis increased by 0.2 years per calendar year, with an average age of diagnosis of 43.7 years old in 1986 versus 49.5 years old in 2016 (p<0.01). The proportion of patients diagnosed with cervical cancer over the age of 65 did not significantly differ over time (17.2 % in 1986 vs. 14.8 % in 2016, p=0.39). 19.0 % of women diagnosed with cervical cancer over the age of 65 developed cancer despite exiting screening appropriately. CONCLUSIONS: In our cohort, the age of diagnosis of cervical cancer increased over time, however, there was no significant difference in the percentage of women diagnosed over the age of 65.

Effect of Obesity on Cervical Cancer Screening and Outcomes.

OBJECTIVES: The aims of the study were to identify whether obese women are less appropriately screened for cervical cancer before diagnosis and to explore related cancer outcomes. METHODS: We retrospectively reviewed all cervical cancer patients at a single institution between 1986 and 2016 and collected demographic information including age, cancer stage, body mass index (BMI), screening information, and cancer outcomes. Morbid obesity was defined as BMI of 40 kg/m or greater, obesity as BMI of 30 to less than 40 kg/m, and nonobese as BMI of less than 30 kg/m. χ, Fisher exact, and Wilcoxon rank sum tests were used to compare variables between BMI categories. Cox regression models were used to evaluate recurrence-free survival and overall survival (OS). RESULTS: A total of 1,080 patients were reviewed, of whom 311 (29.4%) were obese and 107 (10.1%) morbidly obese. A significant association between BMI and cytology screening was evidenced with morbidly obese women having the highest incorrect rate (64.4%), followed by obese (51.5%) and nonobese women (46.0%, p < .01). There was no significant difference in presence of symptoms at presentation (p = .12) or stage (p = .06) between BMI categories. In multivariable analysis of cancer outcomes, higher BMI was associated with worse OS (p < .01) with a hazard ratio of 1.25 (95% CI = 0.92-1.69) for obese women and hazard ratio 2.27 (95% CI = 1.56-3.31) for morbidly obese women relative to normal weight but recurrence-free survival did not differ between BMI groups (p = .07). CONCLUSIONS: Our study strengthens evidence that obese and morbidly obese women have disproportionate inappropriate screening before cervical cancer diagnosis, and morbidly obese women have worse OS than their counterparts.

Prevalence, attitudes and knowledge of misoprostol for self-induction of abortion in women presenting for abortion at Midwestern reproductive health clinics.

In the setting of increasing restrictions to legal abortion in the United States, reports have emerged of self-induced termination of pregnancies with misoprostol, obtained without a prescription or provider. This study seeks to describe the prevalence of women seeking or employing misoprostol for self-induced abortion, and how they access information. In a cross-sectional study of women immediately following their abortion at three reproductive health clinics in the Midwestern United States, an anonymous survey queried gestational age, barriers, online investigation about self-induction and opinions concerning the availability of medical abortion. From June to September 2016, 276 women participated out of 437 presenting to the clinics during the study period. One hundred and ninety-one (74.6%) women had investigated abortion options online, and of those, 58 (30.9%) investigated misoprostol online, for home use. Women who investigated online options were less likely to have had a prior abortion than those who did not investigate online (29.3% vs. 63.1%, p < .01). They were also more likely to report prior home attempts to end this pregnancy (8.6% vs. 0%, p = .05). Overall, four (1.6%) of the respondents purchased misoprostol and three (1.2%) used it. A majority of women seeking an abortion sought online information prior to their clinic appointment, and almost a third of those had investigated misoprostol for home use. Women are accessing information regarding misoprostol for self-induction of abortion on the Internet. As barriers to legal abortion increase, women may be more likely to self-induce abortion.

Repurposing tromethamine as inhaled therapy to treat CF airway disease.

In cystic fibrosis (CF), loss of CF transmembrane conductance regulator (CFTR) anion channel activity causes airway surface liquid (ASL) pH to become acidic, which impairs airway host defenses. One potential therapeutic approach is to correct the acidic pH in CF airways by aerosolizing HCO3- and/or nonbicarbonate pH buffers. Here, we show that raising ASL pH with inhaled HCO3- increased pH. However, the effect was transient, and pH returned to baseline values within 30 minutes. Tromethamine (Tham) is a buffer with a long serum half-life used as an i.v. formulation to treat metabolic acidosis. We found that Tham aerosols increased ASL pH in vivo for at least 2 hours and enhanced bacterial killing. Inhaled hypertonic saline (7% NaCl) is delivered to people with CF in an attempt to promote mucus clearance. Because an increased ionic strength inhibits ASL antimicrobial factors, we added Tham to hypertonic saline and applied it to CF sputum. We found that Tham alone and in combination with hypertonic saline increased pH and enhanced bacterial killing. These findings suggest that aerosolizing the HCO3--independent buffer Tham, either alone or in combination with hypertonic saline, might be of therapeutic benefit in CF airway disease.

Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense.

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl(-) and bicarbonate (HCO3 (-)) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl(-) and HCO3 (-) transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization.

pH modulates the activity and synergism of the airway surface liquid antimicrobials ß-defensin-3 and LL-37.

The pulmonary airways are continuously exposed to bacteria. As a first line of defense against infection, the airway surface liquid (ASL) contains a complex mixture of antimicrobial factors that kill inhaled and aspirated bacteria. The composition of ASL is critical for antimicrobial effectiveness. For example, in cystic fibrosis an abnormally acidic ASL inhibits antimicrobial activity. Here, we tested the effect of pH on the activity of an ASL defensin, human ß-defensin-3 (hBD-3), and the cathelicidin-related peptide, LL-37. We found that reducing pH from 8.0 to 6.8 reduced the ability of both peptides to kill Staphylococcus aureus. An acidic pH also attenuated LL-37 killing of Pseudomonas aeruginosa. In addition, we discovered synergism between hBD-3 and LL-37 in killing S. aureus. LL-37 and lysozyme were also synergistic. Importantly, an acidic pH reduced the synergistic effects of combinations of ASL antibacterials. These results indicate that an acidic pH reduces the activity of individual ASL antimicrobials, impairs synergism between them, and thus may disrupt an important airway host defense mechanism.