Distraction Enterogenesis in Rats: A Novel Approach for the Treatment of Short Bowel Syndrome.

BACKGROUND: Surgeons often encounter patients with intestinal failure due to inadequate intestinal length ("short bowel syndrome"/SBS). Treatment in these patients remains challenging and the process of physiologic adaptation may take years to complete, which frequently requires parenteral nutrition. We propose a proof-of-concept mechanical bowel elongation approach using a self-expanding prototype of an intestinal expansion sleeve (IES) for use in SBS to accelerate the adaptation process. METHODS: IESs were deployed in the small intestines of Sprague Dawley rats. Mechanical characterization of these prototypes was performed. IES length-tension relationships and post-implant bowel expansion were measured ex vivo. Bowel histology before and after implantation was evaluated. RESULTS: IES mechanical studies demonstrated decreasing expansive force with elongation. The deployment of IES devices produced an immediate 21 ± 8% increase in bowel length (p < 0.001, n = 11). Mechanical load testing data showed that the IESs expressed maximum expansive forces at 50% compression of the initial pre-contracted length. The small-intestine failure load in the rats was 1.88 ± 21 N. Intestinal histology post deployment of the IES showed significant expansive changes compared to unstretched bowel tissue. CONCLUSIONS: IES devices were scalable to the rat intestinal model in our study. The failure load of the rat small intestine was many times higher than the force exerted by the contraction of the IES. Histology demonstrated preservation of intestinal structure with some mucosal erosion. Future in vivo rat studies on distraction enterogenesis with this IES should help to define this organogenesis phenomenon.

STABILITY (Symptomatic Review during Biologic Therapy) of Inflammatory Bowel Disease Patients Receiving Infusion Therapy Improves Clinical Outcomes.

Several studies have correlate improved patient outcomes with increased physician-patient contacts, particularly in chronic diseases. Extending this approach to inflammatory bowel disease (IBD) care presents a promising means of improving outcomes. At LSU Health Shreveport (LSUHS), a new approach called "STABILITY" (Symptomatic Review during Biologic Therapy) was implemented during infusion therapy visits for IBD patients. These brief 15 min physician-patient interviews aimed to discuss the patients' current IBD-related symptoms and evaluate the need for any changes in their treatment plan. Our goal was to remove a care gap and prevent intensifying symptoms created by missed appointments and loss of contact. To analyze the effectiveness of the STABILITY approach, a retrospective chart review was conducted on 111 IBD patients (18 with ulcerative colitis, 93 with Crohn's disease) seen at LSUHS between 2011 and 2022. Since March 2019, STABILITY has been mandatory for all infusion therapy visits. The data collected included patients' demographics, lab levels for biomarkers (fecal calprotectin, C-reactive protein, and erythrocyte sedimentation rates), hospitalizations, medication changes, and diagnosis dates before and after the implementation of STABILITY. Additionally, voluntary, anonymous infusion patient satisfaction surveys post-STABILITY were used to gather patient responses. In males with IBD, disease severity and hospitalizations were reduced significantly (p = 0.004 and 0.0234, respectively). In females with IBD, disease severity and hospitalizations were also reduced significantly (p = 0.0001 and 0.0072, respectively). In patients with UC and CD, there were significant improvements in disease severity (p = 0.043 and p = 0.0001, respectively), and CD hospitalizations were also improved (p = 0.0013). In males and females with UC, disease severity was marginally and significantly reduced (p = 0.0781 and p = 0.0379, respectively). In males and females with CD, disease severity was significantly reduced (p = 0.0161 and 0.0003, respectively), and CD male and female hospitalizations were also reduced significantly (p = 0.0436 and 0.013). Analyzing of survey responses, we found that the most patients reported improved IBD symptoms (56%), gained understanding of their condition (84%) and were in favor of continuing STABILITY consultations during infusion therapy (93%). To further investigate the impact of STABILITY, we conducted a comparative analysis between IBD patients undergoing STABILITY infusion therapy and LSUHS patients solely on self-injectable biologics. Our paired data analysis showed significant improvements in disease severity in female IBD patients (1.69 ± 0.13 vs. 1.41 ± 0.12, p = 0.0001) and male IBD patients (1.58 ± 0.16 vs. 1.2 ± 0.135, p = 0.004), in UC patients (1.833 ± 0.4.2 vs. 1.444, p = 0.043), in all CD patients (1.59 ± 0.11 vs. 1.29 ± 0.01, p = 0.0001), in male CD patients (1.52 ± 0.167 vs. 1.15 ± 0.15, p = 0.016), in female CD patients (1.66 ± 0.15 vs. 1.4 ± 0.13, p = 0.0003), in female UC patients (1.82 ± 0.32 vs. 1.45 ± 0.31, p = 0.0379), and marginally in male UC patients (p = 0.0781). Similarly, hospitalizations were significantly reduced in CD patients considered in aggregate (0.21 ± 0.04 vs. 0.11 ± 0.03, p = 0.0013), in male IBD patients (0.175 ± 0.06 vs. 0.05 ± 0.035, p = 0.024), in female IBD patients (0.21 ± 0.05 vs. 0.11 ± 0.04, p = 0.0072), in male CD patients (0.18 ± 0.07 vs. 0.06 ± 0.042, p = 0.0436), and in females with CD (0.23 ± 0.06 vs. 0.13 ± 0.04, p = 0.013). Although average values for fecal calprotectin, CRP, and sedimentation rate were frequently reduced after STABILITY interviews, these data did not reach statistical significance. These preliminary findings suggest that STABILITY may be effective in maintaining low disease activity or remission in IBD patients.

Reply to Singh, G.D. Comment on "Dao et al. Retrospective Analysis of Real-World Data for the Treatment of Obstructive Sleep Apnea with Slow Maxillary Expansion Using a Unique Expansion Dental Appliance (DNA). Pathophysiology 2023, 30, 199-208".

In response to the commentary "Response to 'Retrospective analysis of real-world data for the treatment of obstructive sleep apnea with slow maxillary expansion'" [...].

Retrospective Analysis of Real-World Data for the Treatment of Obstructive Sleep Apnea with Slow Maxillary Expansion Using a Unique Expansion Dental Appliance (DNA).

In addition to mandibular advancement devices, dental expansion appliances are an important clinical approach for achieving an increased intra-oral space that promotes airflow and lessens the frequency or severity of apneic events in patients diagnosed with obstructive sleep apnea (OSA). It has been thought that dental expansion in adults must be preceded by oral surgery; however, in this paper, we examine the results of a new technique for slow maxillary expansion without any surgical procedures. The palatal expansion device, DNA (Daytime-Nighttime Appliance), was reviewed in this retrospective study, particularly regarding its effects on measurements of transpalatal width, airway volume, and apnea-hypopnea indices (AHI) as well as its common modalities and complications. The DNA effectively reduced AHI by 46% (p = 0.00001) and significantly increased both airway volume and transpalatal width (p < 0.00001). After DNA treatment, 80% of patients showed some improvement in AHI scores with 28% of patients having their OSA symptoms completely resolved. Compared to the use of mandibular appliances, this approach is intended to create a sustained improvement in airway management that can reduce or eliminate dependence on continuous positive airway pressure (CPAP) or other OSA treatment devices.

Methamphetamine and Designer Stimulants Modulate Tonic Human Cerebrovascular Smooth Muscle Contractility: Relevance to Drug-Induced Neurovascular Stress.

To avoid criminal prosecution, clandestine chemists produce designer stimulants that mimic the pharmacological and psychoactive effects of conventional stimulants, such as methamphetamine. Following persistent or high-dose exposure, both acute vasoconstriction and loss of vascular homeostasis are reported dangers of conventional stimulants, and designer stimulants may pose even greater dangers. To compare the effects of a conventional stimulant and two designer stimulants on vascular contraction, this study examined the direct effects of 1,3-benzodioxolylbutanamine (BDB) and N-butylpentylone in comparison to methamphetamine on the function of human brain vascular smooth muscle cells (HBVSMCs). HBVSMCs suspended in collagen gels were exposed to varying concentrations of each drug, and the degree of constriction was assessed over one week. The MTT assay was used to measure the impact of the three drugs on the cellular metabolic activity as a marker of cellular toxicity. The highest concentration tested of either methamphetamine or N-butylpentylone produced a loss of HBVSMC contractility and impaired cellular metabolism. BDB showed a similar pattern of effects, but, uniquely, it also induced vasoconstrictive effects at substantially lower concentrations. Each drug produced direct effects on HBVSMC contraction that may be a mechanism by which the cardiovascular system is damaged following high-dose or persistent exposure, and this could be exacerbated by any sympathomimetic effects of these compounds in whole organisms. BDB appears to impact HBVSMC function in ways distinct from methamphetamine and N-butylpentylone, which may present unique dangers.

'Distraction Vaginogenesis': Preliminary Results Using a Novel Method for Vaginal Canal Expansion in Rats.

Vaginal atresia is seen in genetic disorders such as Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, which can cause significant sexual dysfunction. Current treatments include surgical reconstruction or mechanical dilation of the vaginal canal. Mechanical dilation requires patients to be highly motivated and compliant while surgical reconstruction has high rates of complications. This study evaluated a novel vaginal expansion sleeve (VES) method as an alternative treatment for vaginal atresia. The proprietary cylindrical VES is a spring-like device consisting of polyethylene terephthalate helicoid trusses capped at each end with a fixed diameter resin cap for fixation within tissues. Following the development of the VES and mechanical characterization of the force-length relationships within the device, we deployed the VES in Sprague Dawley rat vaginas anchored with nonabsorbable sutures. We measured the VES length-tension relationships and post-implant vaginal canal expansion ex vivo. Vaginal histology was examined before and after implantation of the VES devices. Testing of 30 mm sleeves without caps resulted in an expansion force of 11.7 ± 3.4 N and 2.0 ± 0.1 N at 50% and 40%, respectively. The implanted 20 mm VES resulted in 5.36 mm ± 1.18 expansion of the vaginal canal, a 32.5 ± 23.6% increase (p = 0.004, Student t test). Histological evaluation of the VES implanted tissue showed a significant thinning of the vaginal wall when the VES was implanted. The novel VES device resulted in a significant expansion of the vaginal canal ex vivo. The VES device represents a unique alternative to traditional mechanical dilation therapy in the treatment of vaginal atresia and represents a useful platform for the mechanical distension of hollow compartments, which avoids reconstructive surgeries and progressive dilator approaches.

Dysregulated Sulfide Metabolism in Multiple Sclerosis: Serum and Vascular Endothelial Inflammatory Responses.

Multiple sclerosis (MS) is a leading cause of neurodegenerative disability in younger individuals. When diagnosed early, MS can be managed more effectively, stabilizing clinical symptoms and delaying disease progression. The identification of specific serum biomarkers for early-stage MS could facilitate more successful treatment of this condition. Because MS is an inflammatory disease, we assessed changes in enzymes of the endothelial hydrogen sulfide (H2S) pathway in response to inflammatory cytokines. Blotting analysis was conducted to detect Cystathionine γ-lyase (CSE), Cystathionine beta synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (MST) in human brain microvascular endothelial apical and basolateral microparticles (MPs) and cells following exposure to tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). CSE was increased in MPs and cells by exposure to TNF-α/IFN-γ; CBS was elevated in apical MPs but not in cells or basolateral MPs; MST was not significantly affected by cytokine exposure. To test how our findings relate to MS patients, we evaluated levels of CSE, CBS, and MST in serum samples from healthy control and MS patients. We found significantly decreased levels of CBS and MST (p = 0.0004, 0.009) in MS serum samples, whereas serum levels of CSE were marginally increased (p = 0.06). These observations support increased CSE and lower CBS and MST expression being associated with the vascular inflammation in MS. These changes in endothelial-derived sulfide enzymes at sites of inflammation in the brain may help to explain sulfide-dependent changes in vascular dysfunction/neuroinflammation underlying MS. These findings further support the use of serum samples to assess enzymatic biomarkers derived from circulating MPs. For example, "liquid biopsy" can be an important tool for allowing early diagnosis of MS, prior to the advanced progression of neurodegeneration associated with this disease.