Microglial Cells Impact Gut Microbiota and Gut Pathology in Angiotensin II-Induced Hypertension.

RATIONALE: Increased microglial activation and neuroinflammation within autonomic brain regions have been implicated in sustained hypertension, and their inhibition by minocycline-an anti-inflammatory antibiotic-produces beneficial effects. These observations led us to propose a dysfunctional brain-gut communication hypothesis for hypertension. However, it has been difficult to reconcile whether an anti-inflammatory or antimicrobial action is the primary beneficial effect of minocycline in hypertension. Accordingly, we utilized chemically modified tetracycline-3 (CMT-3)-a derivative of tetracycline that has potent anti-inflammatory activity-to address this question. OBJECTIVE: Test the hypothesis that central administration of CMT-3 would inhibit microglial activation, attenuate neuroinflammation, alter selective gut microbial communities, protect the gut wall from developing hypertension-associated pathology, and attenuate hypertension. METHODS AND RESULTS: Rats were implanted with radiotelemetry devices for recording mean arterial pressure. Ang II (angiotensin II) was infused subcutaneously using osmotic mini-pumps to induce hypertension. Another osmotic mini-pump was surgically implanted to infuse CMT-3 intracerebroventricularly. Intracerebroventricular CMT- 3 infusion was also investigated in SHR (spontaneously hypertensive rats). Physiological, pathological, immunohistological parameters, and fecal microbiota were analyzed. Intracerebroventricular CMT-3 significantly inhibited Ang II-induced increases in number of microglia, their activation, and proinflammatory cytokines in the paraventricular nucleus of hypothalamus. Further, intracerebroventricular CMT-3 attenuated increased mean arterial pressure, normalized sympathetic activity, and left ventricular hypertrophy in Ang II rats, as well as in the SHR. Finally, CMT-3 beneficially restored certain gut microbial communities altered by Ang II and attenuated pathological alterations in gut wall. CONCLUSIONS: These observations demonstrate that inhibition of microglial activation alone was sufficient to induce significant antihypertensive effects. This was associated with unique changes in gut microbial communities and profound attenuation of gut pathology. They suggest, for the first time, a link between microglia and certain microbial communities that may have implications for treatment of hypertension.

Hypertension-Linked Pathophysiological Alterations in the Gut.

RATIONALE: Sympathetic nervous system control of inflammation plays a central role in hypertension. The gut receives significant sympathetic innervation, is densely populated with a diverse microbial ecosystem, and contains immune cells that greatly impact overall inflammatory homeostasis. Despite this uniqueness, little is known about the involvement of the gut in hypertension. OBJECTIVE: Test the hypothesis that increased sympathetic drive to the gut is associated with increased gut wall permeability, increased inflammatory status, and microbial dysbiosis and that these gut pathological changes are linked to hypertension. METHODS AND RESULTS: Gut epithelial integrity and wall pathology were examined in spontaneously hypertensive rat and chronic angiotensin II infusion rat models. The increase in blood pressure in spontaneously hypertensive rat was associated with gut pathology that included increased intestinal permeability and decreased tight junction proteins. These changes in gut pathology in hypertension were associated with alterations in microbial communities relevant in blood pressure control. We also observed enhanced gut-neuronal communication in hypertension originating from paraventricular nucleus of the hypothalamus and presenting as increased sympathetic drive to the gut. Finally, angiotensin-converting enzyme inhibition (captopril) normalized blood pressure and was associated with reversal of gut pathology. CONCLUSIONS: A dysfunctional sympathetic-gut communication is associated with gut pathology, dysbiosis, and inflammation and plays a key role in hypertension. Thus, targeting of gut microbiota by innovative probiotics, antibiotics, and fecal transplant, in combination with the current pharmacotherapy, may be a novel strategy for hypertension treatment.

Accessory plantaris muscle can result in symptomatic hardware impingement following ACL reconstruction.

Anatomic variants of lower extremity musculature, such as the gastrocnemius, popliteus, and the plantaris have been well described in the literature. The impact of these anatomical variations on clinical outcomes depends on their proximity to and effects on adjacent anatomical structures, particularly in the context of planned surgical procedures in the region. While the presence of the accessory plantaris is rare, no previous cases have described it negatively affecting surgical outcomes to our knowledge. We present a case of a 42-year-old patient who underwent an anterior cruciate ligament (ACL) reconstruction using a femoral Endobutton for graft fixation positioned just beneath an accessory plantaris, leading to impingement and persistent knee pain. This case highlights the importance of understanding anatomical variations when planning and performing surgical procedures and suggests the need for further research in this area.

Unusual case of delayed congenital diaphragmatic hernia in Loeys-Dietz syndrome: a case report.

Congenital diaphragmatic hernias rarely present after 2 months of age and are typically diagnosed in the perinatal period. Moderate to severe diaphragmatic hernias present with respiratory symptoms, while late-onset hernias have a more varied presentation, depending on the age and content of the hernia. Very rarely, such hernias are found on incidental imaging, in which surgical repair is frequently recommended. A young girl with Loeys-Dietz syndrome and prior abdominal surgeries presents with 1-year history of increasingly severe, intermittent, abdominal and left shoulder pain. Prior imaging incidentally revealed a left diaphragmatic hernia with omentum protruding into the thoracic cavity. This was managed expectantly due to her other medical and surgical issues. Serial imaging revealed that the herniated omentum was increasing in size and symptoms began to develop. An uncomplicated primary thoracoscopic repair was performed. We report the first case of a congenital diaphragmatic hernia in a patient with Loeys-Dietz syndrome.

Septic Arthritis Among Users of Injection Drugs: Clinical Course and Microbial Characteristics.

Injection drug use (IDU) is a risk factor for septic arthritis (SA) of native joints. Amid the opioid crisis, IDU rates have increased. This study assessed differences in pre-operative characteristics, microbial characteristics, and postoperative outcomes of 177 cases of SA treated operatively from 2015 to 2019 at 3 US hospitals, by self-reported IDU status. Forty cases (23%) involved patients who reported IDU. Patient characteristics, comorbidities, microbial characteristics, duration of hospital stay, discharge destination, follow-up rates, and rates of persistent/secondary infection were compared by self-reported IDU status. Compared with non-IDU-associated SA (non-IDU-SA), IDU-associated SA (IDU-SA) was associated with female sex (P=.001), younger age (P<.001), lower body mass index (P<.001), tobacco use (P<.001), and psychiatric diagnosis (P=.04) and was more likely to involve methicillin-resistant Staphylococcus aureus (P<.001). The IDU-SA was associated with discharge to a skilled nursing facility or against medical advice (P<.001) and with loss to follow-up (P=.01). The 2 groups did not differ in terms of American Society of Anesthesiologists classification, joint involved, Gram stain positivity, presence of bacteremia, peripherally inserted central catheter placement, return to hospital within 3 months, or persistent/secondary positive results on culture within 3 months. Patients with IDU-SA were younger, were more likely to be female, had lower body mass index, and had fewer medical comorbidities but were more likely to use tobacco and to have a psychiatric diagnosis compared with patients with non-IDU-SA. Methicillin-resistant S aureus was more common in the IDU-SA group, as was discharge to a skilled nursing facility or against medical advice. Patients with IDU-SA were less likely to return for follow-up than patients with non-IDU-SA. [Orthopedics. 2021;44(6):e747-e752.].

Pulmonary arterial hypertension-associated changes in gut pathology and microbiota.

Emerging evidence implicates an interplay among multiple organs such as brain, vasculature, gut and lung in the development of established pulmonary arterial hypertension (PAH). This has led us to propose that activated microglia mediated-enhanced sympathetic activation contributes to PAH pathophysiology. Since enhanced sympathetic activity is observed in human PAH and the gut is highly innervated by sympathetic nerves that regulate its physiological functions, we hypothesized that PAH would be associated with gut pathophysiology. A monocrotaline rat model of PAH was utilized to investigate the link between gut pathology and PAH. Haemodynamics, histology, immunocytochemistry and 16S RNA gene sequencing were used to assess cardiopulmonary functions, gut pathology and gut microbial communities respectively. Monocrotaline treatment caused increased right ventricular systolic pressure, haemodynamics and pathological changes associated with PAH. PAH animals also showed profound gut pathology that included increased intestinal permeability, increased muscularis layer, decreased villi length and goblet cells. These changes in gut pathology were associated with alterations in microbial communities, some unique to PAH animals. Furthermore, enhanced gut-neural communication involving the paraventricular nucleus of the hypothalamus and increased sympathetic drive were observed. In conclusion, our data show the presence of gut pathology and distinct changes in gut microbiota and increased sympathetic activity in PAH. They suggest that dysfunctional gut-brain crosstalk could be critical in PAH and considered a future therapeutic target for PAH.

Gut Pathology and Its Rescue by ACE2 (Angiotensin-Converting Enzyme 2) in Hypoxia-Induced Pulmonary Hypertension.

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH. ACE2 knockin and wild-type (WT; C57BL/6) mice were subjected to chronic hypoxia (10% FIO2) or room air for 4 weeks. Cardiopulmonary hemodynamics, histology, immunohistochemistry, and fecal 16S rRNA microbial gene analyses were evaluated. Hypoxia significantly increased right ventricular systolic pressure, sympathetic activity as well as the number and activation of microglia in the paraventricular nucleus of the hypothalamus in WT mice. This was associated with a significant increase in muscularis layer thickening and decreases in both villi length and goblet cells and altered gut microbiota. Global overexpression of ACE2 prevented changes in hypoxia-induced pulmonary and gut pathophysiology and established distinct microbial communities from WT hypoxia mice. Furthermore, WT mice subjected to fecal matter transfer from ACE2 knockin mice were resistant to hypoxia-induced PH compared with their controls receiving WT fecal matter transfer. These observations demonstrate that ACE2 ameliorates these hypoxia-induced pathologies and attenuates PH. The data implicate dysfunctional brain-gut-lung communication in PH and provide novel avenues for therapeutic interventions.

Devastating Vertebral Osteomyelitis After Epidural Steroid Injection: A Case Report.

CASE: A 62-year-old man with no comorbidities presented with back and bilateral leg pain and progressive paraplegia that developed over a 1-week period. He had received 2 lumbar epidural steroid injections (LESIs) for lumbar stenosis 39 and 25 days before presentation. Workup revealed osteomyelitis of L4 and L5 with epidural abscesses. He ultimately underwent all-posterior L4 and L5 corpectomy with reconstruction and L1-pelvis arthrodesis, followed by 8 weeks of intravenous antibiotics. His weakness improved, but neurological deficits persisted. CONCLUSIONS: This case illustrates a catastrophic complication after LESI, resulting in permanent neurological injury in a patient with no apparent risk factors.

Opioid-related compartment syndrome and associated morbidity.

INTRODUCTION: Opioid-related compartment syndrome (ORCS) is an understudied complication related to opioid overdose. We hypothesized that ORCS would be associated with worse clinical outcomes, including higher amputation rates, need for multiple surgical procedures, and rhabdomyolysis on admission, compared with nonopioid-related compartment syndrome (NORCS). METHODS: We used Current Procedural Terminology codes for fasciotomy as a proxy marker for cases of compartment syndrome treated at 1 health system from January 1, 2016, to December 21, 2018. We excluded patients younger than 18 years, those treated for exertional compartment syndrome, and those who underwent elective fasciotomies. Seventy-four patients met our inclusion criteria. Data reviewed included patient characteristics, cause of compartment syndrome, time until evaluation for compartment syndrome, peak creatinine kinase levels, number of surgical procedures required, duration of hospital stay, and postoperative inpatient morbidity and death. Patients were categorized as having ORCS (n = 8) or NORCS (n = 66). Alpha = .05. RESULTS: All cases of ORCS occurred in men. Opioid use was the third most common cause of compartment syndrome. Two patients underwent amputation, both in the ORCS group (p <  0.01). The median number of debridements was significantly higher for the ORCS group (median, 4; interquartile range [IQR]: 3-6) than for the NORCS group (median, 3; IQR 2-4) (p =  0.03). Duration of hospital stay was longer for the ORCS group (median, 27 days; IQR 16-38) compared with the NORCS group (median, 9 days; IQR: 5-13) (p <  0.001). Mean (± standard deviation) peak creatinine kinase level was significantly higher in the ORCS group (224,000 ± 225,052 U/L) compared with the NORCS group (7550 ± 32,500) (p <  0.001). The proportion of patients who underwent hemodialysis was higher in the ORCS group (88%) than in the NORCS group (35%) (p <  0.001). All ORCS patients presented >8 h after immobilization in a dependent position. CONCLUSION: Patients in the ORCS group had delayed presentations and significantly more morbidity compared with patients in the NORCS group.

Sustained Captopril-Induced Reduction in Blood Pressure Is Associated With Alterations in Gut-Brain Axis in the Spontaneously Hypertensive Rat.

Background We have demonstrated that the antihypertensive effect of the angiotensin-converting enzyme inhibitor, captopril ( CAP ), is associated with beneficial effects on gut pathology. Coupled with the evidence that CAP exerts prolonged reduction in blood pressure ( BP ) after discontinuation of treatment, we investigate whether persistent beneficial actions of CAP are linked to alterations of gut microbiota and improvement of hypertension-induced gut pathology. Methods and Results Spontaneously hypertensive rats ( SHR ) and Wistar Kyoto rats were treated with CAP (250 mg/kg/day) for 4 weeks followed by withdrawal for 16 weeks. Gut microbiota, gut pathology, BP, and brain neuronal activity were assessed. CAP resulted in a ≈60 mm Hg decrease in systolic BP after 3 weeks of treatment in SHR , and the decrease remained significant at least 5 weeks after CAP withdrawal. In contrast, CAP caused modest decrease in systolic BP in Wistar Kyoto. 16S rRNA gene-sequencing-based gut microbial analyses in SHR showed sustained alteration of gut microbiota and increase in Allobaculum after CAP withdrawal. Phylogenetic investigation of communities by reconstruction of unobserved states analysis revealed significant increase in bacterial sporulation upon CAP treatment in SHR . These were associated with persistent improvement in gut pathology and permeability. Furthermore, manganese-enhanced magnetic resonance imaging showed significantly decreased neuronal activity in the posterior pituitary of SHR 4 weeks after withdrawal. Conclusions Decreased BP , altered gut microbiota, improved gut pathology and permeability, and dampened posterior pituitary neuronal activity were maintained after CAP withdrawal in the SHR . They suggest that CAP influences the brain-gut axis to maintain the sustained antihypertensive effect of CAP after withdrawal.