Sex-Specific Dysconnective Brain Injuries and Neuropsychiatric Conditions such as Autism Spectrum Disorder Caused by Group B Streptococcus-Induced Chorioamnionitis.

Global health efforts have increased against infectious diseases, but issues persist with pathogens like Group B Streptococcus (GBS). Preclinical studies have elaborated on the mechanistic process of GBS-induced chorioamnionitis and its impact on the fetal programming of chronic neuropsychiatric diseases. GBS inoculation in rodents demonstrated the following: (i) silent and self-limited placental infection, similar to human chorioamnionitis; (ii) placental expression of chemokines attracting polymorphonuclear (PMN) cells; (iii) in vitro cytokine production; (iv) PMN infiltration in the placenta (histologic hallmark of human chorioamnionitis), linked to neurobehavioral impairments like cerebral palsy and autism spectrum disorders (ASD); (v) upregulation of interleukin-1ß (IL-1ß) in the placenta and fetal blood, associated with higher ASD risk in humans; (vi) sex-specific effects, with higher IL-1ß release and PMN recruitment in male placenta; (vii) male offspring exhibiting ASD-like traits, while female offspring displayed attention deficit and hyperactivity disorder (ADHD)-like traits; (viii) IL-1 and/or NF-kB blockade alleviate placental and fetal inflammation, as well as subsequent neurobehavioral impairments. These findings offer potential therapeutic avenues, including sex-adapted anti-inflammatory treatment (e.g., blocking IL-1; repurposing of FDA-approved IL-1 receptor antagonist (IL-1Ra) treatment). Blocking the IL-1 pathway offers therapeutic potential to alleviate chorioamnionitis-related disabilities, presenting an opportunity for a human phase II RCT that uses IL-1 blockade added to the classic antibiotic treatment of chorioamnionitis.

Influence of androgens on the innate immune system.

BACKGROUND: Sexual dimorphism is observed in the occurrence, course, and severity of human disease. The difference in immune response between males and females can in part be attributed to sexual genotype. However, immunological differences can also be explained by endocrine-immune interactions. Specifically, androgens possess the ability of directly modulating the development and function of immune cells. Although androgens generally contribute to immunosuppressive effects, this is not necessarily always the case. AIM: The aim of the review is to uncover the role of androgens in shaping the innate immune response. MATERIAL & METHODS: Authors included papers in this review which discussed the impact of androgens on specific innate immune cells. RESULTS: Androgens modulate the innate immune response through various mechanisms. However, there is conflicting evidence in the literature regarding the interplay betwen androgens and the innate immune system. DISCUSSION: Conflicting evidence presented in this review could in part be explained by the limitations present in interpreting results. CONCLUSION: This review is of great importance for our understanding of occurence and mechanism of human inflammatory disease.

Protective Effects of Interleukin-1 Blockade on Group B Streptococcus-Induced Chorioamnionitis and Subsequent Neurobehavioral Impairments of the Offspring.

Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. Placental infection due to GBS is a major risk factor for fetal organ injuries, preterm birth, perinatal morbidity and mortality, and life-long multiorgan morbidities. Preclinical and clinical studies have shown that GBS-induced infection drives polymorphonuclear (PMN) cell infiltration within the placenta, the hallmark of human chorioamnionitis. In preclinical and clinical studies, the upregulation of interleukin(IL)-1ß in the placenta and maternal/fetal blood was associated with a high risk of neurodevelopmental impairments in the progeny. We hypothesized that targeted IL-1 blockade administered to the dam alleviates GBS-induced chorioamnionitis and the downstream fetal inflammatory response syndrome (FIRS). IL-1 receptor antagonist (IL-1Ra) improved the gestational weight gain of GBS-infected dams and did not worsen the infectious manifestations. IL-1Ra reduced the IL-1ß titer in the maternal sera of GBS-infected dams. IL-1Ra decreased the levels of IL-1ß, IL-6, chemokine (C-X-C motif) ligand 1 (CXCL1), and polymorphonuclear (PMN) infiltration in GBS-infected placenta. IL-1Ra treatment reduced the IL-1ß titer in the fetal sera of GBS-exposed fetuses. IL-1 blockade also alleviated GBS-induced FIRS and subsequent neurobehavioral impairments of the offspring without worsening the outcome of GBS infection. Altogether, these results showed that IL-1 plays a key role in the physiopathology of live GBS-induced chorioamnionitis and consequent neurobehavioral impairments.

Androgens Upregulate Pathogen-Induced Placental Innate Immune Response.

Group B Streptococcus (GBS) is a leading cause of placental infection, termed chorioamnionitis. Chorioamnionitis is associated with an increased risk of neurobehavioral impairments, such as autism spectrum disorders, which are more prominent in males than in female offspring. In a pre-clinical model of chorioamnionitis, a greater inflammatory response was observed in placenta associated with male rather than female fetuses, correlating with the severity of subsequent neurobehavioral impairments. The reason for this sex difference is not understood. Our hypothesis is that androgens upregulate the placental innate immune response in male fetuses. Lewis dams were injected daily from gestational day (G) 18 to 21 with corn oil (vehicle) or an androgen receptor antagonist (flutamide). On G 19, dams were injected with saline (control) or GBS. Maternal, fetal sera and placentas were collected for protein assays and in situ analyses. Our results showed that while flutamide alone had no effect, a decrease in placental concentration of pro-inflammatory cytokines and infiltration of polymorphonuclear cells was observed in flutamide/infected compared to vehicle/infected groups. These results show that androgens upregulate the placental innate immune response and thus may contribute to the skewed sex ratio towards males observed in several developmental impairments resulting from perinatal infection/inflammation.

Animal Models of Chorioamnionitis: Considerations for Translational Medicine.

Preterm birth is defined as any birth occurring before 37 completed weeks of gestation by the World Health Organization. Preterm birth is responsible for perinatal mortality and long-term neurological morbidity. Acute chorioamnionitis is observed in 70% of premature labor and is associated with a heavy burden of multiorgan morbidities in the offspring. Unfortunately, chorioamnionitis is still missing effective biomarkers and early placento- as well as feto-protective and curative treatments. This review summarizes recent advances in the understanding of the underlying mechanisms of chorioamnionitis and subsequent impacts on the pregnancy outcome, both during and beyond gestation. This review also describes relevant and current animal models of chorioamnionitis used to decipher associated mechanisms and develop much needed therapies. Improved knowledge of the pathophysiological mechanisms underpinning chorioamnionitis based on preclinical models is a mandatory step to identify early in utero diagnostic biomarkers and design novel anti-inflammatory interventions to improve both maternal and fetal outcomes.

C-section of Preclinical Animal Model of Chorioamnionitis Triggered by Group B Streptococcus (GBS).

Group B Streptococcus (GBS) is one of the most common bacteria isolated during human pregnancy. It is a leading cause of placental infection/inflammation, termed chorioamnionitis. Chorioamnionitis exposes the developing fetus to a high risk of organ injuries, perinatal morbidity, and mortality, as well as life-long neurobehavioral impairments and other non-neurological developmental issues. The two most frequent subtypes of GBS isolates from maternal and fetal tissues are serotypes Ia (13%-23%) and III (25%-53%). Our lab has developed and characterized a rat model of GBS-induced chorioamnionitis to study subsequent impacts on the central nervous system of the developing fetus and to understand underlying mechanistic aspects. This article presents the design as well as uses of the preclinical rat model, which closely reproduces the hallmark of GBS-induced chorioamnionitis in humans. This article aims to help scientists reproduce the experimental design as well as to provide support through examples of troubleshooting. The present model may also contribute to potential discoveries through uncovering causes, mechanisms, and novel therapeutic avenues, which remain unsettled in many developmental impairments arising from chorioamnionitis. Furthermore, the use of this model may be extended to the studies of perinatal non-neurological common and severe morbidities affecting, for instance, the retina, bowel, lung, and kidney. The main interest of this research is in the field of GBS-induced fetal neurodevelopmental impairments such as cerebral palsy (CP), attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). The rationale supporting this model is presented in this article, followed by procedures and results.

Management of Failed SLAP Repair: A Systematic Review.

BACKGROUND: Superior labrum anterior to posterior (SLAP) tears are a very common shoulder injury. The success rate of SLAP repair, particularly in the throwing athlete, has been variable in the literature. QUESTIONS/PURPOSES: The purpose of this systematic review was to evaluate the reported post-operative outcomes of management techniques for failed SLAP repair. METHODS: The electronic databases MEDLINE, Embase, and PubMed were searched for relevant studies, and pertinent data was abstracted. Only studies reporting outcomes of management techniques for failed SLAP repairs were included. RESULTS: A total of 10 studies (levels III to IV) evaluating 176 patients were included in this systematic review. Most subjects were male (86.6%), with a mean age at surgery of 36.3 years (range, 17 to 67 years). The most commonly reported reason for failed SLAP repair was persistent post-operative mechanical symptoms after index SLAP repair. Common techniques used in the management of failed SLAP repair include biceps tenodesis and revision SLAP repair. Return to activity was significantly higher after biceps tenodesis than after arthroscopic revision SLAP repair. However, compared to primary SLAP repair, biceps tenodesis demonstrated no statistically significant differences in return to work rates. Complications reported in one case were resolved post-operatively, and there was no reported revision failure or reoperation after revision surgery. CONCLUSION: The most common reason for failed SLAP repair is persistent post-operative mechanical symptoms. Revision surgery for failed SLAP repair has a high success rate. The rate of return to activity after biceps tenodesis was significantly higher than the rate after revision SLAP repair. Large high-quality randomized trials are required to provide definitive evidence to support the optimal treatment for failed SLAP repair.

Return to Sport After Coracoid Bone Block Transfer for Shoulder Instability: A Systematic Review.

BACKGROUND: Shoulder dislocations can be devastating for an athlete. Coracoid bone block transfer is often used for the treatment of recurrent shoulder instability. QUESTIONS/PURPOSES: The primary purpose of this study was to determine the rate and mean time of return to sport in athletes after a coracoid bone block transfer at the pre-operative level of competition, a lower level, or a different level. We also sought to determine how return to sport rates after a coracoid bone block procedure compared with rates after several comparator interventions. Finally, we looked to determine the post-operative clinical outcomes and complications reported after a coracoid bone block procedure. METHODS: We systematically searched three databases (PubMed, Embase, and MEDLINE) for studies reporting return to sport after a coracoid bone block procedure. RESULTS: A total of 52 studies (with levels of evidence ranging from II to IV) evaluating 2953 shoulders in 2888 patients were included in this systematic review. The mean rate of return to sport at any level was 88.4% (2291 of 2592 patients). However, the rate of return to the pre-operative level was 70.3% (1387 of 1974 patients). The mean time to return to sport was 5.38 months (range 21 days to 36 months). The rate of return to sport was higher after the Latarjet procedure, as compared with Bankart repair (87.0% and 75.8%, respectively). All studies showed improvements in clinical outcome measures after coracoid bone block intervention. The cumulative complication rate was found to be 6.46% (158 of 2446 patients). CONCLUSION: Coracoid bone block transfer allows for a high rate of return to sport, although the rate of return to sport at athletes' pre-operative level is lower. The rate of return to sport after Latarjet procedure is higher in comparison with Bankart repair. Additionally, coracoid bone block transfer is associated with improvements in a number of clinical outcome measures. Common post-operative complications include non-union between bone block and glenoid, hematoma, and infection.

Surgical treatment of trapezius palsy: A systematic review.

BACKGROUND: Trapezius palsy results from injury to the spinal accessory nerve. The condition presents with loss of shoulder abduction, pain, and winging of the scapula. Surgical treatment may improve functional outcomes and quality of life. PURPOSE: The purpose of this study was to report and evaluate the clinical outcomes following surgical management of trapezius palsy. STUDY DESIGN: Systematic review. METHODS: The electronic databases EMBASE, MEDLINE, and PubMed were searched for studies and relevant data were abstracted. Only studies reporting on outcomes after the surgical treatments of trapezius palsy were included. RESULTS: A total of 10 studies including 192 patients were included in this review. All surgical interventions resulted in improved function and pain reduction. Patients reported high satisfaction (90-92%) following nerve reconstruction or the Eden-Lange procedure, in comparison to neurolysis. The most common procedure reported was the Eden-Lange muscle transfer (32% reported cases) demonstrating the highest patient satisfaction rates with low complication rate of 7.7%. CONCLUSION: Patients failing conservative treatment report good outcomes following surgical treatment of trapezius palsy. All reported surgical procedures demonstrate reduction in pain the best results from the Eden-Lange muscle transfer. Further high-quality comparative studies are required to make definitive conclusions regarding the comparative efficacy of each surgical procedure.

Reverse total shoulder arthroplasty in the younger patient (≤65 years): a systematic review.

The purpose of this study was to evaluate outcomes of reverse total shoulder arthroplasty (RTSA) in patients aged ≤65 years. MEDLINE, Embase, and PubMed were searched for relevant studies from database inception to September 18, 2018. All studies that evaluated RTSA in patients aged ≤65 years were included. Two independent reviewers screened all studies and performed a quality assessment. In the total of 6 studies reviewed, 245 participants underwent RTSA, with the most common indications being failed rotator cuff repair and rotator cuff tear arthropathy. Postoperative functional outcomes indicated a significant level of improvement across all reported outcomes at a mean follow-up of 49 months (range, 19-140 months) (P < .05). The pooled mean complication rate was 18% (n = 44/245), and this higher rate may be due to 36% of patients undergoing an RTSA for a failed arthroplasty procedure and the inclusion of older studies that lacked modern implants and techniques. Although there is a significant improvement in functional outcomes at midterm follow-up for RTSA in the patients aged ≤65 years, the pooled complication rates are high. However, the results of this systematic review are limited because of the heterogenous patient population undergoing surgery for various indications, including revision arthroplasty. Long-term studies and registry data are required using current modern techniques and implants to provide an accurate assessment of outcomes following RTSA in a young patient population.

Return to Sport After Ankle Syndesmotic Injury: A Systematic Review.

CONTEXT:: Ankle syndesmotic injuries present a significant challenge for athletes due to prolonged disability and recovery periods. The optimal management of these injuries and rates of return to sport in athletes remains unclear. OBJECTIVE:: The purpose of this study was to evaluate return to sport for athletes after ankle syndesmotic injuries. DATA SOURCE:: The electronic databases MEDLINE, EMBASE, and PubMed were searched for relevant studies from database inception to January 15, 2017, and pertinent data were abstracted. STUDY SELECTION:: Only studies reporting return-to-sport rates after ankle syndesmotic injuries were included. STUDY DESIGN:: Systematic review. LEVEL OF EVIDENCE:: Level 4. DATA EXTRACTION:: Two reviewers extracted data from the included studies, which were stored in a standardized collection form (Microsoft Excel). Recorded data included demographics (eg, author, year of publication, study design), descriptive statistics (eg, patient age, percentage male, number of athletes, sample size), and outcomes (eg, time to return to sport, proportion of those who returned to sport, the self-reported questionnaire the Olerud-Molander Ankle Score). RESULTS:: A total of 10 studies and 312 patients with ankle syndesmotic injuries were included in this systematic review. The rate of return to preinjury or any injury level of sport after ankle syndesmotic injuries was 93.8% ± 1.2% and 97.6% ± 1.5%, respectively, for the corresponding 7 and 3 studies that reported this characteristic. The mean time to return to sport was 46.4 days (range, 15.4-70 days), with 55.2 ± 15.8 and 41.7 ± 9.8 days for operative and nonoperative management, respectively. CONCLUSION:: This systematic review found a high rate of return to any as well as preinjury level of sport after ankle syndesmotic injury in both operative and nonoperative treatment groups. However, further high-level studies are required to compare operative and nonoperative treatment groups associated with return to sport after ankle syndesmotic injury.