Targeting foamy macrophages by manipulating ABCA1 expression to facilitate lesion healing in the injured spinal cord.

Spinal cord injury (SCI) triggers a complex cascade of events, including myelin loss, neuronal damage, neuroinflammation, and the accumulation of damaged cells and debris at the injury site. Infiltrating bone marrow derived macrophages (BMDMϕ) migrate to the epicenter of the SCI lesion, where they engulf cell debris including abundant myelin debris to become pro-inflammatory foamy macrophages (foamy Mϕ), participate neuroinflammation, and facilitate the progression of SCI. This study aimed to elucidate the cellular and molecular mechanisms underlying the functional changes in foamy Mϕ and their potential implications for SCI. Contusion at T10 level of the spinal cord was induced using a New York University (NYU) impactor (5 g rod from a height of 6.25 mm) in male mice. ABCA1, an ATP-binding cassette transporter expressed by Mϕ, plays a crucial role in lipid efflux from foamy cells. We observed that foamy Mϕ lacking ABCA1 exhibited increased lipid accumulation and a higher presence of lipid-accumulated foamy Mϕ as well as elevated pro-inflammatory response in vitro and in injured spinal cord. We also found that both genetic and pharmacological enhancement of ABCA1 expression accelerated lipid efflux from foamy Mϕ, reduced lipid accumulation and inhibited the pro-inflammatory response of foamy Mϕ, and accelerated clearance of cell debris and necrotic cells, which resulted in functional recovery. Our study highlights the importance of understanding the pathologic role of foamy Mϕ in SCI progression and the potential of ABCA1 as a therapeutic target for modulating the inflammatory response, promoting lipid metabolism, and facilitating functional recovery in SCI.

Consequences and mechanisms of myelin debris uptake and processing by cells in the central nervous system.

Central nervous system (CNS) disorders and trauma involving changes to the neuronal myelin sheath have long been a topic of great interest. One common pathological change in these diseases is the generation of myelin debris resulting from the breakdown of the myelin sheath. Myelin debris contains many inflammatory and neurotoxic factors that inhibit remyelination and make its clearance a prerequisite for healing in CNS disorders. Many professional and semiprofessional phagocytes participate in the clearance of myelin debris in the CNS. These cells use various mechanisms for the uptake of myelin debris, and each cell type produces its own unique set of pathologic consequences resulting from the debris uptake. Examining these cells' phagocytosis of myelin debris will contribute to a more complete understanding of CNS disease pathogenesis and help us conceptualize how the necessary clearance of myelin debris must be balanced with the detrimental consequences brought about by its clearance.

Fibrotic Scar in CNS Injuries: From the Cellular Origins of Fibroblasts to the Molecular Processes of Fibrotic Scar Formation.

Central nervous system (CNS) trauma activates a persistent repair response that leads to fibrotic scar formation within the lesion. This scarring is similar to other organ fibrosis in many ways; however, the unique features of the CNS differentiate it from other organs. In this review, we discuss fibrotic scar formation in CNS trauma, including the cellular origins of fibroblasts, the mechanism of fibrotic scar formation following an injury, as well as the implication of the fibrotic scar in CNS tissue remodeling and regeneration. While discussing the shared features of CNS fibrotic scar and fibrosis outside the CNS, we highlight their differences and discuss therapeutic targets that may enhance regeneration in the CNS.

Genetic Study of Hereditary Angioedema Type I and Type II (First Report from Iranian Patients: Describing Three New Mutations).

BACKGROUND: Hereditary Angioedema (HAE) is a rare autosomal dominant immunodeficiency disease with mutation in C1 inhibitor gene (SERPING1) which deficient and dysfunction of C1-INH protein result in HAE type I or type II, respectively. The present study aimed to define the genetic spectrum of HAE type I and type II among Iranian patients. METHODS: Thirty-four patients with clinical phenotype of recurrent edematous attacks in face, upper and lower limbs, hands, and upper airway entered the study. Mutations in SERPING1 were analyzed using PCR and Sanger Sequencing. In addition, Multiplex Ligation-dependent Probe Amplification (MLPA) was performed to discover large deletions or duplications in negative screening samples by Sanger. RESULTS: Twenty-three patients were diagnosed with HAE type I and 11 with HAE type II. Fourteen distinctive pathogenic variations including five frameshift (p.G217Vfs*, p.V454Gfs*18, p.S422Lfs*9, p.S36Ffs*21, p.L243Cfs*9), seven missense (p.A2V, p.G493R, p.V147E, p.G143R, p.L481P, p.P399H, p.R466C), one nonsense (p.R494*), and one splicing defect (C.51 + 2 T˃C), which three of these mutations were identified novel. However, no mutation was found in seven patients by Sanger sequencing and MLPA. CONCLUSION: Final diagnosis with mutation analysis of HAE after clinical evaluation and assessment of C1INH level and function can prevent potential risks and life-threatening manifestations of the disorder. In addition, genetic diagnosis can play a significant role in facilitating early diagnosis, pre-symptomatic diagnosis, early diagnosis of children, asymptomatic cases, and those patients who have the borderline biochemical results of C1-INH deficiency and/or C4.

For Better or for Worse: A Look Into Neutrophils in Traumatic Spinal Cord Injury.

Neutrophils are short-lived cells of the innate immune system and the first line of defense at the site of an infection and tissue injury. Pattern recognition receptors on neutrophils recognize pathogen-associated molecular patterns or danger-associated molecular patterns, which recruit them to the destined site. Neutrophils are professional phagocytes with efficient granular constituents that aid in the neutralization of pathogens. In addition to phagocytosis and degranulation, neutrophils are proficient in creating neutrophil extracellular traps (NETs) that immobilize pathogens to prevent their spread. Because of the cytotoxicity of the associated granular proteins within NETs, the microbes can be directly killed once immobilized by the NETs. The role of neutrophils in infection is well studied; however, there is less emphasis placed on the role of neutrophils in tissue injury, such as traumatic spinal cord injury. Upon the initial mechanical injury, the innate immune system is activated in response to the molecules produced by the resident cells of the injured spinal cord initiating the inflammatory cascade. This review provides an overview of the essential role of neutrophils and explores the contribution of neutrophils to the pathologic changes in the injured spinal cord.

Fresh frozen plasma for on-demand hereditary angioedema treatment in South Africa and Iran.

BACKGROUND: International guideline-recommended on-demand treatments for hereditary angioedema (HAE) include: C1-esterase inhibitor (plasma-derived or recombinant), or bradykinin-receptor antagonists. In most low- and middle-income countries (LMIC) these products are not registered or are unaffordable. Solvent-detergent, fresh or freeze-dried plasma therapy is thus the only available on-demand treatment in these settings; but published data on efficacy and safety are limited. This study evaluated the efficacy and safety of on-demand plasma treatment of acute HAE in two LMICs. METHODS: A retrospective folder or patient registry review of acute swelling episodes necessitating emergency room attendance amongst known HAE patients was conducted at treatment centers in South Africa and Iran. Data collected included the site of angioedema, timing and amount of fresh frozen plasma (FFP) administered, time-to-resolution, hospital length of stay and adverse events. RESULTS: There were 176 acute swelling episodes amongst 43 HAE patients; 98 were treated with FFP. The face, upper airway, and abdomen were involved in 15.3% (15/98), 53.1% (52/98) and 29.6% (29/98) of episodes treated with FFP respectively. Median (interquartile range ([IQR]) of FFP administered was 400 (280-560) mLs. In all episodes except two, FFP led to resolution, with median (IQR) hours to resolution 4 (2-12). Five transfusion reactions occurred, with one case of anaphylaxis and no deaths; giving an adverse reaction rate of 5%. Differences between South Africa and Iran included: (1) proportion of HAE type II(2) median (IQR) hours to FFP administration and hospitalization, (3) number of intubations after FFP infusion. Healthcare cost for FFP treatment was USD369- 791 in South Africa and USD275-550 in Iran, largely influenced by hospital length of stay. CONCLUSIONS: Plasma (fresh-frozen) remains the only available effective on-demand treatment for acute HAE in many countries. FFP is effective and safe, but time-to-resolution is slower and adverse events are more frequent than published data on targeted therapies. Overall healthcare cost of FFP approaches that of targeted therapies - now available through global access programs - when hospitalization is prolonged.

The potential anti-inflammatory role of adiponectin in food allergy: a case-control study on children.

We aimed to assess the possible relationship between food allergy and two key adipokines - leptin and adiponectin - in children with food allergy. A total of forty patients with definite diagnosis of food allergy according to clinical history and specific IgE (sIgE) for food allergens (group I) were enrolled in this pilot study. The control group (group II) included thirty children with no evidence of allergic symptoms. Serum levels of leptin and adiponectin were measured by ELISA. Meanwhile, sIgE was measured for the eight most common food allergens by the immunoblot method in all participants. The median ages in groups I and II were 18·5 and 23·5 months, respectively. The respective Caesarean section rate was 64·9 and 16·7 % in groups I and II (P<0·001). Serum levels of adiponectin were significantly higher in the patient group compared with controls (24·11 (sd 12·14) v. 10·67 (sd 12·23) µg/ml, P<0·001), whereas no statistically meaningful difference was detected in serum leptin concentrations (P=0·92). There was a significant inverse relationship between age and adiponectin levels in group I (P=0·002, r -0·479) and group II (P=0·04, r -0·365), and it was more significant in group I. The most common allergens in the patient group were wheat (52·5 %), hazelnut (52·5 %), cow's milk (50 %) and egg white (30 %). The results of this study suggest an essential link between adiponectin and food allergy that is probably unlikely to be affected by obesity as a confounding factor.

Examination of the Effects of Auditory and Textual Stimuli on Response Accuracy and Latency during a Math Task and Tangram Puzzle.

Although Skinner (1957) provided a behavioral account of verbal thinking, additional research is needed to evaluate stimuli that may influence covert verbal behavior that occurs between the onset of a verbal stimulus and the emission of a response during an episode of verbal thinking. The present investigation examined the effects of auditory distractors and/or textual stimuli during arithmetic problems and tangram puzzles on the participants' response latency and accuracy. In addition, we measured and categorized occurrences of vocal verbal behavior during the response interval. In Experiments 1 and 2, the experimenter played auditory distractors during a proportion of arithmetic problems. In Experiment 2, the experimenter also presented a textual stimulus of the arithmetic problem. In Experiment 3, the experimenter played auditory distractors during a proportion of tangram puzzles. Results showed that auditory distractors led to longer response latencies and reduced accuracy in Experiment 1. The addition of the textual stimulus during trials in Experiment 2 improved accuracy and reduced differences in response latency when the auditory distractors were and were not present during the response interval. The auditory distractors during tangram puzzles in Experiment 3 produced no differential effects on accuracy or latency to respond.

Type I and Type II Hereditary Angioedema: Clinical and Laboratory Findings in Iranian Patients.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by C1-INH (C1 esterase inhibitor), low serum levels (type I), dysfunction (type II) or normal serum levels and function (type III), which lead to subcutaneous and submucosal edema attacks. The aim of this study was to investigate the demographic, clinical and laboratory findings of Iranian patients with HAE. METHODS: The patients with a history or symptoms of angioedema who were referred to Immunology, Asthma and Allergy Research Institute (IAARI) between Jan 2006 and Jan 2014, were assessed based on a specific questionnaire and laboratory evaluation. The patients with a definite diagnosis of HAE type I and type II were entered into this study. RESULTS: Among 51 patients, 63.3% were diagnosed with HAE type I and 36.7% with HAE type II. Fifteen patients were under 18 years and 36 were adults. The mean age of symptoms onset and diagnosis were 12.33 ± 10.20 years and 24.48 ± 14.64 years, respectively. The mean delay of diagnosis was 11.02 ± 11.60 years. The most commonly involved locations of edema were hands, face and genitalia. Moreover, laryngeal edema was observed in 61.2% of patients, which led to death in two patients during this study. CONCLUSION: Hereditary angioedema is a life threatening disease with considerable morbidity and mortality. The outcomes of this study can be used to inform clinicians and health care providers about HAE, which can help earlier diagnosis and better management of the patients, specifically in life threatening attacks.