Angiotensin receptor blocker-neprilysin inhibitor for heart failure with reduced ejection fraction.

Heart failure with reduced ejection fraction (HFrEF) is a clinical syndrome characterized by volume overload, impaired exercise capacity, and recurrent hospital admissions. A major contributor to the pathophysiology and clinical presentation of heart failure is the activation of the renin-angiotensin-aldosterone system (RAAS). Normally, RAAS is responsible for the homeostatic regulation of blood pressure, extracellular fluid volume, and serum sodium concentration. In HFrEF, RAAS gets chronically activated in response to decreased cardiac output, further aggravating the congestion and cardiotoxic effects. Hence, inhibition of RAAS is a major approach in the pharmacologic treatment of those patients. The most recently introduced RAAS antagonizing medication class is angiotensin receptor blocker/ neprilysin inhibitor (ARNI). In this paper, we discuss ARNIs' superiority over traditional RAAS antagonizing agents in reducing heart failure hospitalization and mortality. We also tease out the evidence that shows ARNIs' renoprotective functions in heart failure patients including those with chronic or end stage kidney disease. We also discuss the evidence showing the added benefit resulting from combining ARNIs with a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. Moreover, how ARNIs decrease the risk of arrhythmias and reverse cardiac remodeling, ultimately lowering the risk of cardiovascular death, is also discussed. We then present the positive outcome of ARNIs' use in patients with diabetes mellitus and those recovering from acute decompensated heart failure. ARNIs' side effects are also appreciated and discussed. Taken together, the provided insight and critical appraisal of the evidence justifies and supports the implementation of ARNIs in the guidelines for the treatment of HFrEF.

Assessment of early macular microangiopathy in subjects with prediabetes using optical coherence tomography angiography and fundus photography.

AIMS: Early detection of retinal microangiopathy in patients with prediabetes may reduce diabetic retinopathy complications. The aim of this study was to assess early macular vascular changes in prediabetics before development of over diabetes using OCTA and fundus photography. METHODS: In this cross-sectional study, 66 prediabetic individuals and 66 normal controls underwent clinical, laboratory, and fundus photography evaluation followed by OCTA macular imaging to examine for the foveal avascular zone, and area of capillary non-perfusion, thickness, disorganization of vessels, and vessel density perfusion percentage of superficial capillary plexus and deep capillary plexus. RESULTS: Retinal microangiopathy was detected in 36.4% of prediabetics by OCTA and only in 10.6% by fundus photography. None of clinical or laboratory parameters had significant association with DR. Area of capillary non-perfusion and disorganization of SCP were detected in 53.8% and 56.8%, respectively, in prediabetics. VDP of SCP and DCP of whole image, parafoveal, and perifoveal areas was significantly lower in prediabetes group compared to normal control. VDP of DCP of perifoveal area (ß coefficient: - 0.10, OR: 0.91, 95% CI: 0.86-0.96, P < 0.001) and disorganization of DCP (ß coefficient: 1.93, OR: 6.89, 95% CI: 2.5-18.8, P < 0.001) were significant predictors of DR in prediabetics. There was no difference in FAZ in prediabetics with and without retinopathy. CONCLUSIONS: OCTA could detect early retinal vascular changes during the prediabetic state before developing diabetes. VDP was significantly reduced in prediabetic patients. Furthermore, VDP of DCP of perifoveal area and disorganization of DCP were the most important predictors of retinopathy in prediabetic patients.

Concomitant spontaneous spinal and posterior fossa subdural hematoma in an 11-year-old child with aplastic anemia: a case report and review of literature.

PURPOSE: The current article describes an 11-year-old male who has aplastic anemia with an extremely rare condition, that is, concomitant posterior fossa SDH and spinal SDH. METHODS: This is a case report and review of literature. CASE PRESENTATION: This case presents an 11-year-old male known to have aplastic anemia complained of neck and back pain, headache, and persistent vomiting for 3 days. He had no history of head or spine trauma at all. His parents are relatives "positive consanguinity," and his sister suffers from aplastic anemia. Clinical examination revealed severe pallor at the time of presentation, with no neurologic or locomotor deficit and positive Kernig's sign. CONCLUSION: Patients with aplastic anemia or any bleeding disorder conditions should be investigated thoroughly if symptoms denoted a CNS pathology. Concomitant cranial and spinal SDH rarely occurs, and more studies are advocated to be structured to investigate the specific pathophysiology and etiologies of this condition.

The risk of micro and macrovascular disease in Egyptian patients with diabetes and peripheral arterial disease.

Aim: The aim of this study was to assess the prevalence of micro- and macrovascular disease in Egyptian patients with diabetes mellitus (DM) and peripheral arterial disease (PAD). Methods: The study included 161 Egyptian patients with DM and PAD (91.3% had type 2 DM and 67.1% were females). Mean diabetes duration was 14.2 ± 5.2 years. Full history, clinical and fundus examination as well as laboratory investigations were done. PAD was diagnosed through assessment of ankle/brachial index (ABI) by Doppler ultrasonography. Results: ABI was <0.9 in 33.5% and >1.3 in 66.5% of patients. A significant positive correlation was found between abnormal ABI and diabetes duration, ischemic heart disease (IHD), diabetic retinopathy and neuropathy, foot ulcers, elevated blood pressure (BP), creatinine, urine albumin/creatinine ratio (ACR) and triglycerides and a significant negative correlation with HDL. Multivariate regression analysis revealed that the independent predictors for PAD in patients with ABI< 0.9 were neuropathy, creatinine, triglyceride, LDL, urine ACR and low HDL, and in patients with ABI >1.3 were IHD, neuropathy, elevated diastolic BP and triglyceride. Conclusion: The risk of micro- and macrovascular disease is high in Egyptian patients with diabetes and PAD. Early diagnosis and good control of risk factors could reduce PAD progression.

ARTERIAL WALL STIFFNESS AND THE RISK OF ATHEROSCLEROSIS IN EGYPTIAN PATIENTS WITH OVERT AND SUBCLINICAL HYPOTHYROIDISM.

Objective: Hypothyroidism is associated with an increased risk of atherosclerosis. Pulse wave velocity (PWV) is an index of arterial wall stiffness widely used for noninvasive assessment of early atherosclerosis. We assessed PWV in Egyptian patients with hypothyroidism. Methods: The study included 100 Egyptian females aged 18 to 55 years. They were classified into three groups: group I, 40 women with overt hypothyroidism; group II, 40 women with subclinical hypothyroidism; and group III, 20 euthyroid women as a control group. The three groups were age matched. Doppler ultrasonography was used to calculate the heart-femoral PWV. Results: PWV was significantly higher in women with overt and subclinical hypothyroidism as compared with the control group (9.55 ± 1.81 m/s and 9.30 ± 1.28 m/s, respectively vs. 7.82 ± 2.14 m/s; P<.001 and <.01, respectively). There was a positive correlation between thyroid-stimulating hormone (TSH) and PWV in women with overt hypothyroidism and in those with subclinical hypothyroidism (P<.05 for both). Multivariate regression analysis showed that age and diastolic blood pressure were independent determinants of PWV in women with overt and subclinical hypothyroidism (P<.01 for all). TSH was also an independent determinant of PWV in both groups (P<.05 for both). Conclusion: PWV is significantly higher in Egyptian women with overt and subclinical hypothyroidism as compared with normal control subjects. This denotes early increase in arterial wall stiffness in patients with hypothyroidism, even in the subclinical phase. The positive correlation between PWV and TSH in both groups of patients suggests that the risk of atherosclerosis is proportionate to the severity of hypothyroidism. Abbreviations: ABI = ankle/brachial index; baPWV = brachial-ankle pulse wave velocity; BP = blood pressure; CIMT = carotid intima-media thickness; ECG = electrocardiogram; FT4 = free thyroxine; HDL = high-density lipoprotein; hfPWV = heart-femoral pulse wave velocity; LDL = low-density lipoprotein; PTT = pulse transit time; PWV = pulse wave velocity; SCH = subclinical hypothyroidism; TSH = thyroid-stimulating hormone.

Endothelial dysfunction and the risk of atherosclerosis in overt and subclinical hypothyroidism.

Hypothyroidism is associated with increased risk of atherosclerosis. We assessed carotid intima-media thickness (CIMT), as a marker of atherosclerosis, and endothelial function in patients with hypothyroidism. We included 70 female patients with hypothyroidism in the study, 40 patients with overt and 30 patients with subclinical hypothyroidism. Forty, age- and sex-matched, subjects with normal thyroid functions were also included as a control group. CIMT was measured using high-resolution color-coded Doppler ultrasonography. Endothelial function was assessed by measuring the percent of change in blood flow following heat-mediated vasodilation using laser Doppler flowmetry. CIMT was significantly higher in patients with overt and subclinical hypothyroidism as compared with the control group (0.7 ± 0.2 and 0.6 ± 0.2 mm respectively vs 0.45 ± 0.07 mm, P < 0.001 for both). The percent of change in blood flow following heat-mediated vasodilation was significantly impaired in patients with overt and subclinical hypothyroidism as compared with the control group (328 ± 17 and 545 ± 406% respectively vs 898 ± 195%, P < 0.001 for both). The impairment was more significant in overt as compared with subclinical hypothyroidism (P = 0.014). CIMT negatively correlated with percent of change in blood flow following heat-mediated vasodilation in patients with overt and subclinical hypothyroidism (P < 0.001 for both). We concluded that CIMT is significantly higher in patients with overt and subclinical hypothyroidism compared with normal control subjects. Impairment of endothelial function is a contributing factor to the increased risk of atherosclerosis in both groups of patients.

Histological and Histomorphometric Response to SocketKAP™ and SocketKAGE™ Used for Ridge Preservation and Repair: Results From a Randomized Controlled Clinical Trial.

PURPOSE: This study investigated the histologic tissue response to SocketKAP and SocketKAGE as novel devices designed for ridge preservation. MATERIALS AND METHODS: This randomized controlled clinical trial recruited participants among patients who presented to a university dental clinic. The study protocol entailed randomization into 5 intervention groups after tooth extraction: unassisted healing of intact sockets (group A), SocketKAP (group B), anorganic bovine bone minerals (ABBM) plus SocketKAP (group C), unassisted healing of sockets with dehiscence (group D), and SocketKAGE plus ABBM plus SocketKAP (group E). The primary outcome variable was bone volume fraction of total volume (BV/TV). Secondary outcome variables were percentages of residual graft material (RG) and void volume (VV). One-way analysis of variance was run on BV/TV, RG, and VV based on the independent variable (treatment groups). RESULTS: Bone core samples were harvested from participants (N = 22) who presented for implant installation at 6 months after extraction. Sockets without biomaterial filler (groups A and B) showed more mature bone compared with grafted sockets. In groups in which sockets were filled with biomaterial (groups C and E), vital bone was observed in direct apposition to the graft particles. In group E, remnants of SocketKAGE were not readily discernable at 6 months. No substantial inflammatory infiltrate or other adverse histologic patterns were detected. Quantitative analysis showed a statistically significant difference in BV/TV between groups A and C (P = .028) and between groups A and E (P = .019). CONCLUSIONS: Histologic and histomorphometric results showed that the application of SocketKAP and SocketKAGE did not interfere with wound healing of extraction sockets. In agreement with previous reports, the percentage of BV/TV within sites with ABBM was smaller than within sites without biomaterial. The favorable histologic response to SocketKAP and SocketKAGE observed in the present study provided additional insights to the authors' previous studies showing the benefits of these devices in decreasing postextraction dimensional alterations of alveolar bone and tissue contour.

MicroCT Imaging on Living Alligator Teeth Reveals Natural Tooth Cycling.

To study tooth cycling in polyphyodont animals, we chose to work on alligators. Alligators have teeth in three phases of development at each tooth location. This assembly of three teeth is called a tooth family unit. As part of the study, in order to study tooth cycling in alligators, we wanted to know the configuration of the tooth family unit in every tooth position. From the surface of the mouth, this is difficult to assess. Therefore, we decided to use MicroCT which can image X-ray dense materials providing a three-dimensional view. MicroCT provided us with valuable information for this study. The method described below can be applied to study tooth cycling in other vertebrate species.

Effect of Exposure to Portland Cement Dust on the Periodontal Status and on the Outcome of Non-Surgical Periodontal Therapy.

BACKGROUND: Cement dust contains heavy metals like nickel, cobalt, lead and chromium, pollutants hazardous to the biotic environment, with adverse impact for vegetation, human and animal health and ecosystems. OBJECTIVE: To investigate if long term exposure to cement dust can affect the periodontal health and affect the outcome of non-surgical periodontal therapy. METHODS: A total of sixty subjects were included in this study. Forty patients with chronic periodontitis were grouped into; Group I comprised of 20 patients with chronic periodontitis working in the Portland Cement Company and Group II comprised of 20 patients with chronic periodontitis who does not work in cement factories nor live near any of them. Twenty healthy subjects were included in this study as healthy control group (Group III). Clinical parameters including gingival index (GI), plaque index (PI), pocket depth (PD) and clinical attachment loss (CLA) were scored for all patients before and after periodontal therapy. All patients received non-surgical periodontal therapy together with strict oral hygiene program for one month. Gingival crevicular fluid (GCF) samples were collected from both groups at baseline and one month after periodontal therapy. Real time PCR (RT-PCR) was used to analyze the GCF samples for detection and assessment of the levels of IL-1ß and TNFα. RESULTS: The two studied groups responded well to non-surgical periodontal treatment and there was no significant difference between GI and GII (P>0.05). The levels of TNFα was higher in GI than in GII before and after periodontal therapy (P<0.05). The levels of IL-1ß did not show any significant difference between the two groups at base line (P>0.05), but represented with a highly significant difference between G1 and GII after periodontal therapy (P<0.001). A significant positive correlation was found between the levels of both IL-1ß and TNFα and all the clinical parameters in GI before and after periodontal therapy and in GII before periodontal therapy (P<0.05). CONCLUSION: It seems that long term exposure to cement dust does not affect the clinical outcome of non-surgical periodontal treatment but it affects the levels of the pro-inflammatory mediators leading to more periodontal tissue destruction.

An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAP(™) and SocketKAGE(™) : part 2 - three-dimensional alveolar bone volumetric analysis of CBCT imaging.

OBJECTIVES: The aims of this study were (i) to evaluate the efficacy of ridge preservation and repair procedures involving the application of SocketKAP(™) and SocketKAGE(™) devices following tooth removal and (ii) to evaluate alveolar bone volumetric changes at 6 months post-extraction in intact sockets or those with facial wall dehiscence defects using 3-dimensional pre- and postoperative CBCT data. MATERIALS AND METHODS: Thirty-six patients required 61 teeth extracted. Five cohorts were established: Group A: Intact Socket Negative Control Group B: Intact Socket + SocketKAP(™) Group C: Intact Socket Filled with Anorganic Bovine Bone Mineral (ABBM) + SocketKAP(™) Group D: Facial Dehiscence Socket Negative Control Group E: Facial Dehiscence Socket Filled with ABBM + SocketKAP(™) + SocketKAGE(™) . Preoperative CBCT scans were obtained followed by digital subtraction of the test teeth. At 6 months post-extraction, another CBCT scan was obtained. The pre- and postoperative scans were then superimposed, allowing highly accurate quantitative determination of the 3D volumetric alveolar bone volume changes from baseline through 6 months. RESULTS: Significant volumetric bone loss occurred in all sockets, localized mainly in the 0-3 mm zone apical to the ridge crest. For intact sockets, SocketKAP(™) + ABBM treatment led to a statistically significant greater percentage of remaining mineralized tissue volume when compared to negative control group. A significant difference favoring SocketKAP(™) + SocketKAGE(™) + ABBM treatment was observed for sockets with facial dehiscence defects compared to the negative control group. CONCLUSIONS: SocketKAP(™) , with ABBM, appears effective in limiting post-extraction volumetric bone loss in intact sockets, while SocketKAP(™) + SocketKAGE + ABBM appears effective in limiting post-extraction bone loss in sockets with dehiscence defects.

An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAP(™) and SocketKAGE(™) : part 1-three-dimensional volumetric soft tissue analysis of study casts.

OBJECTIVES: The aims of this study were to evaluate (i) the efficacy of ridge preservation and repair involving SocketKAP(™) and SocketKAGE(™) devices following tooth removal; and (ii) ridge contour changes at 6 months post-extraction in intact sockets and sockets with dehiscence defects. MATERIAL AND METHODS: Thirty-six patients required a total of 61 teeth to be extracted. Five cohorts were established with groups A-C involving intact sockets and groups D and E involving facial dehiscence: (A) Negative Control; (B) SocketKAP(™) alone; (C) Anorganic Bovine Bone Mineral (ABBM) + SocketKAP(™) ; (D) Negative Control; and (E) ABBM + SocketKAP(™)  + SocketKAGE(™) . Preoperative CBCT and laser-scanned casts were obtained. Teeth segmented from preoperative CBCT were merged with study cast images to allow for digital removal of teeth from the casts. Volumetric measurements of ridge contour were performed. Images of preoperative and 6 months post-operative casts were superimposed to measure ridge contour changes. RESULTS: Post-extraction contour loss occurred in all sockets primarily in the crestal 3 mm but was also detected up to 6 mm from alveolar crest. For intact sockets, SocketKAP(™) or SocketKAP(™)  + ABBM interventions led to greater percentages of remaining ridge contour when compared to controls. A significant difference favoring SocketKAP(™)  + SocketKAGE(™)  + ABBM treatment was observed for sockets with facial dehiscence when compared to controls. CONCLUSION: SocketKAP(™) , with or without ABBM, significantly limited post-extraction ridge contour loss in intact sockets. In the absence of a group treated with only the SocketKAGE(™) , it is not possible to determine its efficacy, although the combination of SocketKAGE(™)  + SocketKAP(™)  + ABBM was effective in limiting post-extraction ridge contour loss in sockets with dehiscence defects.

Alveolar ridge dimensional changes following ridge preservation procedure: part-2 - CBCT 3D analysis in non-human primate model.

AIM: The aim of this study was to evaluate the efficacy of ridge preservation involving novel devices used for obturation of socket orifice (Socket cap; SocketKAP(™) ) and resorbable cage used for space maintenance in sites with facial wall dehiscence (Socket cage; SocketKAGE(™) ). MATERIAL AND METHODS: Eight teeth were extracted in each of six Macaca fascicularis non-human primates. Six intervention groups consisted of the following: Group A: intact socket negative control. Group B: intact socket: socket cap. Group C: intact socket filled with anorganic bovine bone mineral (ABBM) + socket cap. Group D: dehiscence: negative control. Group E: dehiscence: socket cap + socket cage. Group F: dehiscence: filled with ABBM + socket cap + socket cage. CBCT scans were obtained preoperatively and at 6 and 12 weeks following intervention. The pre- and postoperative scans were superimposed, to quantify 3D volumetric alveolar bone changes. RESULTS: Volumetric bone loss occurred in all sockets, not only within the cretal zone (0-3 mm) to the ridge crest, as has been commonly reported by other investigators, but significant bone loss was also detected in the zone which was 3-6 mm apical to the alveolar crest. For intact sockets, socket cap + ABBM led to significantly greater percentages of remaining bone volume when compared to groups A and B. A significant difference favoring socket cap + socket cage + ABBM treatment was observed for sockets with facial dehiscence defects compared to groups D and E. CONCLUSIONS: Socket cap in conjunction with ABBM appears effective in limiting post-extraction volumetric bone loss in intact sockets, while socket cap + socket cage + ABBM appears effective in limiting post-extraction bone loss in sockets with dehiscence defects.

Plasma adiponectin and carotid intima-media thickness in non-obese patients with type 2 diabetes.

AIM: We assessed the correlation between plasma adiponectin levels and carotid intima media thickness (IMT), as a marker of atherosclerosis, in non-obese patients with type 2 diabetes. METHODS: The study group included 112 (60 males and 52 females) non-obese Egyptian patients with type 2 diabetes. Fasting plasma adiponectin was measured using ELISA technique. Carotid IMT was assessed using high-resolution color- coded Doppler ultrasonography. Forty age, sex and weight matched normal Egyptian subjects were included in the study as a control group. RESULTS: A non-significant inverse correlation was found between plasma adiponectin levels and carotid IMT in the study group (p=0.054). Multiple regression analysis revealed that plasma adiponectin was not a determinant of carotid IMT in the study group (p=0.061). CONCLUSION: The inverse relation between plasma adiponectin and carotid IMT in type 2 diabetes could be explained, at least partially, by obesity.

Doppler assessment of renal hemodynamic alterations in homozygous sickle cell disease and sickle Beta-thalassemia.

We evaluated the renal vascular indices in children and adolescents with sickle cell disease (SCD) using Doppler ultrasonography. We also assessed the renal hemodynamics alterations in patients with homozygous SCD and sickle beta-thalassemia (sickle ß-thalassemia). We studied 75 patients (age range = 3-20 years; M = 9.95 ± 4.15) with SCD: 42 patients suffering from homozygous SCD and 33 patients diagnosed with sickle ß-thalassemia. Thirty, age- and sex-matched, normal subjects were also included as a control group. Both patients and control groups had Doppler assessment of pulsatility (PI) and resistivity (RI) indices of main renal, segmental, interlobar, and arcuate arteries. Both PIs and RIs were significantly higher in SCD patients, compared with the control group. Among patients, PIs and RIs in the main renal, segmental, interlobar, and arcuate arteries were significantly higher in patients with homozygous SCD as compared with those with sickle ß-thalassemia (p values <0.01, <0.001, <0.001, and <0.001 for PIs and <0.001, <0.001, <0.001, and <0.01 for RIs, respectively). We concluded that renal vascular resistance is raised in children and adolescents with SCD. This is more pronounced in patients with homozygous SCD as compared with those with sickle ß-thalassemia.

Retinopathy is a Strong Determinant of Atherosclerosis in Type 2 Diabetes: Correlation with Carotid Intima Media Thickness.

OBJECTIVE: We investigated the correlation between the severity of diabetic retinopathy (DR) and carotid intima media thickness (IMT) as a marker of atherosclerosis in patients with type 2 diabetes. METHODS: The study group consisted of 140 normotensive Egyptian patients (68 males and 72 females) with type 2 diabetes and DR. Carotid IMT was evaluated using high-resolution B-mode ultrasonography. DR was assessed and graded using colored fundus photography and fundus fluorescein angiography, as either nonproliferative DR (NPDR) or proliferative DR (PDR). RESULTS: Carotid IMT was greater in patients with PDR compared to those with NPDR (1.094 ± 0.142 mm vs. 0.842 ± 0.134 mm; P<.001). Carotid IMT showed positive correlation with diabetes duration (P<.01), systolic blood pressure (P<.001), diastolic blood pressure (P<.01), fasting blood glucose (P<.01), postprandial blood glucose (PPBG) (P<.001), glycated hemoglobin (P<.01), total cholesterol (P<.01), triglycerides (TGs) (P<.001), and DR (P<.0001). No significant difference was found between males and females in any of the studied parameters. Multiple regression analysis revealed that the determinants of carotid IMT in the studied group were age (P<.01), PPBG (P<.01), TGs (P<.001), and DR (P<.0001). CONCLUSION: Our study proves that both NPDR and PDR are strong determinants of carotid IMT and atherosclerosis in patients with type 2 diabetes.

Immobilization of murine anti-BMP-2 monoclonal antibody on various biomaterials for bone tissue engineering.

Biomaterials are widely used as scaffolds for tissue engineering. We have developed a strategy for bone tissue engineering that entails application of immobilized anti-BMP-2 monoclonal antibodies (mAbs) to capture endogenous BMPs in vivo and promote antibody-mediated osseous regeneration (AMOR). The purpose of the current study was to compare the efficacy of immobilization of a specific murine anti-BMP-2 mAb on three different types of biomaterials and to evaluate their suitability as scaffolds for AMOR. Anti-BMP-2 mAb or isotype control mAb was immobilized on titanium (Ti) microbeads, alginate hydrogel, and ACS. The treated biomaterials were surgically implanted in rat critical-sized calvarial defects. After 8 weeks, de novo bone formation was assessed using micro-CT and histomorphometric analyses. Results showed de novo bone regeneration with all three scaffolds with immobilized anti-BMP-2 mAb, but not isotype control mAb. Ti microbeads showed the highest volume of bone regeneration, followed by ACS. Alginate showed the lowest volume of bone. Localization of BMP-2, -4, and -7 antigens was detected on all 3 scaffolds with immobilized anti-BMP-2 mAb implanted in calvarial defects. Altogether, these data suggested a potential mechanism for bone regeneration through entrapment of endogenous BMP-2, -4, and -7 proteins leading to bone formation using different types of scaffolds via AMOR.

Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release.

Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.

Functionalization of scaffolds with chimeric anti-BMP-2 monoclonal antibodies for osseous regeneration.

Recent studies have demonstrated the ability of murine anti-BMP-2 monoclonal antibodies (mAb) immobilized on an absorbable collagen sponge (ACS) to mediate de novo bone formation, a process termed antibody-mediated osseous regeneration (AMOR). The objectives of this study were to assess the efficacy of a newly generated chimeric anti-BMP-2 mAb in mediating AMOR, as well as to evaluate the suitability of different biomaterials as scaffolds to participate in AMOR. Chimeric anti-BMP-2 mAb was immobilized on 4 biomaterials, namely, titanium microbeads (Ti), alginate hydrogel, macroporous biphasic calcium phosphate (MBCP) and ACS, followed by surgical implantation into rat critical-size calvarial defects. Animals were sacrificed after 8 weeks and the degree of bone fill was assessed using micro-CT and histomorphometry. Results demonstrated local persistence of chimeric anti-BMP-2 mAb up to 8 weeks, as well as significant de novo bone regeneration in sites implanted with chimeric anti-BMP-2 antibody immobilized on each of the 4 scaffolds. Ti and MBCP showed the highest volume of bone regeneration, presumably due to their resistance to compression. Alginate and ACS also mediated de novo bone formation, though significant volumetric shrinkage was noted. In vitro assays demonstrated cross-reactivity of chimeric anti-BMP-2 mAb with BMP-4 and BMP-7. Immune complex of anti-BMP-2 mAb with BMP-2 induced osteogenic differentiation of C2C12 cells in vitro, involving expression of RUNX2 and phosphorylation of Smad1. The present data demonstrated the ability of chimeric anti-BMP-2 mAb to functionalize different biomaterial with varying characteristics to mediate osteogenesis.

Impact of stem cells in craniofacial regenerative medicine.

Interest regarding stem cell based therapies for the treatment of congenital or acquired craniofacial deformities is rapidly growing. Craniofacial problems such as periodontal disease, cleft lip and palate, ear microtia, craniofacial microsomia, and head and neck cancers are not only common but also some of the most burdensome surgical problems worldwide. Treatments often require a multi-staged multidisciplinary team approach. Current surgical therapies attempt to reduce the morbidity and social/emotional impact, yet outcomes can still be unpredictable and unsatisfactory. The concept of harvesting stem cells followed by expansion, differentiation, seeding onto a scaffold and re-transplanting them is likely to become a clinical reality. In this review, we will summarize the translational applications of stem cell therapy in tissue regeneration for craniofacial defects.