Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Efficacy of Atezolizumab Plus Bevacizumab Versus Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma: a Meta-analysis.

INTRODUCTION: Hepatocellular carcinoma is a lethal disease and there has been a debate regarding the first-line treatment of its advanced and unresectable form. Observational studies have explored atezolizumab plus bevacizumab versus lenvatinib, yielding mixed results. This systematic review and meta-analysis aim to compare efficacy and safety of both treatment arms. METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines. Randomized control trials, cohort studies, or case-control that included patients above age 60 with unresectable hepatocellular carcinoma confirmed by radiological imaging were included. At least one of the outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, or adverse events was included in the selected studies. RESULTS: Ten cohorts were included in the analysis with a total of 6493 patients. Nine of the included studies had patients with advanced HCC (BCLC-C) or intermediate HCC (BCLC-B) and 1 study included patients with all three stages (BCLC-A, BCLC-B, and BCLC-C). Of these patients, 2524 patients received atezolizumab plus bevacizumab (A + B) combination while 3969 received lenvatinib. The overall survival was better statistically in the A + B group then the lenvatinib group (MD: - 5.06; 95% CI: - 7.79 to - 2.33; p = 0.0003, I2 = 0%). The progression-free survival was significantly improved in A + B arm as well group (MD: - 4.96; 95% CI: - 7.67 to - 2.26; I2 = 0%, p = 0. 0003). There was no significant difference in objective response rate, disease control rate, and frequency of adverse events in either of the group. CONCLUSION: Our study concluded that combination therapy with atezolizumab plus bevacizumab could increase the survival duration without affecting the disease course. Moreover, while the severity of adverse events was greater in the A + B group, their frequency was comparable to the lenvatinib group.

Gallic acid affects chamomile flower's essential oil.

Chamomile essential oil is used in the food and medicinal industries. Gallic acid has been identified as one of the most significant biological elicitors. At dosages of 0, 5, 10, 15, and 20 mg/L, Gallic acid was sprayed on chamomile plants. The yield of flowers and essential oils in dry flowers were assessed. The averages of data were examined statistically using one-way analysis of variance. Oxygenated sesquiterpenes were a major chemical group, while α-bisabolol oxide A, α-bisabolol and chamazulene were the three main components of essential oil. When administered 15 mg/L Gallic acid, plants produced their most flowers and had the highest quantities of the essential oil, α-bisabolol oxide A, α-bisabolol and chamazulene. Essential oil extracted from untreated control plants had the highest concentration of oxygenated sesquiterpenes. It can be infer that Gallic acid increases the production of essential oil and alters its chemical constituents which alter its biological activity.

Co-Occurring X-Linked Agammaglobulinemia and X-Linked Chronic Granulomatous Disease: Two Isolated Pathogenic Variants in One Patient.

We present a unique and unusual case of a male patient diagnosed with two coexisting and typically unassociated X-linked conditions: he was initially diagnosed with X-linked agammaglobulinemia (XLA) followed by a diagnosis of X-linked chronic granulomatous disease (XCGD) and an as of yet unpublished hypomorphic gp91phox variant in the CYBB gene. The latter was tested after the finding of granulomatous gingivitis. Hematopoietic stem cell transplant (HSCT) was performed due to severe colitis and nodular regenerative hyperplasia (NRH) of the liver. Following transplant, complete donor engraftment was observed with the restoration of a normal oxidative burst and full restoration of normal levels of circulating, mature CD19+ B cells. This case is singular in that it does not involve a contiguous gene syndrome in which deleted genes are in close proximity to either BTK and CYBB, which has been previously reported. To our knowledge, this is the first reported case of XLA and XCGD co-existing in a single patient and of having both inborn errors of immunity successfully treated by HSCT.

Clinical Outcomes of Mitral Valve Disease With Mitral Annular Calcification.

The prevalence of mitral valve disease with mitral annular calcification (MAC) and its clinical outcomes remain uncertain. This study sought to evaluate the prevalence of significant mitral disease due to MAC, and the impact of intervention on the clinical outcomes in these patients. All patients who underwent transthoracic echocardiography (TTE) between January 2014 and December 2015 in our health care system were reviewed and identified for having MAC with significant mitral valve disease (i.e., either≥moderate mitral regurgitation (MR) or mitral stenosis (MS)). The primary endpoints of the study were all-cause mortality and a composite outcome of mortality or heart failure hospitalization at 3-year follow-up. Of 41,136 patients who underwent TTE, MAC was identified in 2,855 (6.9%) patients, including 434 (1.1% of total) patients who had significant MR and/or MS (median age [IQR], 80 [73 to 87] years; 63% women). MAC predominately involved the posterior annulus (95%), with the majority having calcification of both trigones (55%), the leaflets (71%), and circumferential involvement (67%). During 3-year follow-up, 59 (14%) patients underwent surgical or transcatheter MV intervention. Patients who did not undergo mitral intervention had higher all-cause mortality (HR 2.80, 95% CI 1.60 to 4.92; p <0.001) and a greater risk of the composite outcome (HR 1.43, 1.00 to 2.04; p = 0.05) than those treated. Survival at 3-year follow-up was markedly greater in those with mitral intervention (78% vs 50%; p <0.001). This survival benefit remained after multivariable adjustment. In conclusion, MAC affects approximately % of patients who undergo echocardiography. Those with significant mitral valve disease due to any degree of MAC have poor survival, which may be ameliorated with transcatheter or surgical intervention.

Relation of Guideline Adherence to Outcomes in Patients With Asymptomatic Severe Primary Mitral Regurgitation.

Current guidelines empirically recommend serial clinical evaluations for asymptomatic patients with severe mitral regurgitation (MR). However, there is a paucity of data on the effectiveness of such monitoring. This study sought to examine the potential benefit of guideline adherence among asymptomatic patients with severe primary MR. Asymptomatic patients with severe primary MR who had been evaluated in the Allina Health system between January 1, 2012 and May 30, 2018 were examined. The medical records were manually reviewed for demographics, comorbidities, echocardiographic data, subsequent interventions, and clinical outcomes. Patients were grouped according to occurrence of guideline adherence, which was defined as a serial clinical evaluation with echocardiography every 12 ± 1 month until mitral valve surgery, or death. Over the study period, 246 patients (67.3 ± 15.5 years, 61.4% men) with severe, asymptomatic primary MR were identified, including 154 patients (62.6%) with and 92 patients (37.4%) without guideline adherence. Overall, there were no differences in demographics, morbidities, MR severity, or left ventricular function between patient adherence groups. During follow-up (40.9; 21.2, 58.3 months), patients with adherence more frequently had surgery or transcatheter therapy performed (64.3% vs 18.5%; p <0.001) and the time to intervention was earlier (13.6 [3.9-22.7] vs 44.2[25.6-57.3] months; p <0.001). Compared to non-adherent patients, those with guideline adherence had a significantly higher five-year survival free from all-cause mortality (92.0% vs 74.3%, p = 0.002), and freedom from death or hospitalization for heart failure (90.1% vs 69.3%, p = 0.001). Adherent patients also had a significantly better survival free from combined endpoint of death, re-hospitalization for heart failure, myocardial infarction, and stroke (84.5% vs 63.2%, p = 0.002). In patients with asymptomatic severe primary MR, guideline adherence with serial evaluations every 12 months or less is associated with earlier therapy and improved long-term outcomes. These data support educational efforts to promote guideline adherence.

FGF gene expression in injured tendons as a prognostic biomarker of 1-year patient outcome after Achilles tendon repair.

PURPOSE: Healing outcome after Achilles Tendon Rupture (ATR) is variable and unsatisfactory. Many ATR patients still exhibit pain, functional deficits and limitations in walking one-year post-surgery. The present study was designed to investigate the association between the expression of healing biomarkers and patient outcome after ATR. METHODS: Tendon biopsies were collected from 25 ATR patients during surgery. At 1-year post surgery, all patients completed questionnaires; Achilles tendon Total Rupture Score (ATRS) and Foot and Ankle Outcome Score (FAOS), and were tested for functional outcomes by heel-rise test. In biopsies, FGF, COL III, FN, COL I and MMP-9 mRNA levels were assessed by quantitative RT-PCR while protein expression was studied by immunohistochemistry (IHC). RESULTS: Our analysis confirmed the presence of FGF, COL III, FN, COL I and MMP-9 at mRNA and protein levels in tendon biopsies. FGF gene expression associated positively with improved total ATRS and better functional outcomes. Additionally, FGF mRNA levels were associated with less pain, less running limitations and less loss in physical activity. In addition, higher COL III mRNA expression was associated with more tendon strength. CONCLUSION: Our findings indicate that FGF gene expression is associated with improved patient-reported outcome. FGF expression in surgical biopsies could potentially be used to assist the prognostic evaluation of patient outcome and may be used as a predictor for healing. However, further studies are needed to evaluate the role of FGF in Achilles tendon healing. LEVEL OF EVIDENCE: II.

Submacular choroiditis in common variable immunodeficiency associated with a pathogenic mutation in the tumor necrosis factor gene.

PURPOSE: To report on a case of submacular choroiditis in a patient with common variable immunodeficiency (CVID). OBSERVATIONS: An 80-year-old man was referred with a diagnosis of a central retinal vein occlusion with CME and later developed intraocular inflammation. History was notable for recurrent bacterial infections and myelodysplastic syndrome known to be due to CVID. Ophthalmic examination and multimodal imaging revealed mild intraocular inflammation, retinal vasculitis, submacular choroiditis, and CME. Genetic testing identified a point mutation in TNFRSF13B, a pathogenic variant in the tumor necrosis factor gene known to be associated with CVID, but not with CVID-associated uveitis. CONCLUSIONS AND IMPORTANCE: The diagnosis of CVID should be considered in patients with uveitis and a history of recurrent bacterial infections. Genetic testing can support the diagnosis.

Nonatherosclerotic Abdominal Vasculopathies.

BACKGROUND: Nonatherosclerotic abdominal arterial vasculopathies (NAVs), including mesenteric or renal artery dissection, aneurysm, stenosis, and vasculitis, are rare but have great clinical significance. Patients may present emergently with life-threatening complications such as arterial rupture and hemorrhagic shock. Herein, we present our center's experience with NAVs and provide extensive literature review to close the gap in the scarce, related literature. METHODS: From a single-center retrospective data analysis, we identified and characterized subjects (aged 18-60 years) who presented with NAV between January 2000 and December 2015. Of the 1416 charts reviewed, 118 met inclusion criteria. RESULTS: The average age of patients with NAV was 47.0 ± 9.9 years, mostly affecting women (64%). Primary diagnoses included fibromuscular dysplasia (FMD) (25.4%), isolated aneurysms (24.6%), and median arcuate ligament syndrome (MALS) (15.3%). Less common diagnoses were localized vasculitis of the gastrointestinal tract (LVGT) (7.6%), isolated dissection (5.1%), microscopic polyangiitis and granulomatosis with polyangiitis (5.1%), trauma (4.2%), segmental arterial mediolysis (4.2%), Ehlers-Danlos syndrome (2.5%), Takayasu's arteritis (2.5%), polyarteritis nodosa (1.7%), idiopathic abdominal aortitis (0.8%), and Loeys-Dietz syndrome (0.8%). Females constituted 90% of patients with FMD, 77.8% with MALS, 77.8% with isolated aneurysms, 66.7% with Takayasu arteritis, and 55.6% with LVGT. Prevalent comorbidities included tobacco use (43.6%) and hypertension (52.1%). Coil embolization was used in 14.4%, anticoagulation in 11.9%, angioplasty/stenting in 11.9%, open resection/surgical revascularization in 10.2%, and prednisone in 10.2% of the cases. Conservative management was pursued in 33.1% of the patients. A high degree of symptom relief was shown in 91.7%. CONCLUSIONS: NAV are rare and can be caused by different etiologies that primarily affect females. Hypertension and tobacco use were prevalent. Various imaging strategies revealed aneurysms, stenosis, dissection, and/or thrombosis affecting renal and celiac arteries. Most patients improved with conservative, medical, endovascular, or surgical approach. More research is needed to standardize management approach to patients with NAV.

NF-κB-Associated Pain-Related Neuropeptide Expression in Patients with Degenerative Disc Disease.

The role of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) has been highlighted in mechanisms underlying inflammatory and neuropathic pain processes. The present study was designed to investigate whether NF-κB signaling is associated with pain-related neuropeptide expression in patients with chronic back pain related to degenerative disc disease (DDD). Intervertebral disc (IVD) tissues were collected from forty DDD patients undergoing disc replacement or fusion surgery, and from eighteen postmortem (PM) control subjects. RELA, NFKB1, CGRP, TAC1, TRPV1, and MMP-3 gene expression were analyzed by RT-qPCR, while NF-κB subunit RelA and NF-κB1⁻DNA binding in nuclear extracts and calcitonin gene related peptide (CGRP), substance P (SP), and transient receptor potential, subfamily V, member 1 (TRPV1) protein levels in cytosolic extracts of tissues were assessed by enzyme-linked immunosorbent assay (ELISA). An upregulated NF-κB1⁻DNA binding, and higher CGRP and TRPV1 protein levels were observed in DDD patients compared to PM controls. In DDD patients, NF-κB1⁻DNA binding was positively correlated with nuclear RelA levels. Moreover, NF-κB1⁻DNA binding was positively associated with TRPV1 and MMP-3 gene and SP and TRPV1 protein expression in DDD patients. Our results indicate that the expression of SP and TRPV1 in IVD tissues was associated with NF-κB activation. Moreover, NF-κB may be involved in the generation or maintenance of peripheral pain mechanisms by the regulation of pain-related neuropeptide expression in DDD patients.

Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.

Characterization of neuroinflammation and periphery-to-CNS inflammatory cross-talk in patients with disc herniation and degenerative disc disease.

The aim of the study was to identify inflammatory cytokines/chemokines associated with neuroinflammation and periphery-to-CNS inflammatory cross-talk in degenerative disc disease (DDD) and lumbar disc herniation (LDH), common causes of low back pain (LBP). A secondary aim was to investigate the associations between cytokines and symptom severity. METHODS: In total, 40 DDD and 40 LDH patients were recruited from a surgical waiting list, as well as 39 healthy controls (HC) and 40 cerebrospinal fluid (CSF) controls. The subjects completed questionnaires and pressure algometry was performed at the lumbar spine and forearm. The CSF, serum and disc tissues were collected during surgery. Inflammatory mediators TNF, INFg, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13 and MCP1 were analysed by immunoassay (Meso Scale Discovery) and quantitative real-time polymerase chain reaction (qPCR) was used for analysis of IL-6, IL-8, MCP1 and TSPO expression in intervertebral discs (IVDs). RESULTS: In the LDH group, we found elevated IL-8 concentrations in CSF indicating neuroinflammation, while IL-8 and MCP1 concentrations in serum were lower compared to HC. The IVD expression of IL-6, IL-8 and TSPO was lower in LDH patients compared to DDD. LDH patients had a positive correlation between IL-8 concentrations in CSF and serum and IL-8 in CSF was associated with higher pain intensity and increased spinal pressure pain sensitivity. The MCP1 concentration in serum was associated with higher global pain ratings and increased spinal pressure pain sensitivity, while IL-6 serum concentration correlated with the intensity of the neuropathic pain component (leg pain) in LDH patients. IVD expression of TSPO in LDH patients was associated with increased intensity of back pain. No differences were found in cytokine CSF concentrations between DDD patients and CSF controls, but DDD patients had lower IL-8 and MCP1 serum concentrations than HC. In female DDD patients, IL-8 and MCP1 concentrations in serum were associated with increased intensity of back pain. CONCLUSION: Our results suggest that neuroinflammation mediated by elevated IL-8 concentrations in CSF and IL-8 mediated periphery-to-CNS inflammatory cross-talk contributes to pain in LDH patients and suggest a link between TSPO expression in discs and low back pain.

Contemporary Reasons and Clinical Outcomes for Patients With Severe, Symptomatic Aortic Stenosis Not Undergoing Aortic Valve Replacement.

BACKGROUND: Although aortic valve replacement (AVR) can be lifesaving, many patients with symptomatic aortic stenosis do not undergo appropriate therapy. This study sought to examine the characteristics, outcomes, and reasons for not pursuing AVR in a contemporary cohort. METHODS AND RESULTS: We examined 548 patients with severe, symptomatic aortic stenosis not treated with AVR through March 2017. Patients were grouped according to AVR appropriateness based on the presence of medical futility. Demographics, rationale for no AVR therapy, and outcomes were assessed. There were 359 (65.5%) potentially appropriate candidates for AVR and 189 (34.5%) others patients with futility. Among potentially appropriate patients, 62.1% had severe symptoms, 74.4% had not been referred for AVR, and 40.1% were low risk. Patient refusal was common (54.6%), with incorrect symptom assignment or aortic stenosis severity classification accounting for nearly all other explanations. Compared with patients with futility, potentially appropriate AVR patients had lower rates of both referral to cardiology or surgery (85.2% versus 92.6%; P=0.01) and complete heart team evaluations (10.6% versus 17.5%; P=0.02). Palliative consultation occurred in only 124 patients (22.6%) overall and in only 10.0% of those without futility. Overall, the 1-year mortality was 54.7%, with heart failure hospitalization occurring in 19.3%. CONCLUSIONS: In this contemporary study, two-thirds of patients with symptomatic aortic stenosis treated medically were potentially appropriate AVR candidates and had poor outcomes. Most had incomplete heart team evaluations, commonly had severe symptoms or lesion severity misinterpreted, and were not evaluated by palliative care. Given the potential for beneficial outcomes among those untreated, further efforts to address these shortcomings are needed.

Activation of NF-κB in Synovium versus Cartilage from Patients with Advanced Knee Osteoarthritis: A Potential Contributor to Inflammatory Aspects of Disease Progression.

The aim was to assess the activation and association of the NF-κB system across synovial membrane (SM) and articular cartilage (AC) in patients with knee osteoarthritis (OA) and ascertain its potential effects on catabolic mediator expression in advanced OA. SM and AC were obtained from 40 OA patients undergoing total knee arthroplasty and from 19 postmortem control subjects. NF-κB subunit RelA in nuclear and cytosolic fractions and NF-κB1-DNA binding in nuclear extracts was assessed by ELISA, whereas NFKB1, RELA, IL-8, IL-6, and MMP3 gene expression were analyzed by reverse transcriptase-quantitative PCR in tissues. We observed higher SM nuclear RelA protein levels and upregulated NF-κB1-DNA binding in OA patients compared with postmortem controls. However, in AC, lower nuclear RelA levels were observed compared with cytosolic extracts in patients. Nuclear RelA levels correlated positively with NF-κB1-DNA binding in SM and AC in patients. SM RELA and MMP3 mRNA levels were upregulated, whereas IL-8 and IL-6 as well as AC RELA were downregulated in patients compared with controls. In SM, nuclear RelA levels correlated positively with MMP3 gene expression in patients. A negative correlation was observed between SM nuclear RelA levels and AC NF-κB1-DNA binding, and SM nuclear NF-κB1-DNA binding correlated negatively with AC MMP3 and NFKB1 mRNA levels in patients. These findings highlight NF-κB-triggered cross-talk and feedback mechanisms between SM and AC in OA. Further, our findings strongly support a role for an activated NF-κB system in the transcriptional mechanism of inflammatory processes, especially in SM of patients with advanced OA.

Medical Management of Extensive Arterial Thromboembolism in a Patient with Essential Thrombocythemia and Warfarin Failure.

Chronic myeloproliferative disorders share a stem cell-derived clonal myeloproliferation. This group of disorders include essential thrombocythemia (ET), polycythemia vera (PV), chronic myeloid leukemia, and primary myelofibrosis (PMF), with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. These disorders can be associated with genetic mutations affecting protein tyrosine kinases, resulting in different configurations of abnormal signal transduction. The Janus tyrosine kinase 2 mutation can be used as a key diagnostic tool for diagnosing MPDs, specifically, ET, PV, and PMF. Patients with ET and PV are at an increased risk for thromboembolic and hemorrhagic events. We present a unique case of ET causing extensive arterial thromboembolism, despite being on adequate antithrombotic agents including warfarin and aspirin.

Compromised Neurotrophic and Angiogenic Regenerative Capability during Tendon Healing in a Rat Model of Type-II Diabetes.

Metabolic diseases such as diabetes mellitus type-II (DM-II) may increase the risk of suffering painful connective tissue disorders and tendon ruptures. The pathomechanisms, however, by which diabetes adversely affects connective tissue matrix metabolism and regeneration, still need better definition. Our aim was to study the effect of DM-II on expressional changes of neuro- and angiotrophic mediators and receptors in intact and healing Achilles tendon. The right Achilles tendon was transected in 5 male DM-II Goto-Kakizaki (GK) and 4 age-matched Wistar control rats. The left Achilles tendons were left intact. At week 2 post-injury, NGF, BDNF, TSP, and receptors TrkA, TrkB and Nk1 gene expression was studied by quantitative RT-PCR (qRT-PCR) and their protein distribution by immunohistochemistry in intact and injured tendons. The expression of tendon-related markers, Scleraxis (SCX) and Tenomodulin (TNMD), was evaluated by qRT-PCR in intact and injured tendons. Injured tendons of diabetic GK rats exhibited significantly down-regulated Ngf and Tsp1 mRNA and corresponding protein levels, and down-regulated Trka gene expression compared to injured Wistar controls. Intact tendons of DM-II GK rats displayed reduced mRNA levels for Ngf, Tsp1 and Trkb compared to corresponding intact non-diabetic tendons. Up-regulated Scx and Tnmd gene expression was observed in injured tendons of normal and diabetic GK rats compared to intact Wistar controls. However, these molecules were not up-regulated in injured DM-II GK rats compared to their corresponding controls. Our results suggest that DM-II has detrimental effects on neuro- and angiotrophic pathways, and such effects may reflect the compromised repair seen in diabetic Achilles tendon. Thus, novel approaches for regeneration of injured, including tendinopathic, and surgically repaired diabetic tendons may include therapeutic molecular modulation of neurotrophic pathways such as NGF and its receptors.

Effects of Sterculia setigera Del. Stem Bark Extract on Hematological and Biochemical Parameters of Wistar Rats.

Africa is rich in a wide range of flora that are exploited as herbal medicines and remedies. Several diseases such as diabetes, diarrhea, dysentery and jaundice have been successfully managed using herbal medicines. Herbal decoctions or concoctions have been used as pain killers, antibiotics, and hematinics. This study evaluated the hematopoietic and biochemical properties of the stem bark of Sterculia setigera Del. in Wistar rats. Results showed that S. setigera decoction has copiously high tannin and cardiac glycoside levels. Ingestion of the decoction by rats over a 16-day period significantly (P < 0.05) increased the body weights of rats by 22.4% in the S. setigera-treated group. Hematological profiles showed raised levels of red blood cells, hemoglobin, packed cell volume, mean corpuscular volume, mean cell hemoglobin, mean cell hemoglobin concentration, and platelets, while biochemical parameters showed lower levels of alanine aminotransferase and aspartate aminotransferase, and slight increase in albumin and TP levels. We posit that the results justify the use of the stem bark of S. setigera as a hematinic by traditional medical practitioners and show its relative safety. Further experiments are needed to evaluate its safety.

Changes in growth, hormones levels and essential oil content of Ammi visnaga L. plants treated with some bioregulators.

The effects of foliar application of different concentrations of amino acids (tyrosine and phenylalanine) and phenolic acids (trans-cinnamic acid, benzoic acid and salicylic acid) on growth, pigment content, hormones levels and essential oil content of Ammi visnaga L were carried out during two successive seasons. It is clear that foliar application of either amino acids or phenolics significantly promoted the growth parameters in terms of shoot height, fresh and dry biomass, number of branches and number of umbels per plant. The increment of growth parameter was associated with elevated levels of growth promoters (IAA, GA3, total cytokinins) and low level of ABA. The greatest increase in the previously mentioned parameters was measured in plants exposed to different concentrations of phenols particularly in benzoic acid-treated plants. Such effect was concentration dependent. All treatments led to significant increments in yield seeds and oil content. Moreover, gas liquid chromatographic analysis revealed that the main identified components of essential oil were 2,2-dimethyl butanoic acid, isobutyl isobutyrate, α-isophorone, thymol, fenchyl acetate and linalool. Phenolics and amino acid treatments resulted in qualitative differences in these components of essential oil.

Large thoracic aortic aneurysm and dissection with rare complication.

Thoracic aortic aneurysms can be found incidentally, however, patients can also present with acute dissection and or rupture that can be fatal. Symptoms that might indicate dissection include chest and back pain as well as lightheadedness. The diagnosis can be made with imaging studies such as computed tomography or magnetic resonance angiogram and sometimes transesophageal echocardiogram. Management is based on the aneurysmal size, location, extension, and the presence of complications. Although smaller localized and slow growing aneurysms can be monitored, larger and or complicated ones may warrant immediate repair. Less-common complications include compression over anatomic structures in the vicinity including vessels and the mediastinum. We report a unique case of a 71-year-old man who presented with a very large thoracic aortic aneurysm with dissection causing compression over the brachiocephalic veins and the mediastinum leading to facial and upper extremity swelling, dysphagia, and cough. This case represents a rare but significant complication of thoracic aortic aneurysm and emphasizes the challenges of its management.

Embryonic stem cells improve cardiac function in Doxorubicin-induced cardiomyopathy mediated through multiple mechanisms.

Doxorubicin (DOX) is an effective antineoplastic agent used for the treatment of a variety of cancers. Unfortunately, its use is limited as this drug induces cardiotoxicity and heart failure as a side effect. There is no report that describes whether transplanted embryonic stem (ES) cells or their conditioned medium (CM) in DOX-induced cardiomyopathy (DIC) can repair and regenerate myocardium. Therefore, we transplanted ES cells or CM in DIC to examine apoptosis, fibrosis, cytoplasmic vacuolization, and myofibrillar loss and their associated Akt and ERK pathway. Moreover, we also determined activation of endogenous c-kit(+ve) cardiac stem cells (CSCs), levels of HGF and IGF-1, growth factors required for c-kit cell activation, and their differentiation into cardiac myocytes, which also contributes in cardiac regeneration and improved heart function. We generated DIC in C57Bl/6 mice (cumulative dose of DOX 12 mg/kg body weight, IP), and animals were treated with ES cells, CM, or cell culture medium in controls. Two weeks post-DIC, ES cells or CM transplanted hearts showed a significant (p < 0.05) decrease in cardiac apoptotic nuclei and their regulation with Akt and ERK pathway. Cardiac fibrosis observed in the ES cell or CM groups was significantly less compared with DOX and cell culture medium groups (p < 0.05). Next, cytoplasmic vacuolization and myofibrillar loss was reduced (p < 0.05) following treatment with ES cells or CM. Moreover, our data also demonstrated increased levels of c-kit(+ve) CSCs in ES cells or CM hearts and differentiated cardiac myocytes from these CSCs, suggesting endogenous cardiac regeneration. Importantly, the levels of HFG and IGF-1 were significantly increased in ES cells or CM transplanted hearts. In conclusion, we reported that transplanted ES cells or CM in DIC hearts significantly decreases various adverse pathological mechanisms as well as enhances cardiac regeneration that effectively contributes to improved heart function.