HDAC2/3 inhibitor MI192 mitigates oligodendrocyte loss and reduces microglial activation upon injury: A potential role of epigenetics.

Background: During development, oligodendrocyte (OL) lineage cells are susceptible to injury, leading to life-long clinical neurodevelopmental deficits, which lack effective treatments. Drugs targeting epigenetic modifications that inhibit histone deacetylases (HDACs) protect from many clinical neurodegenerative disorders. Aim: This study aimed to investigate the therapeutic potential of histone deacetylase 2/3 (HDAC2/3) inhibitor MI192 on white matter (WM) pathology in a model of neonatal rat brain injury. Methods: Wistar rats (8.5-day-old, n = 32) were used to generate brain tissues. The tissues were cultured and then randomly divided into four groups and treated as following: group I (sham); the tissues were cultured under normoxia, group II (vehicle); DMSO only, group III (injury, INJ); the tissues were exposed to 20 minutes oxygen-glucose deprivation (OGD) insult, and group IV (INJ + MI192); the tissues were subjected to the OGD insult and then treated with the MI192 inhibitor. On culture day 10, the tissues were fixed for biochemical and histological examinations. Results: The results showed that inhibition of HDAC2/3 activity alleviated WM pathology. Specifically, MI192 treatment significantly reduced cell death, minimized apoptosis, and mitigates the loss of the MBP+ OLs and their precursors (NG2+ OPCs). Additionally, MI192 decreased the density of reactive microglia (OX-42+). These findings demonstrate that the inhibition of HDAC2/3 activity post-insult alleviates WM pathology through mechanism(s) including preserving OL lineage cells and suppressing microglial activation. Conclusion: The findings of this study suggest that HDAC2/3 inhibition is a rational strategy to preserve WM or reverse its pathology upon newborn brain injury.

Patellar luxation in Hejazi goats.

Background: Patellar luxation (PL) is a common orthopedic affection among farm and pet animals with mostly congenital (environmental and/or genetic) background. Aim: We report here the first observation of lateral PL in Hejazi goats bred in Libya. Methods: Five Hejazi goats aged between 4 months and 2 years with severe hind limb lameness were admitted to Al-Sorouh veterinary clinic in Tripoli during the period from 2016 to 2018. The goats were thoroughly examined clinically and radiographically. Two goats were surgically treated, and the other three cases were not because of either the cost limitation or expected poor prognosis. The surgical intervention involved femoral trochlear sulcoplasty, medial joint capsule imbrication, and tibial tuberosity transposition. Results: The clinical examination showed grade III-IV lateral PL. Radiologically, there were unilateral or bilateral, ventrocaudal, and dorsal PLs. Two cases were referred to surgical correction. One case almost restored the normal movement of stifle joint together with a good general status 1 year postsurgery. However, the surgical treatment was not effective in correcting the luxated patella in the second case. Conclusion: Lateral PL is common among orthopedic affections in Hejazi goats in Libya, and its surgical treatment provided a quite convenient approach. An association between inbreeding and the PL was suggested in those cases.

Benefits of flavonoid and metronidazole use after excisional hemorrhoidectomy: a randomized double-blind clinical trial.

BACKGROUND: Excisional hemorrhoidectomy remains the most effective treatment for a significant group of patients with hemorrhoids, despite the potential for postoperative pain. The purpose of this study was to evaluate the effects of flavonoid and metronidazole use in the postoperative period on patients undergoing excisional hemorrhoidectomy. METHODS: A double-blind randomized clinical study was performed. Sixty-eight patients underwent excisional hemorrhoidectomy and were randomized into 4 groups of 17 patients each to receive double-placebo (G1), metronidazole plus placebo (G2), flavonoids plus placebo (G3) or metronidazole plus flavonoids (G4) in the postoperative period. A standard analgesic protocol was offered equally for all groups. Postoperative pain, bleeding, edema, pruritus and tenesmus were evaluated during the following three periods: from immediately after the operation until postoperative day (POD)7, from POD 8 to POD 14, and from POD 15 to POD 30. The patients were required to complete symptom questionnaires and to attend postoperative follow-up on PODs 7, 14 and 30. The effect of each drug was assessed for each symptom, and the groups were compared with each other and over time. RESULTS: There was less severe pain in all postoperative periods in the groups using flavonoids (G3 and G4, both p < 0.0001), with an observed synergistic effect of flavonoids combined with metronidazole during the first 14 days after surgery (p < 0.0001). Flavonoid use was also associated with decreased bleeding (G3, p = 0.031 and G4, p = 0.016) between the first and second postoperative weeks CONCLUSIONS: The use of flavonoids alone and in combination with metronidazole resulted in a reduction of most symptoms, particularly pain, after excisional hemorrhoidectomy. TRIAL REGISTRATION: The present study was registered in the SISNEP (document CAAE-0035.0.240.000-11), after approval by the research ethics committee (CEP) of the Hospital Felício Rocho (protocol nº393 / 11).

Insulin and Its Cardiovascular Effects: What Is the Current Evidence?

PURPOSE OF REVIEW: In this article, we examine the nature of the complex relationship between insulin and cardiovascular disease. With metabolic abnormalities comes increased risk for cardiovascular complications. We discuss the key factors implicated in development and progression of cardiovascular disease, its relationship to insulin therapy, and what can be learned from large, recent cardiovascular outcome studies. RECENT FINDINGS: Preclinical studies suggest that insulin has positive effects of facilitating glucose entry into cells and maintaining euglycemia and negative effects of favoring obesity and atherogenesis under certain conditions. Confounding this relationship is that cardiovascular morbidity is linked closely to duration and control of diabetes, and insulin is often used in patients with diabetes of longer duration. However, more recent clinical studies examining the cardiovascular safety of insulin therapy have been reassuring. Diabetes and cardiovascular outcomes are closely linked. Many studies have implicated insulin resistance and hyperinsulinemia as a major factor for poor cardiovascular outcomes. Additional studies link the anabolic effects of therapeutic insulin to weight gain, along with hypoglycemia, which may further aggravate cardiovascular risk in this population. Though good glycemic control has been shown to improve microvascular risks in type 1 and type 2 diabetes, what are the known cardiovascular effects of insulin therapy? The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes. Recent studies have demonstrated that ultra-long-acting insulin analogs like insulin degludec are non-inferior to insulin glargine with regard to cardiovascular outcomes.

Allelopathic Activity of Extracts from Different Brazilian Peanut (Arachis hypogaea L.) Cultivars on Lettuce (Lactuca sativa) and Weed Plants.

Peanut (Arachis hypogaea L.) is the fourth most consumed oleaginous plant in the world, producing seeds with high contents of lipids, proteins, vitamins, and carbohydrates. Biological activities of different extracts of this species have already been evaluated by many researchers, including antioxidant, antitumoral, and antibacterial. In this work, the allelopathic activity of extracts from different Brazilian peanut cultivars against lettuce (Lactuca sativa) and two weed plants (Commelina benghalensis and Ipomoea nil) was studied. Aerial parts, roots, seeds, and seed coats were used for the preparation of crude extracts. Seed extract partitioning was performed with n-hexane, dichloromethane, ethyl acetate, n-butanol, and aqueous residue. Germination and growth of hypocotyls and rootlets were evaluated after one and five days of incubation with plant extracts, respectively. Crude seed extract and its dichloromethanic partition displayed highest allelopathic activity. These results contribute for the study of new potential natural herbicides.

Cryopreservation of Passiflora pohlii nodal segments and assessment of genetic stability of regenerated plants.

Passiflora pohlii is a wild species native to Brazil, with a potential agronomic interest due to its tolerance to soil-borne pathogens that cause damage to the passion fruit culture, and could be used in breeding. Because this species occurs in impacted regions, the goal of this study was the development of in vitro conservation strategies, using nodal segments from axenic plants. Encapsulation-vitrification and vitrification techniques were tested for cryopreservation of nodal segments. The highest recovery (65%) was obtained with the vitrification technique using treatment with the PVS3 vitrification solution from 30 to 120 min. Post-rewarming recovery was achieved on MSM medium supplemented with 30.8 µM BAP with incubation in the dark for 30 days before transfer in the presence of light. No differences were detected between control and cryopreserved materials as assayed by RAPD and ISSR.

Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1.

The imprinted expression of the IGF2 and H19 genes is controlled by the imprinting control region 1 (ICR1) located at chromosome 11p15.5. DNA methylation defects involving ICR1 result in two growth disorders with opposite phenotypes: an overgrowth disorder, the Beckwith-Wiedemann syndrome (maternal ICR1 hypermethylation in 10% of BWS cases) and a growth retardation disorder, the Silver-Russell syndrome (paternal ICR1 loss of methylation in 60% of SRS cases). In familial BWS, hypermethylation of ICR1 has been found in association with microdeletion of repetitive DNA motifs within ICR1 that bind the zinc finger protein CTCF; but more recently, ICR1 point mutations were described in BWS pedigrees. We present a case report of two brothers with BWS and prolonged post-pubertal growth resulting in very large stature. A maternally inherited point mutation was identified in ICR1 in both brothers, which altered binding of OCT transcription factors. The same mutation was present on the paternally inherited allele of their unaffected mother. This is a second report of a point mutation causing ICR1 hypermethylation by altering an OCT-binding motif. The atypical growth phenotype of the brothers may be connected to the unusual underlying cause of their BWS.

In vitro conservation of Passiflora suberosa L.: slow growth and cryopreservation.

Passiflora suberosa is a tropical species used as an ornamental, in popular medicine and in improvement programs. The goal of this study was the development of in vitro conservation strategies for this species, including medium-term storage through slow growth, and long-term storage through cryopreservation using vitrification-based techniques. Plants were maintained under slow growth conditions on half strength MSM or one quarter strength MSM medium for 12 months without decrease in regrowth ability. The efficiency of vitrification and encapsulation-vitrification protocols was compared in order to determine the optimal conditions for successful cryopreservation. Several parameters were evaluated, including pregrowth on medium with high sucrose concentrations, type of vitrification solution (PVS2 and PVS3), exposure time to vitrification solutions, and recovery conditions. The highest recovery was obtained with the encapsulation-vitrification protocol after a pretreatment with 0.3 M sucrose and post-cryopreservation incubation in the dark for 30 days on MSM medium supplemented with 0.44 micromole BA.

Conversion from intravenous insulin to subcutaneous insulin after cardiovascular surgery: transition to target study.

BACKGROUND: No study of transition from intravenous to subcutaneous insulin after cardiac surgery with dose based on percentage of intravenous total daily insulin (TDI) has reported a clearly superior regimen for achieving target blood glucose. We compared three first-dose transition strategies for insulin glargine: two based on TDI alone and one that also took body weight into account. METHODS: Mostly obese, type 1 and type 2 diabetes patients (n = 223) undergoing cardiac surgery were randomized to receive insulin glargine subcutaneously at 60% or 80% of TDI or in a dose based on TDI and body weight. RESULTS: Transition to subcutaneous insulin occurred 27.4 ± 6.6 h after surgery. Over the study period, mean proportion of blood glucose values within target range (80-140 mg/dL) were 0.34 ± 0.24, 0.35 ± 0.24, and 0.36 ± 0.22 in the 60% TDI, 80% TDI, and weight-based groups, respectively. This difference was not significant. Significantly more insulin corrections were needed in the 60% TDI group than in the weight-based group. There was only one incidence of hypoglycemia (blood glucose < 40 mg/dL). CONCLUSIONS: No subcutaneous insulin regimen implemented approximately 1 day after cardiac surgery showed significantly better control of blood glucose over the 3-day study period. Further studies are needed to determine optimal formulae for effecting an early transition to subcutaneous insulin after cardiac surgery or whether it is preferable and/or necessary to continue intravenous insulin therapy for an additional period of time.

Distinguishing among incretin-based therapies. Glucose-lowering effects of incretin-based therapies.

Extensive experience from randomized clinical trials demonstrates the efficacy of GLP-1 agonists and DPP-4 inhibitors as monotherapy and in combination with metformin and other agents, although reductions in FPG and PPG, and consequently A1C, are greater with GLP-1 agonists than with DPP-4 inhibitors. This difference may result from the pharmacologic levels of GLP-1 activity that are achieved with the GLP-1 agonists and their direct action on the GLP-1 receptor. The GLP-1 agonists have attributes that would make either of them an appropriate choice in the management of all 3 patients in our case studies, while either DPP-4 inhibitor would be an appropriate choice for Case 1. Differences in dosing, administration, safety, and tolerability should be considered.

Distinguishing among incretin-based therapies. Patient education and self-management.

Working closely with patients and providing ongoing education, ideally in conjunction with a diabetes care team, can help ensure that the best treatment options are selected for an individual patient and that the patient is capable of effective self-management.

Distinguishing among incretin-based therapies. Safety, tolerability, and nonglycemic effects of incretin-based therapies.

The overall safety profiles of GLP-1 agonists and DPP-4 inhibitors are favorable, with a low incidence of hypoglycemia. This attribute, along with their weight and cardiovascular benefits, particularly with the GLP-1 agonists, make them appropriate choices in our 3 patient cases. Ongoing safety investigations with GLP-1 agonists and DPP-4 inhibitors will provide further clarity to the complete safety profiles of these agents.

Distinguishing among incretin-based therapies. Pathophysiology of type 2 diabetes mellitus: potential role of incretin-based therapies.

The multifactorial nature of the pathogenesis of T2DM provides an opportunity to combine treatments that act upon different mechanisms. In addition to improving insulin resistance and pancreatic ß-cell dysfunction, the GLP-1 agonists and DPP-4 inhibitors improve the impaired incretin response, as well as increase insulin secretion and reduce glucagon secretion, both in a glucose-dependent manner. As a result of these multiple actions, the GLP-1 agonists and DPP-4 inhibitors lower both fasting and postprandial glucose levels. The effects of GLP-1 agonists tend to be greater, probably because they produce pharmacologic levels of GLP-1 compared to physiologic levels with the DPP-4 inhibitors. Another difference is that unlike the DPP-4 inhibitors, the GLP-1 agonists also slow gastric emptying and promote satiety.

Distinguishing among incretin-based therapies. Introduction.

The "treat to target" approach is to quickly achieve the target glycosylated hemoglobin (AIC) goal of <7% in most people, and then intensify or change therapy as needed to maintain glycemic control. Results of an online survey demonstrate uncertainty regarding the clinical differences between glucagon-like peptide (GLP-1) agonists and dipeptidyl peptidase (DPP)-4 inhibitors. The increasingly important roles of the GLP-1 agonists and DPP-4 inhibitors stem from their overall good efficacy and safety profiles compared with other treatment options.

Practical applications of therapy with a glucagon-like peptide-1 receptor agonist.

Patients such as ML represent a common challenge in the primary care management of patients with T2DM. After some response to initial therapy with lifestyle management and metformin, the A1C goal of <7.0% after 2 to 3 months was not achieved, necessitating the initiation of combination therapy. The 4 groups of medications recommended by the ADA/EASD panel as the preferred therapies are basal insulin, the sulfonylureas, the TZD pioglitazone, and GLP-1 receptor agonists. In addition to considering efficacy, safety, cost, and other medication-related factors, the treatment plan must take into account the patient's individual needs, concerns, and capabilities. These additional considerations help to foster increased patient self-management and greater treatment adherence. To achieve these objectives, comprehensive patient education is essential. The unique mechanism of action of the GLP-1 receptor agonist class of medications makes these agents a desirable choice as add-on therapy to metformin.

Effectiveness of the novel anti-diabetes medication exenatide in everyday practice: Comparison with clinical trials.

We evaluated effectiveness of exenatide in 81 unselected patients and compared the results with clinical trials. Patients achieved a similar reduction in A1C and lost more weight than patients in the clinical trials. Thirty-seven (46%) were treated off-label. Exenatide was effective on and off-label in this unselected patient group.

Cryopreservation of Arachis species by vitrification of in vitro-grown shoot apices and genetic stability of recovered plants.

A storage protocol at cryogenic temperature was established for shoot apices from in vitro plants of the cultivated groundnut (Arachis hypogaea) and wild Arachis species (A. retusa and A. burchellii) using a basic vitrification protocol with direct immersion in liquid nitrogen (LN). The effect of pre-treatments of donor-plants with ABA as well as of different supplements in the post-thaw culture medium was studied. After rapid warming at 40 C, the explants were cultured on MS medium devoid of growth regulators (MS0) or MS supplemented with 4.4(M benzylaminopurine (BAP) and 0.5(M naphthalene acetic acid (NAA) plus 5(M silver nitrate (AgNO3), 0.25% polyvinylpyrrolidone (PVP) or 0.2% activated charcoal. Non-frozen explants from the three species formed one shoot through meristematic amplification when cultured on MS0 medium. These explants also developed callus on MS supplemented with growth regulators (4.4(M BAP and 0.5(M NAA) alone or plus PVP or AgNO3. Callus formation was suppressed in the presence of activated charcoal. Post-thaw regeneration ocurred only through indirect organogenesis on media containing AgNO3 or PVP. Preculturing on medium supplemented with abscisic acid (ABA) improved regrowth rate in these media. Recovery failed to occur in the presence of activated charcoal. The genetic stability of shoots of A. burchellii originated from shoot apices was analyzed through Random Amplified Polymorphic DNA (RAPD) markers.

Cryopreservation of cultivated and wild Arachis species embryonic axes using desiccation and vitrification methods.

The effects of two methods of cryopreservation involving chemical vitrification and air desiccation) were studied on isolated embryonic axes of A. hypogaea. Vitrification with PVS2 and desiccation in a laminar flow cabinet resulted in high levels (70-90%) of whole plant recovery after cryopreservation. A desiccation protocol based on 1h exposure of explants to the air flow was successfully applied to six wild species of section Extranervosae, resulting in recovery levels of 70-90% after liquid nitrogen treatment.

Medical therapy of gonadotropin-producing and nonfunctioning pituitary adenomas.

Clinically nonfunctioning pituitary adenomas are one of the most common types of pituitary tumors. Unless they present with symptoms related to local mass effect, most tumors are detected incidentally when imaging studies are performed for other reasons. Although clinically nonfunctioning, most of these tumors have evidence, in vitro, of gonadotropin hormone or glycoprotein subunit production. The gonadotropins or their monomer submits rarely cause clinically identifiable effects. When these tumors present as macroadenomas, often with associated mass effect and hypopituitarism, primary therapy is neurosurgery. The role for medical therapy will be reviewed here.