Neonatal hyperglycemia alters the neurochemical profile,dendritic arborization and gene expression in the developing rat hippocampus

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long‐term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate‐HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe‐HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo ¹H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule‐associated protein (MAP)‐2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe‐HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP‐2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu‐Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long‐term hippocampus‐mediated cognitive deficits in human ELGANs.     

Balloon Retrograde Transvenous Obliteration Versus Endoscopic Cyanoacrylate in Bleeding Gastric Varices: Comparison of Rebleeding and Mortality with Extended Follow-up

Purpose

To assess short- and long-term mortality and rebleeding with endoscopic cyanoacrylate (EC) versus balloon-occluded retrograde transvenous obliteration (BRTO).

Topical henna ameliorated capecitabine-induced hand-foot syndrome

Background: Hand-foot syndrome (HFS) is the most frequently reported side effect of oral capecitabine therapy. In addition to treatment interruption and dose reduction, supportive treatments can help alleviate symptoms. Although its efficacy has not been proven in clinical studies, certain authors report on the use of prophylactic or therapeutic pyridoxine supplementation for the prevention of minimization to be useful in preventing worsening of HFS but are no substitute for dose modifications.

Case report: We report a case of an interesting observation in a patient with pancreatic cancer receiving capecitabine whose HFS was improved with the use of “henna”.

Discussion: Henna has been used for histories as a medicine, preservative, and cosmetic. Our case underlines the basis to further evaluate the anti-inflammatory, antipyretic, and analgesic effects of henna. We encourage other investigators to publish any similar cases or any other herbal or non-drug therapies. HFS is a common side effect of many drugs, including capecitabine, sorafinib and regorafenib. HFS is bothersome for patients even in low grades and impacts quality of life of patients. HFS cannot be prevented and currently the treatments aimed at controlling syndrome are not very effective. Exploring other potential treatment or management options such as henna is of high value.     

Erythropoietin,a novel repurposed drug: An innovative treatment for wound healing in patients with diabetes mellitus

Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional development costs. As the safety profile of a repurposed drug is already well known, any new investigations could then focus on its efficacy and other therapeutic benefits. Recombinant erythropoietin (EPO) is a potential candidate for repurposing because the results of numerous studies have shown that systemic and topical EPO is therapeutically beneficial when it is administered to healthy and diabetic animals with acute and chronic skin wounds and burns. Moreover, the molecular mechanisms of EPO's actions have been elucidated: EPO acts on those nonhematopoietic cells which are involved in the innate immune response where it promotes cellular proliferation and differentiation, exerts its cytoprotective actions, and inhibits apoptosis. In this review, the mechanism of EPO's action in skin wound healing is reviewed, and its potential for treating acute and chronic skin wounds and stimulating tissue regeneration in diabetic patients is discussed.     

Liver kinase B1 depletion from astrocytes worsens disease in a mouse model of multiple sclerosis

Liver kinase B1 (LKB1) is a ubiquitously expressed kinase involved in the regulation of cell metabolism, growth, and inflammatory activation. We previously reported that a single nucleotide polymorphism in the gene encoding LKB1 is a risk factor for multiple sclerosis (MS). Since astrocyte activation and metabolic function have important roles in regulating neuroinflammation and neuropathology, we examined the serine/threonine kinase LKB1 in astrocytes in a chronic experimental autoimmune encephalomyelitis mouse model of MS. To reduce LKB1, a heterozygous astrocyte-selective conditional knockout (het-cKO) model was used. While disease incidence was similar, disease severity was worsened in het-cKO mice. RNAseq analysis identified Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enriched in het-cKO mice relating to mitochondrial function, confirmed by alterations in mitochondrial complex proteins and reductions in mRNAs related to astrocyte metabolism. Enriched pathways included major histocompatibility class II genes, confirmed by increases in MHCII protein in spinal cord and cerebellum of het-cKO mice. We observed increased numbers of CD4+ Th17 cells and increased neuronal damage in spinal cords of het-cKO mice, associated with reduced expression of choline acetyltransferase, accumulation of immunoglobulin-γ, and reduced expression of factors involved in motor neuron survival. In vitro, LKB1-deficient astrocytes showed reduced metabolic function and increased inflammatory activation. These data suggest that metabolic dysfunction in astrocytes, in this case due to LKB1 deficiency, can exacerbate demyelinating disease by loss of metabolic support and increase in the inflammatory environment.     

Dose-dependent suppression by ethanol of transient auditory 40-Hz response

Rationale: Acute alcohol (ethanol) challenge is known to induce various cognitive disturbances, yet the neural basis of the effect is poorly known. The auditory transient evoked gamma-band (40-Hz) oscillatory responses have been suggested to be associated with various perceptual and cognitive functions in humans; however, alcohol effects on auditory 40-Hz responses have not been investigated to date. Objectives: The objective of the study was to test the dose-related impact of alcohol on auditory transient evoked 40-Hz responses during a selective-attention task. Methods: Ten healthy social drinkers ingested, in four separate sessions, 0.00, 0.25, 0.50, or 0.75 g/kg of 10% (v/v) alcohol solution. The order of the sessions was randomized and a double-blind procedure was employed. During a selective attention task, 300-Hz standard and 330-Hz deviant tones were presented to the left ear, and 1000-Hz standards and 1100-Hz deviants to the right ear of the subjects (P=0.425 for each standard, P=0.075 for each deviant). The subjects attended to a designated ear, and were to detect the deviants therein while ignoring tones to the other ear. Results: The auditory transient evoked 40-Hz responses elicited by both the attended and unattended standard tones were significantly suppressed by the 0.50 and 0.75 g/kg alcohol doses. Conclusions: Alcohol suppresses auditory transient evoked 40-Hz oscillations already with moderate blood alcohol concentrations. Given the putative role of gamma-band oscillations in cognition, this finding could be associated with certain alcohol-induced cognitive deficits. Received: 20 January 1999 / Final version: 9 August 1999     

Temporal integration: intentional sound discrimination does not modulate stimulus-driven processes in auditory event synthesis

Objective: Our previous study showed that the auditory context could influence whether two successive acoustic changes occurring within the temporal integration window (approximately 200 ms) were pre-attentively encoded as a single auditory event or as two discrete events (Cogn Brain Res 12 (2001) 431). The aim of the current study was to assess whether top-down processes could influence the stimulus-driven processes in determining what constitutes an auditory event.Methods: Electroencepholagram (EEG) was recorded from 11 scalp electrodes to frequently occurring standard and infrequently occurring deviant sounds. Within the stimulus blocks, deviants either occurred only in pairs (successive feature changes) or both singly and in pairs. Event-related potential indices of change and target detection, the mismatch negativity (MMN) and the N2b component, respectively, were compared with the simultaneously measured performance in discriminating the deviants.Results: Even though subjects could voluntarily distinguish the two successive auditory feature changes from each other, which was also indicated by the elicitation of the N2b target-detection response, top-down processes did not modify the event organization reflected by the MMN response.Conclusions: Top-down processes can extract elemental auditory information from a single integrated acoustic event, but the extraction occurs at a later processing stage than the one whose outcome is indexed by MMN.Significance: Initial processes of auditory event-formation are fully governed by the context within which the sounds occur. Perception of the deviants as two separate sound events (the top-down effects) did not change the initial neural representation of the same deviants as one event (indexed by the MMN), without a corresponding change in the stimulus-driven sound organization.     

Chronic mesenteric ischaemia: 28-year experience of endovascular treatment

Objective

To report the outcomes associated with endovascular therapy for patients with chronic mesenteric ischemia (CMI).

Methods

A retrospective review of patients who underwent endovascular therapy for CMI between April 1981 and September 2009 at a single institution was performed. Procedural details, mesenteric arteries treated, technical and clinical success rates, outcomes per patient and per vessel were assessed.

Results

In 166 patients treatment was attempted using a variety of balloon and stent platforms during the 28-year period. The technical success rate was 97% per patient and 94% per vessel. The technical success rate of stenting (99.4%) was higher than for percutaneous transluminal angioplasty (PTA; 86%; P = 0.0001). Immediate clinical improvement was seen in 146 out of 166 (88.2%). The type of guidewire or device platform, brachial vs. femoral artery access, balloon and/or stent diameters used, and stenosis vs. occlusion had no statistical impact on mortality or the primary patency of any mesenteric artery outcomes. The outcome of the superior mesenteric artery (SMA) with PTA appears to be superior to that of stenting (P = 0.014).

Conclusion

Technical success rates are improved with the use of stents; however, PTA use in the SMA seems to offer better primary patency rates.

Key Points

• Superior mesenteric artery (SMA) stenosis is often responsible for ischaemic symptoms.

• Treatment with percutaneous transluminal angioplasty (PTA) seems superior to stenting

• Although technical success rates are improved with the use of stents.

• Higher mortality in the elderly and those presenting with nausea/vomiting/bloody stools.

     

FDG PET/CT imaging in the diagnosis of osteomyelitis in the diabetic foot

Purpose

Osteomyelitis, the most serious complication of the diabetic foot, occurs in about 20?% of patients. Early diagnosis is crucial. Appropriate treatment will avoid or decrease the likelihood of amputation. The objective of this study was to assess the value of FDG PET/CT in diabetic patients with clinically suspected osteomyelitis.

Methods

Enrolled in this prospective study were 39 consecutive diabetic patients (29 men and 10 women, mean age 57?years, range 28–71?years) with 46 suspected sites of foot infection. Of these 39 patients, 38 had type 2 and 1 type 1 diabetes for 4–25?years, and 28 were receiving treatment with insulin. FDG PET/CT was interpreted for the presence, intensity (SUVmax) and localization of increased FDG foci. Final diagnosis was based on histopathology and bacteriology of surgical samples, or clinical and imaging follow-up.

Results

Osteomyelitis was correctly diagnosed in 18 and excluded in 21 sites. Of 20 lesions with focal bone FDG uptake, 2 were false-positive with no further evidence of osteomyelitis. Five sites of diffuse FDG uptake involving more than one bone on CT were correctly diagnosed as diabetic osteoarthropathy. FDG PET/CT had a sensitivity, specificity and accuracy of 100?%, 92?% and 95?% in a patient-based analysis and 100?%, 93?% and 96?% in a lesion-based analysis, respectively, for the diagnosis of osteomyelitis in the diabetic foot.

Conclusion

FDG PET/CT was found to have high performance indices for evaluation of the diabetic foot. The PET component identified FDG-avid foci in sites of acute infection which were precisely localized on fused PET/CT images allowing correct differentiation between osteomyelitis and soft-tissue infection.     

Ablation of cholesterol biosynthesis in neural stem cells increases their VEGF expression and angiogenesis but causes neuron apoptosis

Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain, the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed. Here we have conditionally ablated the activity of squalene synthase (SQS), a key enzyme for endogenous cholesterol production, in the neural stem and progenitor cells of the ventricular zone (VZ) of the embryonic mouse brain. Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers, and died at birth. Analyses of the E11.5–E15.5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons, implying that this progeny of the SQS-ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival. Interestingly, the neural stem and progenitor cells of the VZ, the primary target of SQS inactivation, did not undergo significant apoptosis. Instead, vascular endothelial growth factor (VEGF) expression in these cells was strongly upregulated via a hypoxia-inducible factor-1–independent pathway, and angiogenesis in the VZ was increased. Consistent with an increased supply of lipoproteins to these cells, the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated. Our study establishes a direct link between intracellular cholesterol levels, VEGF expression, and angiogenesis. Moreover, our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis.