Effects of Chronic Morphine Treatment on Β-Endorphin-Related Peptides in the Caudal Medulla and Spinal Cord

The effects of chronic morphine treatment on Β-endorphin (ΒE)-immunoreactive (ΒE-ir) peptide levels were determined in the rat caudal medulla and different areas of the spinal cord. Seven days of morphine pelleting had no effect on total ΒE-ir peptides in the caudal medulla. In contrast, it significantly increased ΒE-ir peptide concentrations in the cervical and thoracic regions of the spinal cord compared with placebo-pelleted controls, whereas in the lumbosacral region this trend did not reach statistical significance. Injections of the opiate receptor antagonist naloxone 1 h before the rats were killed had no effect on the morphine-induced increases in the cord. Chromatographic analyses revealed that enzymatic processing of ΒE-related peptides in the spinal cord seemed unaffected by the morphine and/or naloxone treatments. In light of previous data showing that morphine down-regulates ΒE biosynthesis in the hypothalamus, the present results suggest that the regulation of ΒE-ir peptides in the spinal cord is distinct from that found in other CNS areas. These data provide support for previous results suggesting that ΒE-expressing neurons may be intrinsic to the spinal cord.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65660/1/j.1471-4159.1993.tb03518.x.pd

Immunocytochemistry of the C-terminal peptide of propressophysin (CPP): Relationship to vasopressin, oxytocin and neurophysin

Arginine-vasopressin (AVP) and its associated neurophysin (AVP-NP) are synthesized via a precursor, propressophysin, which also contains a 39 amino acid glycopeptide at its C-terminus (C-terminus of propressophysin, or CPP). In the present study, immunocytochemical techniques were used to determine the cellular co-localization of CPP with AVP, oxytocin (OXY), AVP-NP and OXY-NP in the rat hypothalamus using colchicine pre-treatment and serial 5 [mu]m section analysis. Extensive cross-competition studies of antisera raised against each peptide with the various antigens yielded no significant crossreactivity of the CPP, AVP, OXY and NP antisera. The NP antiserum, although directed against both AVP-NP and OXY-NP, demonstrated a preference for OXY-NP at a dilution of 1:20,000. CPP and AVP were always co-localized within the same magnocellular neurons of the supraoptic, paraventricular and circularis nuclei, and further showed very similar patterning in the suprachiasmatic nucleus as well. In conrast, no cellular overlap could be detected between CPP and OXY, in any of the above nuclei (the suprachiasmatic nucleus is devoid of OXY). Likewise, no examples of co-localization of CPP and OXY-NP were found in the magnocellular nuclei. These results are in strong agreement with a biosynthetic relationship between CPP, AVP and AVP-NP, and their separateness from the OXY and OXY-NP precursor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25176/1/0000615.pd

Mesenteric panniculitis of the sigmoid colon: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Mesenteric panniculitis of the sigmoid colon is a rare occurrence in surgical practice. The aim of this article is to present a case of mesenteric panniculitis of the sigmoid colon and a short review of the literature.</p> <p>Case presentation</p> <p>We reviewed the hospital record of a 63-year-old man who presented with a palpable mass in the left abdomen and clinical signs of a partial bowel obstruction. The pre-operative impression was a possible cancer of the sigmoid colon. A laparotomy was performed through a midline incision. The mesentery was found to be markedly thickened, constricted and puckered. The normal architecture of the adipose tissue had been lost and replaced with an irregular nodular mass. The microscopic pathologic sections demonstrated a chronic reactive inflammatory process with an exuberant proliferation of fibroblasts and fibrocytes. The adipose tissue contained scattered areas of steatonecrosis with foci of lipid-laden macrophages, lymphocytes and plasma cells. The sigmoid colon and its mesocolon were resected. The postoperative course was uneventful and the patient was discharged in good condition, and followed up for the next two years.</p> <p>Conclusion</p> <p>Mesenteric panniculitis of sigmoid is an extremely rare entity of unknown origin in which the normal architecture of the mesentery is replaced by fibrosis, necrosis and calcification. On gross examination the alterations may be mistaken for a neoplastic process. A frozen section may be necessary for confirmation of the diagnosis. When the advanced inflammatory changes became irreversible and bowel obstruction occurs, resection may be indicated.</p

Pre- and Posttranslational Regulation of Β-Endorphin Biosynthesis in the CNS: Effects of Chronic Naltrexone Treatment

There appear to be two anatomically distinct Β-endorphin (ΒE) pathways in the brain, the major one originating in the arcuate nucleus of the hypothalamus and a smaller one in the area of the nucleus tractus solitarius (NTS) of the caudal medulla. Previous studies have shown that these two proopiomelanocortin (POMC) systems may be differentially regulated by chronic morphine treatment, with arcuate cells down-regulated and NTS cells unaffected. In the present experiments, we examined the effects of chronic opiate antagonist treatment on ΒE biosynthesis across different CNS regions to assess whether the arcuate POMC system would be regulated in the opposite direction to that seen after opiate agonist treatment and to determine whether different ΒE-containing areas might be differentially regulated. Male adult rats were administered naltrexone (NTX) by various routes for 8 days (subcutaneous pellets, osmotic minipumps, or repeated intraperitoneal injections). Brain and spinal cord regions were assayed for total ΒE-ir, different molecular weight immunoreactive Β-endorphin (ΒE-ir) peptides, and POMC mRNA. Chronic NTX treatment, regardless of the route of administration, reduced total ΒE-ir concentrations by 30–40% in diencephalic areas (the arcuate nucleus, the remaining hypothalamus, and the thalamus) and the midbrain, but had no effect on ΒE-ir in the NTS or any region of the spinal cord. At the same time, NTX pelleting increased POMC mRNA levels in the arcuate to ∼ 140% of control values. These data suggest that arcuate POMC neurons are up-regulated after chronic NTX treatment (whereas NTS and spinal cord systems remain unaffected) and that they appear to be under tonic inhibition by endogenous opioids. Chromatographic analyses demonstrated that, after chronic NTX pelleting, the ratio of full length ΒE 1–31 to more processed ΒE-ir peptides (i.e., ΒE 1–27 and ΒE 1–26 ) tended to increase in a dose-dependent manner in diencephalic areas. Because ΒE 1–31 is the only POMC product that possesses opioid agonist properties, and ΒE 1–27 has been posited to function as an endogenous anatgonist of ΒE 1–31 , the NTX-induced changes in the relative concentrations of ΒE 1–31 and ΒE 1–27 /ΒE 1–26 may represent a novel regulatory mechanism of POMC cells to alter the opioid signal in the synapse.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65603/1/j.1471-4159.1993.tb05820.x.pd

Capacitative calcium influx and proliferation of human osteoblastic-like MG-63 cells

Adult bone tissue is continuously being remodelled and bone mass is maintained by a balance between osteoclastic bone resorption and osteoblastic bone formation. Alteration of osteoblastic cell proliferation may account in part for lack of balance between these two processes in bone loss of osteoporosis. There is calcium (Ca2+) control in numerous cellular functions; however, involvement of capacitative Ca2+ entry (CCE) in proliferation of bone cells is less well investigated. OBJECTIVES: The study described here was aimed to investigate roles of CCE in the proliferation of osteoblast-like MG-63 cells. MATERIALS AND METHODS: Pharmacological characterizations of CCE were undertaken in parallel, with evaluation of the expression of transient receptor potential canonical (TRPC) channels and of cell proliferation. RESULTS: Intracellular Ca2+ store depletion by thapsigargin induced CCE in MG-63 cells; this was characterized by a rapid transient increase of intracellular Ca2+ followed by significant CCE, induced by conditions that stimulated cell proliferation, namely serum and platelet-derived growth factor. Inhibitors of store-operated Ca2+ channels (2-APB and SKF-96365) prevented CCE, while voltage-dependent Ca2+ channel blockers had no effect. Expression of various TRPC channels was shown in the cells, some having been shown to be responsible for CCE. Voltage-dependent Ca2+ channel blockers had no effect on osteoblast proliferation while thapsigargin, 2-APB and SKF-96395, inhibited it. Cell cycle analysis showed that 2-APB and SKF-96395 lengthen the S and G2/M phases, which would account for the reduction in cell proliferation. CONCLUSIONS: Our results indicate that CCE, likely attributed to the activation of TRPCs, might be the main route for Ca2+ influx involved in osteoblast proliferation

Traumatic brain injury as a risk factor for Alzheimer disease. Comparison of two retrospective autopsy cohorts with evaluation of ApoE genotype

BACKGROUND AND PURPOSE: The impact of traumatic brain injury (TBI) on the pathogenesis of Alzheimer disease (AD) is still controversial. The aim of our retrospective autopsy study was to assess the impact of TBE and ApoE allele frequency on the development of AD. MATERIAL AND METHODS: We examined 1. the incidence of AD pathology (Braak stageing, CERAD, NIA-Reagan Institute criteria) in 58 consecutive patients (mean age ± SD 77.0 ± 6.8 years) with residual closed TBI lesions, and 2. the frequency of TBI residuals in 57 age-matched autopsy proven AD cases. In both series, ApoE was evaluated from archival paraffin-embedded brain material. RESULTS: 1. TBE series: 12.1 % showed definite and 10.3% probable AD (mean age 77.6 and 75.2 years), only 2/13 with ApoEε3/4. From 45 (77.6%) non-AD cases (mean age 78.2 years), 3 had ApoEε3/4. The prevalence of 22.4% AD in this small autopsy cohort was significantly higher than 3.3% in a recent large clinical series and 14% in the general population over age 70. 2. In the AD cohort with ApoEε4 allele frequency of 30% similar to other AD series, residuals of closed TBI were seen in 4 brains (7%) (mean age ± SD 78.2 ± 6.4), all lacking the ApoEε4 allele. TBI incidence was slightly lower than 8.5% in the clinical MIRAGE study. CONCLUSIONS: The results of this first retrospective autopsy study of TBI, ApoEε allele frequency, and AD confirm clinical studies suggesting severe TBI to be a risk factor for the development AD higher in subjects lacking ApoEε4 alleles. Further studies in larger autopsy series are needed to elucidate the relationship between TBI, genetic predisposition, and AD

A phase-field model for phase transformations in glass-forming alloys

A phase-field model is proposed for phase transformations in glass-forming alloys. The glass transition is introduced as a structural relaxation, and the competition between the glass and crystalline phases is investigated. The simulations are performed for Cu-Zr alloys, employing thermodynamic and kinetic parameters derived from reported thermodynamic modeling and molecular dynamics simulation results,[1–3] respectively. Four distinct phase fields are treated with a multi-phase-field approach, representing the liquid/glass, Cu10Zr7, CuZr, and CuZr2 phases. In addition, a continuum-field method is applied to the liquid to accommodate the liquid–glass transformation. The combined phase-field approach is used to investigate the glass formation tendency, and critical cooling rates are estimated and compared with the reported experimental values

All-d-Enantiomer of β-Amyloid Peptide Forms Ion Channels in Lipid Bilayers

Alzheimer’s disease (AD) is the most common type of senile dementia in aging populations. Amyloid β (Aβ)-mediated dysregulation of ionic homeostasis is the prevailing underlying mechanism leading to synaptic degeneration and neuronal death. Aβ-dependent ionic dysregulation most likely occurs either directly via unregulated ionic transport through the membrane or indirectly via Aβ binding to cell membrane receptors and subsequent opening of existing ion channels or transporters. Receptor binding is expected to involve a high degree of stereospecificity. Here, we investigated whether an Aβ peptide enantiomer, whose entire sequence consists of d-amino acids, can form ion-conducting channels; these channels can directly mediate Aβ effects even in the absence of receptor–peptide interactions. Using complementary approaches of planar lipid bilayer (PLB) electrophysiological recordings and molecular dynamics (MD) simulations, we show that the d-Aβ isomer exhibits ion conductance behavior in the bilayer indistinguishable from that described earlier for the l-Aβ isomer. The d isomer forms channel-like pores with heterogeneous ionic conductance similar to the l-Aβ isomer channels, and the d-isomer channel conductance is blocked by Zn2+, a known blocker of l-Aβ isomer channels. MD simulations further verify formation of β-barrel-like Aβ channels with d- and l-isomers, illustrating that both d- and l-Aβ barrels can conduct cations. The calculated values of the single-channel conductance are approximately in the range of the experimental values. These findings are in agreement with amyloids forming Ca2+ leaking, unregulated channels in AD, and suggest that Aβ toxicity is mediated through a receptor-independent, nonstereoselective mechanism

Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention

Age-related increases in prevalent dementia over the next 30–40 years risk collapsing medical resources or radically altering the way we treat patients. Better prevention of dementia therefore needs to be one of our highest medical priorities. We propose a perspective on the pathological basis of dementia based on a cerebrovascular-Alzheimer disease spectrum that provides a more powerful explanatory framework when considering the impact of possible public health interventions. With this in mind, a synthesis of evidence from basic, clinical and epidemiological studies indeed suggests that the enhanced treatment of hypertension could be effective for the primary prevention of dementia of either Alzheimer or vascular etiology. In particular, we focus on candidate preventative mechanisms, including reduced cerebrovascular disease, disruption of hypoxia-dependent amyloidogenesis and the potential neuroprotective properties of calcium channel blockers. Following the successful translation of large, long-term and resource-intense trials in cardiology into improved vascular health outcomes in many countries, new multinational prevention trials with dementia-related primary outcomes are now urgently required