Biomedical subjects

S M Jackson

Publications and source records attributed to S M Jackson.

At least 55 records · Page 3Linked to original sources

PubMed1994

Identification of a 6-base pair element involved in the sterol-mediated transcriptional regulation of farnesyl diphosphate synthase.

Previous studies identified a 115-base pair (bp) region of the farnesyl diphosphate (FPP) synthase promoter which is involved in the transcriptional regulation of this gene by sterols (Spear, D. H., Kutsunai, S. Y., Correll, C. C., and Edwards, P. A. (1992) J. Biol. Chem. 267, 14462-14469). In the current study we fused a 117-bp fragment, containing this region of interest, upstream of the heterologous minimal promoter of the herpes simplex virus thymidine kinase gene linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Chinese hamster ovary (CHO) cells were stably transfected with this fusion gene and incubated in the absence or presence of sterols. Analysis of CAT mRNA by primer extension indicated that transcription of the fusion gene was under sterol-mediated control. Thus, when cellular sterols were present, the CAT mRNA levels were reduced 2-4-fold. To further localize the FPP synthase sterol-responsive element(s), additional promoter-reporter gene constructs containing either deletions or mutations were constructed and transfected into CHO or CV-1 cells. These studies localized a 6-bp region (ATTGGC) that is required for both transcriptional induction in the absence of sterols and transcriptional repression in the presence of sterols. Gel shift and footprinting analyses demonstrated that nuclear proteins isolated from CHO cells bound to six distinct regions of the promoter between nucleotides -293 to -47. Taken together, these results further define both the cis-acting elements controlling normal transcription of the FPP synthase gene and identify a novel sequence involved in sterol regulation.

Alkyl and Aryl Transferases↗

PubMed1994

Adjuvant systemic therapy and survival after breast cancer.

BACKGROUND AND METHODS: We examined the effect of adjuvant systemic therapy on survival after breast cancer among the residents of the Canadian province of British Columbia. Data on survival were collected for all women in whom breast cancer was diagnosed in British Columbia during each of three calendar years chosen to represent different province-wide treatment recommendations: 1974, when no adjuvant systemic therapy was recommended; 1980, when adjuvant chemotherapy was recommended only for premenopausal women with node-positive disease; and 1984, when adjuvant chemotherapy was also recommended for premenopausal women with node-negative disease and lymphatic, vascular, or neural invasion and tamoxifen was recommended for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neural invasion unless their tumors were negative for estrogen receptors. RESULTS: For women less than 50 years of age, disease-specific survival at seven years (i.e., with censoring of data on women who died from causes other than breast cancer) improved from 65.2 to 76.3 percent between 1974 and 1984 (P = 0.008), and overall survival improved from 64.8 to 74.6 percent (P = 0.02). For women from 50 through 89 years of age, disease-specific survival at seven years improved from 62.5 to 70.4 percent between 1980 and 1984 (P = 0.001), and overall survival improved from 53.9 to 58.3 percent (P = 0.05). The timing of the improvements in survival correlated with the introduction of adjuvant systemic therapy in each group. CONCLUSIONS: Survival among women with breast cancer improved significantly in a geographically defined population during the period when adjuvant systemic therapy became widely used.

Adult↗

PubMed1994

Impact of laparoscopic cholecystectomy on the management of cholelithiasis in children with sickle cell disease.

Children with sickle cell disease, well known to have a high incidence of cholelithiasis, are frequently admitted to the hospital for episodes of abdominal pain. Before the advent of laparoscopy, few children with sickle cell and cholelithiasis underwent cholecystectomy unless absolutely necessary, because of the high morbidity of an open cholecystectomy (OC). We reviewed our records of all children with sickle cell disease and cholelithiasis treated from 1985 to 1992 to investigate the impact of laparoscopic cholecystectomy (LC). During that period, 32 children underwent cholecystectomy: 10 OC and 22 LC (all since December 1990). Before December 1990, all children had either classic biliary tract symptoms or abdominal pain of unknown etiology. However, of the 22 LC children, five had asymptomatic cholelithiasis. Only three of the 32 patients had choledocholithiasis, although 30 of 32 had elevated total bilirubins. Two LC children presented with choledocholithiasis and were initially treated with endoscopic sphincterotomy and stent placement. A standard intraoperative cholangiogram (IOC) through the cystic duct was performed in all OC cases. In 19 of 22 LC cases, an IOC through the gallbladder was performed before any dissection; unsuspected choledocholithiasis was not found, but the IOC did allow visualization of the course of the cystic duct, facilitating its subsequent dissection. Total operative length was comparable between the two groups, but the LC patients' postoperative length of stay was half that of the OC patients (2.1 v 4.6 days). Postoperative complications in the OC group included three children who had severe pain, atelectasis, fever, and hypoxemia (30%).

Adolescent↗

PubMed1994

Pain in children and adolescents with sickle cell anemia: a prospective study utilizing self-reporting.

PURPOSE: The purpose of this study was to characterize pain reporting among children with sickle cell anemia (SCA) experiencing painful vaso-occlusive crises. These patients were managed according to a protocol based on self-reports of pain. PATIENTS AND METHODS: Seventeen children (3-18 years) with SCA (Hb SS) who were admitted for painful crisis were asked to report their pain according to a rating scale of 0-5. These pain scores were analyzed according to the Mann-Whitney method to determine differences in pain reporting among young children (3-12 years) and adolescents (13-18 years). The Kruskal-Wallis method was utilized to determine relationships between the number of painful body sites, reported pain scores, and length of hospital stay. RESULTS: Children (3-12 years) reported significantly less severe pain than adolescents (13-18 years) (p < 0.01). The severity of pain reported was not related to the number of painful sites. However, the length of stay was significantly longer in patients with greater numbers of painful sites (p < 0.05). Patients who reported pain scores of > 2 at 24 h had significantly longer periods of hospitalization. CONCLUSION: A protocol based upon self-reports of pain was successfully utilized to provide analgesia during painful crises. There were characteristic differences between young children and adolescents in self-reporting of pain. Pain scores may be helpful in predicting length of hospitalization for painful crises.

Adolescent↗

PubMed1994

Role of exogenous oxygen in cutaneous barrier repair.

Occlusion of the skin with a water-vapor-impermeable membrane following disruption of the permeability barrier prevents the epidermal changes which lead to the restoration of barrier function, suggesting that water transit could be an important regulatory signal for barrier repair. However, occlusion with a water-vapor-impermeable membrane also prevents the movement of gases, which could also potentially influence permeability barrier homeostasis. Since O2 is known to have an effect on epidermal cell function, we have determined the effect of gases containing different levels of O2 on barrier repair 6 h following topical treatment of hairless mice with acetone. The disrupted barrier of air-exposed animals (O2 approximately 20%) recovered by 50.8 +/- 3.4% (mean +/- SEM) after 6 h. Under flowing air (O2 approximately 20%), O2/CO2 95/5% and argon (O2 = 0%) the barrier recovered by 43.9 +/- 28, 36.2 +/- 8.5 and 39.2 +/- 4.6%, respectively. These values were not statistically different from each other. The slightly lower levels of recovery at 6 h with the flowing gases in comparison to exposure to static air probably can be attributed to a slight cooling of the skin caused by the flowing gases. These results suggest that exogenous O2 is neither required for barrier repair nor a signal for barrier repair.

Animals↗

PubMed1994

Antiplatelet and antithrombotic efficacy of DMP 728, a novel platelet GPIIb/IIIa receptor antagonist.

BACKGROUND: Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus, we have identified a systemically active peptide analogue (DMP 728) of the arginine-glycine-aspartic acid (RGD) recognition sequence that mediates the binding of ligands such as fibrinogen to the platelet glycoprotein (GP) IIb/IIIa receptors. The goals of the present study were to determine the antiplatelet and antithrombotic efficacies of DMP 728 in various arterial thrombosis models. METHODS AND RESULTS: DMP 728 demonstrated antiplatelet efficacy in vitro in inhibiting ADP-induced human platelet aggregation (IC50, 46 +/- 2 nmol/L) and fibrinogen binding to human platelets (IC50, 2.3 +/- 0.8 nmol/L) or purified human GPIIb/IIIa receptors (IC50, 0.6 +/- 0.1 nmol/L). DMP 728 demonstrated high affinity and specificity for human platelet GPIIb/IIIa over other adhesion molecules. In anesthetized mongrel dogs, DMP 728 at 0.001 to 1.0 mg/kg IV produced dose-dependent antiplatelet effects in inhibiting ex vivo platelet aggregation induced by ADP and in prolonging template bleeding time. DMP 728 effects on bleeding time prolongation were more rapidly reversible than those on platelet aggregation inhibition. A maximal antiplatelet effect for DMP 728 was demonstrated at 0.01 mg/kg IV bolus. The antithrombotic efficacy of DMP 728 was examined in vitro and in vivo after IV administration at different doses in various models of arterial thrombosis. In the coronary artery Folts model in dogs, DMP 728 demonstrated maximal antithrombotic efficacy at 0.01 mg/kg IV bolus with an ED50 of 0.005 mg/kg IV bolus in inhibiting cyclic flow reductions. Additionally, DMP 728 demonstrated 100% prevention of primary thrombosis and rethrombosis (P < .01) after treatment with different thrombolytics, including tissue plasminogen activator and streptokinase, in an electrolytically induced femoral artery thrombosis model in dogs. CONCLUSIONS: Acute intravenous DMP 728 administration (0.001 to 1.0 mg/kg) has dose-dependent antiplatelet and antithrombotic effects in different arterial thrombosis models. These data suggest that DMP 728, a low-molecular-weight GPIIb/IIIa receptor antagonist, may have therapeutic potential as an effective antithrombotic agent in coronary and peripheral artery thromboembolic disorders.

Angina, Unstable↗

PubMed1994

Permeability barrier requirements regulate epidermal beta-glucocerebrosidase.

The intercellular spaces of the outermost layers of the epidermis (stratum corneum, SC) of terrestrial mammals contain a mixture of lipids, enriched in ceramides that are critical for the epidermal permeability barrier. Whereas glucosylceramides (GlcCer) are synthesized in abundance in the epidermis, they disappear coincident with an increase of ceramides (Cer) in the SC. Hence, hydrolysis of GlcCer to Cer by beta-glucocerebrosidase (GlcCer'ase), may be required for permeability barrier homeostasis. We determined first whether modulations in epidermal GlcCer'ase activity and mRNA levels occur in response to barrier disruption; and second, how GlcCer'ase inhibitors influence barrier function and SC membrane ultrastructure. Barrier disruption significantly increased epidermal GlcCer'ase mRNA levels, with a 2.8-fold increase over untreated control levels at 8 h (P < 0.01). GlcCer'ase activity was increased in whole epidermis (34%; P < 0.02) 24 h after barrier disruption. Localization of GlcCer'ase activity showed an increase (33%; P < 0.05) in the outer epidermis (SC and stratum granulosum), without a change in lower epidermal activity (stratum spinosum and stratum basale). Furthermore, a single topical application of the GlcCer'ase inhibitor, bromoconduritol-B-epoxide (BrCBE), inhibited enzyme activity (98%) and significantly delayed permeability barrier recovery after acetone treatment. In addition, BrCBE treatment disrupted SC intercellular lamellar bilayers, without evidence of cellular toxicity. These results indicate that epidermal processing of GlcCer to Cer by GlcCer'ase is required for barrier homeostasis, and that this important enzymatic step is regulated by barrier requirements.

Acetone↗

PubMed1994

Bone marrow transplantation for sickle cell anemia.

PURPOSE: To investigate the role of bone marrow transplantation in patients with severe sickle cell anemia (SCA). PATIENTS AND METHODS: We have designed a protocol for selecting patients with severe SCA who may benefit from bone marrow transplantation (BMT). On the basis of this protocol, a girl 3 9/12 years of age who had severe recurrent pain crises and splenic dysfunction received a BMT from her brother, who is homozygous for hemoglobin A. RESULTS: Transplantation resulted in prompt engraftment, followed by durable hematologic and immunologic reconstitution with donor cells. One year after BMT, the patient continued to do well. She did not experience any graft versus host disease, her growth velocity increased, and recovery of splenic function was demonstrated. Since undergoing BMT, she has not experienced any painful crises. CONCLUSIONS: Bone marrow transplantation is an effective therapeutic modality that should be considered in patients with severe SCA.

Anemia, Sickle Cell↗

PubMed1993

Gel electrophoresis of individual cells to quantify hypoxic fraction in human breast cancers.

A new gel electrophoresis method has been used to quantify hypoxic fraction in human tumors. Radiation-induced DNA damage was measured in individual tumor cells, where the radiobiologically hypoxic cells were observed as a subpopulation showing a 3-fold reduction in DNA strand breaks. Patients receiving palliative radiotherapy for breast cancers were given a single dose of 5-10 Gy, and a fine needle aspiration biopsy was taken immediately after irradiation. Hypoxic cells were detected in seven of eight tumors. In four tumors, bivariate analyses of DNA content versus DNA damage to individual cells allowed distinction between the response of diploid normal cells and aneuploid tumor cells. These early results indicate that "comet assay" shows considerable promise for resolving the extent and significance of hypoxia in human tumors.

Adult↗

PubMed1993

Helix-loop-helix proteins are present and differentially expressed in different cell lines from the anterior pituitary.

The basic-helix-loop-helix (bHLH) class of transcriptional activators, important in the establishment of many different cell lineages, share two important properties: the ability to heterodimerize with other members of this family and to bind DNA containing the loose consensus sequence CANNTG. This study takes advantage of these shared characteristics to begin to address whether or not bHLH proteins are present in pituitary cells. Gel-shift and Southwestern assays using an oligonucleotide containing a bHLH binding consensus sequence demonstrate that pituitary-specific proteins are present in extracts from adult pituitary tissue and pituitary cell lines and bind specifically to this sequence. Pituitary extracts were also found to contain several factors which interact with Id protein, a negative regulator of bHLH activity, in Far-Western assays of protein-protein interactions. Finally, messenger RNA for Id is present in pituitary cell lines but is absent in adult pituitary tissue. Together, these studies indicate that bHLH proteins are present in pituitary cells and their levels are differentially regulated in the separate cell types.

Animals↗

PubMed1993

Acute chest syndrome in sickle cell disease: CT evidence of microvascular occlusion.

Patients with sickle cell disease often develop acute chest syndrome (ACS). Signs of ACS include chest pain, fever, prostration, and pulmonary opacities. Pneumonia and infarction have been implicated in the pathogenesis of this syndrome. Infarction as a result of microvascular occlusion and pneumonia are not easily differentiated with chest radiography or ventilation-perfusion scintigraphy. The authors evaluated the ability of thin section (3-mm) chest computed tomography (CT) to help diagnose microvascular occlusion in ACS and thus help differentiate two of its most likely causes. CT scans of the chest of 10 patients with moderate to severe ACS were retrospectively reviewed by two observers, who listed the number of bronchopulmonary segments showing consolidation; areas of ground-glass attenuation due to early hemorrhagic edema; and paucity or absence of small vessels, arterioles, and venules. In all patients, the degree of hypoxia was out of proportion to the extent of consolidation evident at chest radiography. The CT scans showed microvascular occlusion and areas of ground-glass attenuation in nine patients. Infection was ruled out in eight patients. High-resolution CT may play an important role in the initial evaluation and timely selection of an appropriate treatment regimen aimed at improving tissue perfusion, thus forestalling irreversible organ damage and chronic pulmonary arterial hypertension in patients with sickle cell disease.

Acute Disease↗

PubMed1993

Pathobiology of the stratum corneum.

The epidermis is a dynamic system whose metabolic activity is regulated in large part by the integrity of the permeability barrier. This barrier resides in the stratum corneum and comprises a unique 2-compartment system of structural protein-enriched corneocytes embedded in a lipid-enriched intercellular matrix. Lipid extraction or metabolic imbalances, such as essential fatty acid deficiency, produce barrier abnormalities that in turn result in epidermal hyperproliferation, scaling, and inflammation. When the barrier remains intact, lipid imbalances, such as an abnormal cholesterol sulfate:cholesterol ratio in recessive X-linked ichthyosis, can lead to abnormal corneocyte adhesion (visible scale). Both cellular and intercellular proteins also participate in normal desquamation, and protein abnormalities may provoke abnormal scaling (such as filaggrin in ichthyosis vulgaris). Thus, perturbations of the stratum corneum may be the catalyst for a number of skin diseases, rather than the end result of processes that are initiated in subjacent skin layers.

Cell Membrane Permeability↗

PubMed1992

Interaction of basal positive and negative transcription elements controls repression of the proximal rat prolactin promoter in nonpituitary cells.

The proximal rat prolactin (rPRL) promoter contains three cell-specific elements, designated footprints I, III, and IV, which restrict rPRL gene expression to anterior pituitary lactotroph cells. Footprint II (-130 to -120) binds a factor, which we have termed F2F, present in pituitary and nonpituitary cell types. Here we demonstrate that a key role of the footprint II site is to inhibit rPRL promoter activity in nonpituitary cells, specifically, by interfering with the basal activating function of a vicinal element. Gene transfer analysis revealed 20-fold activation of the rPRL promoter in nonpituitary cell types when footprint II was either deleted or specifically mutated. Similar activation of the intact rPRL promoter was obtained by in vivo F2F titration studies. In GH4 rat pituitary cells, the footprint II inhibitory activity was masked by the redundant, positively acting cell-specific elements and was inhibitory only if the two upstream sites, footprints III and IV, were deleted. Deletion of the -112 to -80 region in the footprint II site-specific mutant background resulted in complete loss of rPRL promoter activity in both pituitary and nonpituitary cell types, mapping a basal activating element that is operative irrespective of cell type to this region. While the basal activating element imparted an activating function in a heterologous promoter assay, the footprint II sequence did not display any inherent repressor function and actually induced several minimal heterologous promoters. However, the inhibitory activity of the footprint II site was detected only if it was in context with the basal activating element. These data underscore the importance of ubiquitous activating and inhibitory factors in establishing cell-specific gene expression and further emphasize the complexity of the molecular mechanisms which restrict gene expression to specific cell types. We provide a novel paradigm to study rPRL promoter function and hormone responsiveness independently of lactotroph cell-specific requirements.

Animals↗

PubMed1992

Cutaneous barrier perturbation stimulates cytokine production in the epidermis of mice.

The disruption of the cutaneous permeability barrier results in metabolic events that ultimately restore barrier function. These include increased epidermal sterol, fatty acid, and sphingolipid synthesis, as well as increased epidermal DNA synthesis. Because tumor necrosis factor (TNF) and other cytokines are known products of keratinocytes and have been shown to modulate lipid and DNA synthesis in other systems, their levels were examined in two acute models and one chronic model of barrier perturbation in hairless mice. Acute barrier disruption with acetone results in a 72% increase in epidermal TNF 2.5 h after treatment, as determined by Western blotting. Furthermore, epidermal TNF mRNA was elevated ninefold over controls 2.5 h after acetone treatment. This elevation in TNF mRNA was maximal at 1 h after acetone, and decreased to control levels by 8 h. After tape stripping, a second acute model of barrier disruption that avoids application of potentially toxic chemicals, TNF mRNA was elevated fivefold over controls at 2.5 h. Moreover, the mRNA levels for epidermal IL-1 alpha, IL-1 beta, and granulocyte macrophage-colony-stimulating factor (GM-CSF) also were elevated several-fold over controls, after either acetone treatment or tape stripping, but their kinetics differed. GM-CSF mRNA reached a maximal level at 1 h after acetone, while IL-1 alpha and IL-1 beta were maximal at 4 h after treatment. In contrast, mRNAs encoding IL-6 and IFN gamma were not detected either in control murine epidermis or in samples obtained at various times after tape stripping or acetone treatment. The relationship of the cytokine response to barrier function is further strengthened by results obtained in essential fatty acid deficient mice. In this chronic model of barrier perturbation mRNA levels for epidermal TNF, IL-1 alpha, IL-1 beta, and GM-CSF were each elevated several-fold over controls. These results suggest that epidermal cytokine production is increased after barrier disruption and may play a role in restoring the cutaneous permeability barrier.

Animals↗

PubMed1992

Cyclic adenosine 3',5'-monophosphate activation of the rat prolactin promoter is restricted to the pituitary-specific cell type.

Pituitary lactotroph cell function and PRL gene expression are highly regulated by the cAMP-protein kinase-A (PKA) pathway. To further our understanding of the molecular mechanisms by which cAMP/PKA regulates rat (r) PRL promoter activity and to determine whether cAMP regulation is cell type specific, we 1) transected intact (-425), internal and 5'-deletion, and site-specific mutants of the rPRL promoter ligated to the firefly luciferase reporter gene into both pituitary and nonpituitary cell lines; and 2) assessed the role of the cAMP-cAMP response element-binding protein (CREB) pathway in GH4 rat pituitary cells. The data show that deleting the rPRL promoter from -425 to -116 did not abolish cAMP regulation, implying that proximal elements, such as the basal transcription element (-112/-80) or the pituitary-specific footprint (FP) I (-67/-45), mediate the cAMP response. However, nucleotide changes within FP I or FP II (-130/-120) did not alter the rPRL promoter response to 1 microM forskolin (FSK), despite the 77% and 26% reductions in basal rPRL promoter activity caused by these mutations, respectively. Furthermore, internal deletion of either the basal transcription element of FP I element also failed to affect cAMP regulation of the rPRL promoter, again despite the 90% and 93% reductions in basal promoter activity by these deletions, respectively. Since these internal deletion constructs otherwise contain rPRL promoter sequences from -425 to +73, including the up-stream pituitary-specific FPs III and IV, the data suggest that any one of these cell-specific elements is capable of imparting cAMP regulation to the proximal rPRL promoter. To directly test the implication that the cAMP response of the rPRL promoter is restricted to the pituitary-specific cell type, we took advantage of a 5'-deletion mutant truncated at position -116 and a FP II site-specific mutant, since constructs containing these rPRL promoters are active in nonpituitary cells. Despite the 6.6- and 18.5-fold stimulations over wild-type rPRL promoter activity in nonpituitary cells, respectively, these mutations remained completely unresponsive to FSK treatment. To document that the cAMP-CREB pathway was functional in GC/GH4 rat pituitary cells, CREB was affinity purified from GC rat pituitary cells, and DNase-I protection studies showed that it does not bind to the proximal rPRL promoter. Also, the human glycoprotein alpha-subunit promoter was induced 10-fold by FSK in GH4 rat pituitary cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1992

The use of sequential fine-needle aspiration biopsy with flow cytometry to monitor radiation induced changes in breast carcinoma.

Thirteen patients with locally advanced or recurrent breast carcinoma were monitored during radiation therapy by multiple, sequential, fine-needle aspiration biopsies (FNAB) with flow cytometry. The material was analyzed for qualitative cytomorphological evidence of radiation effect and for DNA content and cell cycle alterations. DNA ploidy was not affected by the radiation therapy, although the aneuploid tumors showed an increased frequency of cell cycle alterations. The most common change seen was an increase in S-G2M (58%). Other changes included a decrease in the proliferative/growth fraction (17%) and no significant redistribution of cells (25%). There was a relationship between the initial proliferative activity of the tumors and the type of cell cycle change which occurred. Flow cytometric analysis was a better predictor of early clinical response than was cytomorphological assessment. Sequential FNAB with flow cytometry is an effective method of monitoring the response of breast cancer to radiation therapy.

Biopsy, Needle↗

PubMed1992

Effect of cutaneous permeability barrier disruption on HMG-CoA reductase, LDL receptor, and apolipoprotein E mRNA levels in the epidermis of hairless mice.

Disruption of the permeability barrier results in an increase in cholesterol synthesis in the epidermis. Inhibition of cholesterol synthesis impairs the repair and maintenance of barrier function. The increase in epidermal cholesterol synthesis after barrier disruption is due to an increase in the activity of epidermal HMG-CoA (3-hydroxy-3-methylglutaryl CoA) reductase. To determine the mechanism for this increase in enzyme activity, in the present study we have shown by Western blot analysis that there is a 1.5-fold increase in the mass of HMG-CoA reductase after acute disruption of the barrier with acetone. In a chronic model of barrier disruption, essential fatty acid deficiency, there is a 3-fold increase in the mass of HMG-CoA reductase. Northern blot analysis demonstrated that after acute barrier disruption with acetone or tape-stripping, epidermal HMG-CoA reductase mRNA levels are increased. In essential fatty acid deficiency, epidermal HMG-CoA reductase mRNA levels are increased 3-fold. Thus, both acute and chronic barrier disruption result in increases in epidermal HMG-CoA reductase mRNA levels which could account for the increase in HMG-CoA reductase mass and activity. Additionally, both acute and chronic barrier disruption increase the number of low density lipoprotein (LDL) receptors and LDL receptor mRNA levels in the epidermis. Moreover, epidermal apolipoprotein E mRNA levels are increased by both acute and chronic perturbations in the barrier. Increases in these proteins in response to barrier disruption may allow for increased lipid synthesis and transport between cells and facilitate barrier repair.

Acetone↗

PubMed1991

Lipids, proteins and corneocyte adhesion.

Three factors were examined for their relative contribution to corneocyte cohesion in normal adult pig ear: (1) extracellular lipids derived from membrane-coating granules (MCG); (2) corneosomes (modified stratum corneum desmosomes); and (3) corneocyte covalently bound lipid envelopes. Cohesion strength of the outer stratum corneum was measured directly by cohesometry, then altered by removing MCG lipids with solvents of varying potency. Cohesion changes were related to degree of lipid removal and ultrastructural alterations. Trypsin was also used to see if proteolysis of corneosomes promoted squame shedding. Potent solvents increased cohesion in relation to the amount of MCG lipid extracted. Tighter cohesion was due to fusion of the outer leaflets from covalently bound lipid envelopes on adjacent corneocytes. However, lipid envelopes are unlikely to mediate normal stratum corneum cohesion since MCG lipids play a significant anti-cohesive role preventing their apposition. Mild solvents partially removed MCG lipids causing a slight decrease in cohesion compared with untreated samples. This suggests a minor cohesive role for MCG lipids, consistent with maintaining their barrier function. We believe that corneosomes are the major determinant of stratum corneum cohesiveness because, in untreated skin, both cohesion and the number of corneosomes increased from the surface towards the granular layer. Furthermore, corneosome digestion with trypsin induced superficial squame shedding.

Animals↗