Vesicular Changes Research Articles

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing(NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

Mitochondria Directed Oxidative Stress and Metal Abnormalities at the Center of Alzheimer’s Disease

For nearly four decades, our research has focused on dissecting the cytopathology of Alzheimer’s disease (AD) with the goal of developing a cure. We have used oxidative stress as a window to view and understand AD. Oxidative damage to sugars, proteins, lipids, and nucleic acids increases in neuronal cytoplasm. The same neuronal compartment has increased redoxactive iron and copper, which can catalyze oxidative damage, and likely derive from mitochondrial debris (in and outside lysosomes) including cytochromes, mitochondria-specific prosthetic groups, and mtDNA. Mitochondria show altered axonal transport, size distribution, energetics, fusion/fission, and degradation in AD that correlate with the extent of oxidative damage suggesting they are the origin. Synaptic mitochondria abnormalities correlate with synaptic vesicular changes. Surprisingly, amyloidβ and tau are quantitatively associated with reduced neuronal oxidative damage. Copper sequestration by amyloidβ blocks copper-mediated oxidation of lipids and vitamin C indicating amyloidβ can be a protective response rather than the initiator of AD. Instead of being bound to amyloidβ, iron is present as 10nm magnetite crystals with super-paramagnetic properties as well as abundant metallic iron, along with metallic copper. This is the first report of metallic iron and copper in humans. Not just amyloidβ, but also tau, may be protective responses induced in AD to maintain neurons with altered balance for decades. While these studies put oxidative stress at the center of AD, they also highlight a complexity of multifaceted alterations that is homeostatic and requires a deeper level of understanding before an effective cure.

Effects of probiotic fermented milk on management of obesity studied in high-fat-diet induced obese rat model

The current study aimed to explore the hypothesis that probiotic bacteria are significantly involved in the control of obesity using Wistar rats as the test group by feeding high fat diets (HFD) induced obesity. A total of four groups of rats were considered viz., normal pellet diet fed (NC), HFD fed (DC), HFD fed rats treated with probiotic fermented milk with soy protein isolate (SPI) and whey protein concentrate (WPC) (T1), HFD fed rats treated with probiotic fermented milk without WPC and SPI (T2). Body weight, abdominal fat weight, liver weight, serum Alanine aminotransferase level, and alkaline phosphatase level significantly (p < 0.05) decreased after giving daily probiotic milk product supplementation with @ 2 ml per day for continuous 4 weeks. Whereas, C-reactive protein and Aspartate aminotransferase levels were not altered to a significant extent. The histology of the liver from the disease model group showed large lipid vacuoles deposited in the parenchyma cells. Product T2 confirmed fewer micro vesicular fatty changes and the appearance of T2 was better than T1. Overall, the in vivo study results indicated that the probiotic fermented milk exerted a better anti-obesity effect.Graphical

BRIGATINIB INDUCED PHOTOSENSITIVITY

<h3>Introduction</h3> Drug-induced photosensitivity is suspected when dermatitis develops in a sun-exposed distribution. Reactions occur by phototoxic, photoallergic, or immune-mediated mechanisms. Brigatinib is an oral tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer. It causes skin rash in 24-40% of patients but is rarely linked with photosensitivity. We present a case of blistering dermatitis suspected secondary to brigatinib. <h3>Case Description</h3> A 65-year-old female with metastatic non-small cell lung cancer on brigatinib for one month presented with a pruritic maculopapular rash without systemic findings. She denied other symptoms or recent illnesses. Vitamin D supplement was the only other medication. Exam was notable for a maculopapular erythematous, partially blanchable rash in a malar distribution, a "V" pattern on the upper chest, flexor surface of arms, dorsal surface of hands with vesicular changes, and erythema of the vaginal labia. Laboratory workup was unremarkable including unchanged chronic mild transaminitis and no peripheral eosinophilia. The rash resolved with brigatinib cessation and mild to moderate potency topical corticosteroids over 2-3 weeks. A month later, brigatinib was reintroduced with sun exposure precautions and without recurrence of rash. <h3>Discussion</h3> We describe a case of suspected photosensitivity drug rash temporally related to use of brigatinib. Photosensitivity has been reported with signal transduction inhibitors, but only one other report is found in literature for brigatinib currently. Given the importance of treatment for this patient, brigatinib was reintroduced at full dose one month following the episode, with careful instructions regarding sun exposure, without rash recurrence.

Protective effect of ethanolic extract of Actinoscirpus grossus tubers against ethanol induced liver toxicity in albino rats

Liver detoxifies majority of chemicals and plays an important role in the maintenance of homeostasis of the body. In the recent years due to overwhelming use of drugs and alcohol there is an increased incidence of liver toxicities. The tubers of Actinoscirpus grossus are used in liver disease as a liver tonic in folklore medicine; However, there is no experimental basis for its therapeutic use. Hence the present study was conducted to evaluate the hepatoprotective potentials of ethanolic extract of Actinoscirpus grossus tubers in ethanol induced hepatotoxicity in albino rats. Daily administration of 20% ethanol v/v p.o. at a dose of 5 g/kg for 30 consecutive days caused significant liver toxicity and there after maintained for 15 consecutive days with normal rat pellet and water ad libitum. The treatment groups were administered with group specific drugs for 15 consecutive days after 30 days of ethanol administration and control group rats were maintained for 15 consecutive days with normal rat pellet and water ad libitum. Liver toxicity was assessed on 45th day by estimating biochemical, histological and antioxidant level. Daily administration of 20% ethanol significantly increased liver enzymes and caused oxidative stress by increase in the lipid peroxidation and reduction in the catalase and glutathione peroxidase activity in liver homogenate. The histopathological examination revealed micro vesicular and macro vesicular fatty changes predominantly with mild periportal inflammation, cell infiltrate and areas of mild dilatation of sinusoids with ballooning degeneration of hepatocytes. Treatment with ethanolic extract of A. grossus tuber significantly restored the liver enzymes especially SGOT and attenuated elevated lipid peroxidation and restored catalase and glutathione peroxidase activity. The histopathological changes revealed significant reduction in the hepatocyte ballooning portal fibrosis. Thus, tubers of A. grossus plant may serve as reservoir of natural products having diverse functions and could be utilised as a potent hepatoprotective agent.

Integrated analysis of proteome and transcriptome changes in the mucopolysaccharidosis type VII mouse hippocampus.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by the deficiency of β-glucuronidase. In this study, we compared the changes relative to normal littermates in the proteome and transcriptome of the hippocampus in the C57Bl/6 mouse model of MPS VII, which has well-documented histopathological and neurodegenerative changes. A completely different set of significant changes between normal and MPS VII littermates were found in each assay. Nevertheless, the functional annotation terms generated by the two methods showed agreement in many of the processes, which also corresponded to known pathology associated with the disease. Additionally, assay-specific changes were found, which in the proteomic analysis included mitochondria, energy generation, and cytoskeletal differences in the mutant, while the transcriptome differences included immune, vesicular, and extracellular matrix changes. In addition, the transcriptomic changes in the mutant hippocampus were concordant with those in a MPS VII mouse caused by the same mutation but on a different background inbred strain.

Landolt ring-shaped epithelial keratopathy: a novel clinical entity of the cornea.

Landolt ring-shaped epithelial keratopathy is a newly identified disease with vesicular changes of unknown origin in the epithelial cells. Eleven Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium were assessed. The main symptoms of Landolt ring-shaped epithelial keratopathy are foreign-body sensation and photophobia. Slitlamp examination indicates that Landolt ring-shaped lesions located only in the corneal epithelium are randomly distributed and occur unilaterally, bilaterally, or asymmetrically. Small lesions are sometimes connected to each other to form a large Landolt ring in a fractal pattern. Confocal microscopy reveals that the Landolt ring lesions are vesicular changes in the epithelial cells from the basal cell layer to the superficial cell layer without inflammation. The lesions form for weeks to months with sporadic exacerbations and natural remissions with or without treatments. The outcomes do not include epithelial disorders in the affected corneas or visual disruptions. We describe a new disease entity of unknown origin referred to as Landolt ring-shaped epithelial keratopathy, which is usually bilateral and characterized by specific Landolt ring-shaped focal epithelial lesions with vesicular changes only in the epithelial cells. The disorder has an insidious onset and self-limiting nature despite treatment and should be included in the differential diagnosis of corneal epithelial disorders.

Clinical features and phylogenetic analysis of Coxsackievirus A9 in Northern Taiwan in 2011

BackgroundCoxsackievirus A9 (CA9) was one of the most prevalent serotype of enteroviral infections in Taiwan in 2011. After several patient series were reported in the 1960s and 1970s, few studies have focused on the clinical manifestations of CA9 infections. Our study explores and deepens the current understanding of CA9.MethodsWe analyzed the clinical presentations of 100 culture-proven CA9-infected patients in 2011 by reviewing their medical records and depicted the CA9 phylogenetic tree.ResultsOf the 100 patients with culture-proven CA9 infections, the mean (SD) age was 4.6 (3.4) years and the male to female ratio was 1.9. For clinical manifestations, 96 patients (96%) had fever and the mean (SD) duration of fever was 5.9 (3.4) days. Sixty one patients (61%) developed a skin rash, and the predominant pattern was a generalized non-itchy maculopapular rash without vesicular changes. While most patients showed injected throat, oral ulcers were found in only 19 cases (19%), among whom, 6 were diagnosed as herpangina. Complicated cases included: aseptic meningitis (n=8), bronchopneumonia (n=6), acute cerebellitis (n=1), and polio-like syndrome (n=1). Phylogenetic analysis for current CA9 strains is closest to the CA9 isolate 27-YN-2008 from the border area of mainland China and Myanmar.ConclusionsThe most common feature of CA9 during the 2011 epidemic in Taiwan is generalized febrile exanthema rather than herpangina or hand, foot, and mouth disease. Given that prolonged fever and some complications are possible, caution should be advised in assessing patients as well as in predicting the clinical course.

Histopathological analysis of vesicular and bullous lesions in Kaposi sarcoma

BackgroundIn this study, the clinical and morphological features of vesiculobullous lesions observed in Kaposi sarcoma are analyzed, and the features of bullous Kaposi sarcoma cases are emphasized.MethodsA total of 178 biopsy materials of 75 cases diagnosed as classic-type cutaneous Kaposi sarcoma were reviewed. Twenty-five cases showing vesiculobullous features were included in the study. Tumor, epidermis, dermis, and clinical data regarding these cases was evaluated.ResultsVesicular changes were observed in 21 (12%) out of 178 lesions of the 75 cases, while bullous changes were present in only 4 (2%). In all cases where vesicular and bullous changes were detected, tumor, epidermis, and dermis changes were similar. All cases were nodular stage KS lesions, whereas hyperkeratosis and serum exudation in the epidermis, marked edema in the dermis, and enlarged lymphatic vessels and chronic inflammatory response were observed.ConclusionsOur findings suggest that changes in vascular resistance occurring during tumor progression are the most important factors comprising vesiculobullous morphology.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1646397188748474

IL28B polymorphism is associated with fatty change in the liver of chronic hepatitis C patients

Several single nucleotide polymorphisms (SNPs) within the interleukin 28B (IL28B) locus are associated with sustained viral response in chronic hepatitis C (HCV) patients who were treated with pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Recently, an association between γ-GTP level and IL28B genotype was identified. In this study, the relationship between IL28B genotype and liver steatosis was analyzed. One hundred fifty-three patients who underwent liver biopsy before PEG-IFN plus RBV combination therapy were enrolled. The level of liver steatosis was measured using a BIOREVO BZ-9000 microscope, and the proportion of fatty change and clear cell change were calculated using Dynamic cell count BZ-H1C software. IL28B SNP genotype (rs8099917) was determined using the Invader Assay. Vesicular change was significantly associated with body mass index (BMI), HCV RNA titer, serum aspartate aminotransferase, γ-GTP, IL28B genotype and liver fibrosis level (P < 0.05). Clear cell change was significantly associated with serum aspartate aminotransferase, γ-GTP and IL28B genotype by univariate logistic regression analysis (P < 0.05). Under multiple logistic regression, IL28B genotype (OR(adj) = 8.158; 95% CI 2.412-27.589), liver fibrosis (OR(adj) = 2.541; 95% CI 1.040-6.207) and BMI (OR(adj) = 1.147; 95% CI 1.011-1.301) were significant independent factors for vesicular change and IL28B genotype (OR(adj) = 3.000; 95% CI 1.282-7.019) for clear cell change. In this study, a new quantitative method to objectively evaluate hepatic steatosis was described. IL28B genotypes were significantly associated with both vesicular and clear cell changes of livers in chronic hepatitis C patients.

Duration dependent effect of intravenous heroin intake on morphological changes in the liver

Intravenous heroin intake leads to significant morphological changes in the liver tissue (vesicular changes, fatty changes, chronic hepatitis and cirrhosis). The intensity of these changes increases with the duration of heroin use. Direct hepatotoxic effects of heroin are vesicular changes in hepatocytes, fatty changes are the result of chronic influence of alcohol, whereas the rest of the morphological liver lesions are the result of the interaction of heroin, viral infection and alcohol. In the present study, we analyzed a total of 50 autopsies, 40 from the group of intravenous heroin users and 10 from the control group (dead bodies of young and healthy people with mechanical injuries that did not affect the liver). For ease of analysis, all autopsy cases of intravenous heroin abuse were divided into 4 groups according to the duration of intravenous heroin intake: up to 2 years, between 2 and 5 years, between 5 and 10 years, and longer than 10 years.

Amyloidosis, change in macrophage number, and dysplasia in the liver of intravenous heroin users

Apart from the usual morphological changes in the liver of intravenous heroin users such as vesicular and fatty changes, various forms of viral hepatitis and development of cirrhosis, the onset of amyloidosis, the change in the number of hepatic sinusoidal macrophages, and dysplastic changes are of particular significance from the forensic point of view since they can indicate heroin abuse, probably associated with alcohol effects, and they can also be a factor for the occurrence of severe morphological liver damage with a possible lethal outcome. A histopathologic and morphometric study of changes in the liver of heroin users aimed to show the presence of rarer morphologic changes in the liver as the indicators of heroin abuse, additional alcohol effects and viral infections. The present study included 40 autopsies of intravenous heroin users and 10 control autopsies. In order to facilitate the investigation, all autopsies of intravenous heroin users were grouped according to the duration of intravenous heroin intake into 4 groups: up to 2 years, 2-5 years; 5-10 years; over 10 years. Paraffin sections 5 µm thick, were stained by hematoxylin method (HE), van Gieson and Congo red. Morphometric investigation of sinusoidal macrophages in the liver was done using the M42 test system. Liver tissue samples taken to be tested for ultrastructural changes were fixed in glutaraldehyde and epon-embedded, and the analysis was done using transmission electron microscopy JEM 100 CX JEOL. Amyloidosis localized in portal tracts, mostly underneath the endothelium of the smaller branches of the hepatic artery was established in 9 cases (22,5%), out of which in 78% (in 7 of 9) the duration of intravenous intake lasted longer than 5 years. In 55,5% of cases (in 5 of 9), amyloidosis was associated with fatty alcohol changes. There was a statistically significant change in the number of sinusoidal macrophages in relation to the controls only in cases with chronic active hepatitis regardless of coexisting cirrhosis, whereas the other cases with established fatty alcohol changes showed no significantly higher number of these cells in relation to controls. Severe dysplastic changes were established in three cases with vesicular and fatty changes complicated with viral hepatitis, two of which were with coexisting cirrhosis; in all three cases (100%), the duration of intravenous heroin abuse lasted longer than 5 years. Long duration of heroin abuse is a condition for the occurrence of liver amyloidosis and dysplastic changes in the liver. The high percentage of association of amyloidosis with fatty alcohol changes in the liver points to the conclusion that the inactivation of hepatic sinusoid macrophages and the reduction of their enzymatic capacities occur due to additive, immunosuppressive effect of alcohol which may enable the onset of liver amyloidosis.

Ultrastructural changes in the liver of intravenous heroin addicts.

The ultrastructural research has a decisive role in gathering the knowledge on the liver's response to the influence of some drugs. The aim of the study was to perform an ultrastructural analysis of the liver in chronic intravenous heroin addicts.The study involved the autopsy conducted on 40 bodies of intravenous heroin addicts and 10 control autopsies. The liver tissue was fixed in glutaraldehyde and moulded with epon for investigation purposes of ultrastructural changes. The analysis was performed using the method of transmission electron microscopy.In the group of intravenous heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic active and persistent hepatitis, cirrhosis, reduction in the amount of glycogen in hepatocytes, as well as the Kupffer cell's dominant hypertrophy. Various changes occur in organelles, plasma membrane of hepatocytes and biliary channels as well as in the nucleus. The most important ultrastructural findings include: hyperplasia and hypertrophy of the smooth endoplasmic reticulum, which is histologically proven vesicular degeneration of hepatocyte occurring as a result of the increased synthesis of enzymes of smooth endoplasmic reticulum due to chronic intravenous heroin intake, and the presence of continuous basal membrane followed by transformation of the sinusoids into capillaries (in the cases of chronic active hepatitis and cirrhosis) which leads to a disorder of microcirculation and further progress of cirrhosis.

Evaluation of morphological changes of the liver caused by heroin abuse in forensic practice

A study of morphological lesions in the liver of heroin addicts enables a precise overview of the type and degree of the liver damages caused by intravenous (i.v.) heroin abuse, additive effects of viral infections and alcohol consumption, as well as whether the expressiveness of these lesions depends on the duration of the time period of heroin application. The aim of the study was to investigate histopathological, ultrastructural and morphometric features of the liver of heroin addicts in forensic samples of the liver. The study involved the autopsy conducted on 40 bodies of i.v. heroin addicts and 10 control autopsies. The investigated group consisted of liver samples of 36 male subjects and 4 female subjects aged 35-40 years and the control group of 8 male and 2 female cadaveric bodies aged 15-35 years. The liver tissue samples were prepared for light microscopy. Sections of the tissue paraffin blocks 5 micro thick were stained using classical Hematoxylin and Eosin method (H&E), as well as PAS Van Gieson, Gomori, and Congo Red techniques. For investigation purposes of ultrastructural changes, liver tissue was fixed in glutaraldehyde and molded with epon. The analysis was performed using the method of transmission electron microscopy. Morphometric investigation of the liver sinusoidal macrophages was performed by using the M42 test system. In the investigated group of i.v. heroin addicts, the liver autopsy samples showed degenerative vesicular and fat changes, chronic hepatitis, cirrhosis, sedimentation of pathologic protein amyloidosis, dysplastic changes, reduction in the amount of glycogen in hepatocytes, as well as the change in the number of Kupfer and endothelial cells. The established changes correlated with the duration of i.v. heroin abuse, whereas sinusoidal macrophages were activated in cases with active hepatitis, and no significant change in their number was found in hepatocytes with alcohol-related fatty changes. CONCLUSION. The study showed that the most present change in the hepatocytes of drug addicts was vesicular degeneration, and it is the only direct consequence of the effect of heroin. Other morphological changes were present due to viral infections and they correlated with the duration of narcotic abuse. The finding of dysplastic changes in this susceptible population of young people is particularly significant. The forensic significance of the established changes in the liver tissue is in the possibility of their practical application for determination of the immediate cause of death of i.v. heroin addicts, as well as the differential diagnosis of not only heroin, but also alcohol, sedative and other substances abuse, and all that on the basis of morphological damages of the liver.

Simultaneous Optical-Electrical Measurement of the Delay between formation of the Fusion Pore and Proton Equilibration in Exocytosis of Single Vesicles

Optical detetction of neutralization of pH in granules or vesicles is often used to define exocytotic events. However, combined measurents of ensemble capacitance and pH-dependent vesicular fluorescence changes have suggested that the movement of protons only becomes possible after fusion pore expansion with a mean delay of > 300 ms (1). To enhance the temporal resolution of such measurements, we have combined capacitance recordings of single vesicle fusion in RBL cells transfected with synapthpHluorin as a reporter of vesicular pH. To monitor cell capacitance steps due to exocytosis of single granules in whole cell patch-clamp mode, we used the piecewise linear technique. Internal solution contained 10 μM free Ca2+ and 300 μM GTPγS.View Large Image | View Hi-Res Image | Download PowerPoint Slide Before establishing whole cell recordings, punctate fluorescence signals could be detected with excitation at 460 nm, while during perfusion with internal solution and excitation at 480 nm, punctate fluorescence signals gradually appeared at corresponding sites. Fluorescence increases clearly lagged capacitance steps by several 100 ms- seconds, supporting the idea that pH equilibration through the fusion pore is delayed.(1) Barg et al.: Neuron, 33, 287-299, 2002.

Targeted Surface-Enhanced Raman Scattering Nanosensors for Whole-Cell pH Imagery

In this paper the ability to develop a gold-core, silver-shell surface-enhanced Raman scattering (SERS) nanosensor that has both a targeting component as well as a sensing component is demonstrated. The nanosensor is capable of targeting through the FcepsilonRI receptor-mediated endocytic pathway due to the adsorption of 2,4-epsilon-dinitrophenol-L-lysine (DNP) ligand on the nanoparticle surface. The nanosensor is also sensitive to pH changes in the endocytic vesicle within the pH range of 4.5-7.5 by 4-mercaptopyridine (4-MPy) adsorbed to the particle surface. The targeting and sensing moieties do not significantly interfere with each other's function. The sensing component of the nanosensor is calibrated with in vivo measurements of rat basophil leukemia (RBL-2H3) cells in standard buffer solutions using the ionophore nigericin, which serves to equilibrate the external [H(+)] concentration with that of the cell compartments. The targeting of the nanosensor is verified with a beta-hexosaminidase assay. It is also demonstrated that the targeted nanosensor is capable of making accurate cellular pH measurements in RBL-2H3 cells, out to ninety minutes after targeted nanosensor addition. Whole-cell, time-lapse, hyperspectral image cubes demonstrating endocytic vesicular pH changes during FcepsilonRI receptor mediated endocytosis are demonstrated.

Fatal Autoimmune Hepatitis Induced by Concurrent Loss of Naturally Arising Regulatory T Cells and PD-1-Mediated Signaling

Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

Common pediatric and adolescent skin conditions

Skin lesions are encountered in all areas of medicine, and it is therefore important for physicians to understand the fundamentals of explaining and diagnosing common skin conditions. This article begins with a discussion of description and documentation of skin lesions based on color, size, morphology, and distribution. Pigmentation disorders such as vitiligo are depicted. Cutaneous growths that are found in the pediatric and adolescent population include acrochordons, dermatofibromas, keloids, milia, neurofibromas, and pyogenic granulomas. Treatment of these growths usually involves observation or curettage with electrodessication. Psoriasis, atopic dermatitis, poison ivy, and eczema are comprised of scaling patches and plaques; poison ivy and atopic dermatitis may also present with bullous and vesicular changes. Therapy typically consists of topical emollients and corticosteroids; phototherapy is reserved for refractory cases. Acne vulgaris is the most common skin disease of the pediatric and adolescent population. This condition can be psychologically debilitating and, therefore, proper treatment is of paramount importance. Therapeutic options include topical as well as oral antibiotics and retinoids. Extreme caution must be used when prescribing retinoids to post-pubescent females, as these agents are teratogenic. Vascular anomalies are most commonly exemplified as port wine stains and hemangiomas. Port wine stains may be treated with pulsed dye laser or may be observed if they are not of concern to the patient or physician. Hemangiomas typically spontaneously regress by age ten; however, there has been recent concern that certain cases may need to be treated. Dermal rashes may be localized or generalized. Treatment of generalized drug eruptions involves elimination of the inciting agent, topical antipruritics, and systemic corticosteroids for severe reactions. Infectious etiologic agents of skin disease include bacteria, fungi, and viruses. Many sexually transmitted diseases are bacterial or viral in origin and present as a rash or ulcer. Impetigo is a bacterial infection which may present as a bullous eruption or as an erosion with a honey colored crust. Other bacterial infections include erythema chronicum migrans, folliculitis, and cellulitis. Fungal infections include the various forms of tinea and are usually treated with topical antifungals; if the infection is located in a hair-bearing area, systemic antifungals are necessary. Viral infections include warts, varicella, molluscum contagiosum, and herpes. Treatment varies from observation or antivirals for varicella to cryosurgery and topical imiquimod for warts. Finally, scabies and lice are infectious agents that can be treated with permethrin and pyrethrin solutions.

Secretory Vesicular Transport from the Golgi Is Altered during ATP-binding Cassette Protein A1 (ABCA1)-mediated Cholesterol Efflux

Apolipoprotein AI (apoAI)-mediated cholesterol efflux is a process by which cells export excess cellular cholesterol to apoAI to form high density lipoprotein. ATP-binding cassette protein A1 (ABCA1) has recently been identified as the key regulator of this process. The pathways of intracellular cholesterol transport during efflux are largely unknown nor is the molecular mechanism by which ABCA1 governs cholesterol efflux well understood. Here, we report that, in both macrophages and fibroblasts, the secretory vesicular transport changes in response to apoAI-mediated cholesterol efflux. Vesicular transport from the Golgi to the plasma membrane increased 2-fold during efflux. This increase in vesicular transport during efflux was observed in both raft-poor and raft-rich vesicle populations originated from the Golgi. Importantly, enhanced vesicular transport in response to apoAI is absent in Tangier fibroblasts, a cell type with deficient cholesterol efflux due to functional ABCA1 mutations. These findings are consistent with an efflux model whereby cholesterol is transported from the storage site to the plasma membrane via the Golgi. ABCA1 may influence cholesterol efflux in part by enhancing vesicular trafficking from the Golgi to the plasma membrane.

Immune attack on the schwann cell surface in acute inflammatory demyelinating polyneuropathy

The localization, mode of action, and roles of complement in the Guillain-Barre syndrome have been controversial. We used high-resolution immunocytochemistry to localize complement activation products in early stages of the acute inflammatory demyelinating polyneuropathy (AIDP) pattern of Guillain-Barre syndrome. Three AIDP subjects who were autopsied had had symptoms for 3 to 9 days at the time of death. Immunocytochemistry was performed on etched, epoxy resin-embedded sections, and the next thin section was compared by electron microscopy (thick/thin sections). Many fibers had a rim of the complement activation marker C3d and the terminal complement complex neoantigen C5b-9 along the outer surface of the Schwann cells. Ultrastructural analysis of these C3d-positive fibers showed mild vesicular changes of the outermost myelin lamellae. Vesicular degeneration was seen before the invasion of macrophages into the myelin, and was the predominant change in the subject with symptoms for 3 days. C3d staining was not found on myelin membranes. The results suggest that at least some forms of AIDP are complement mediated. We speculate that complement is activated by antibody bound to epitopes on the outer surface of the Schwann cell and that the resulting complement activation initiates the vesiculation of myelin.