Morphological Studies of the Pineal Gland in the Common Gull (Larus canus) Reveal Uncommon Features of Pinealocytes

The avian pineal is a directly photosensory organ taking part in the organization of the circadian and seasonal rhythms. It plays an important role in regulation of many behavior and physiological phenomena including migration. The aim of the study was to investigate morphology of the pineal organ in the common gull (Larus canus). The light and electron microscopic studies were performed on the pineals of juvenile birds living in natural conditions of the Baltic Sea coast, which have been untreatably injured during strong storms in autumn and qualified for euthanasia. The investigated pineals consisted of a wide, triangular, superficially localized distal part and a narrow, elongated proximal part, attached via the choroid plexus to the intercommissural region of the diencephalon. The accessory pineal tissue was localized caudally to the choroid plexus. Based on the histological criteria, the organ was classified as the solid‐follicular type. Two types of cells of fotoreceptory line were distinguished: rudimentary–receptor pinealocytes and secretory pinealocytes. Both types of cells were characterized by unusual features, which have been not previously described in avian pinealocytes: the presence of paracrystalline structures in the basal processes and their endings, the storage of glycogen in the form of large accumulations and the arrangement of mitochondria in clusters. Further studies on other species of wild water birds dwelling in condition of cold seas are necessary to explain if the described features of pinealocytes are specific for genus Larus, family Laridae or a larger group of water birds living in similar environmental conditions. Anat Rec, 2012. © 2012 Wiley Periodicals, Inc.     

Emulation of seizure induced brain damage in neural tissue transplants to the anterior chamber of the eye

Summary We have developed a model system in which the mechanisms of neuronal damage due to hyperexcitation can be studied in isolation and where extended observation periods can be used. Substantia nigra pars reticulata (SNPR) develops a hypermetabolic necrosis following status epilepticus (Nevander et al. 1985; Auer et al. 1986). We transplanted rat fetal nigral area alone or together with fetal frontal neocortex to the anterior chamber of the eye in adult rats. Following 3 months of transplant maturation the hosts were subjected to status epilepticus for 60 min. In single nigral transplants no sign of structural damage was found. In the double transplants of frontal cortex and the substantia nigra a tissue necrosis had developed in the nigral part. This was demonstrated by a total loss of glial fibrillary acidic protein (GFA) immunoreactivity within a circumscribed necrotic region in the nigral part of the double transplant. Such a loss of GFA immunofluorescence had also developed in the host SNPR, as we have earlier shown (Eriksdotter Nilsson et al. 1987). Thus, intraocular brain tissue transplants provide a unique model for studies on the development of neuronal damage and functional dependence between different neuronal structures for the development of such damage.Abbreviations SNPR Substantia nigra pars reticulata - SN Substantia nigra     

Limitations in the use of the enzyme-linked immunosorbent assay (ELISA) for identification and quantification of thermogenin

The use of immunological assays, ELISA and RIA, for the identification and quantification of thermogenin (the brown adipose tissue-specific, GDP-binding, 32 kDa uncoupling protein) raises doubts regarding the exclusive occurrence of thermogenin in brown adipose tissue. Weak reactions between mitochondria from rat liver, rat skeletal and heart muscle and hamster white adipose and thermogenin antibodies have been observed (Cannon et al., 1982; Lean et al., 1983; Hansen et al., 1984). In order to study whether these reactions were due to thermogenin in tissues other than brown adipose tissue (BAT) or due to non-specific binding of thermogenin antibodies, a protein from rat liver mitochondria and a protein from tubifex mitochondria were isolated by the same procedure as thermogenin. The 2 proteins had almost the same molecular weight as thermogenin and reacted with thermogenin antibodies in ELISA and dot-blotting, but did not bind GDP and had an amino acid composition different from that of thermogenin. It is concluded that the weak reactions seen between thermogenin antibodies and mitochondria from different tissues other than BAT are due to non-specific binding, and that antibody cross-reactivity alone is unsuitable for the identification of thermogenin.     

Heme oxygenase -1 gene therapy: recent advances and therapeutic applications

Heme oxygenase-1 (HO-1) is regarded as a sensitive and reliable indicator of cellular oxidative stress. Studies on carbon monoxide (CO) and bilirubin, two of the three (iron is the third) end products of heme degradation have improved the understanding of the protective role of HO against oxidative injury. CO is a vasoactive molecule and bilirubin is an antioxidant, and an increase in their production through an increase in HO activity assists other antioxidant systems in attenuating the overall production of reactive oxygen species (ROS), thus facilitating cellular resistance to oxidative injury. Gene transfer is used to insert specific genes into cells that are either otherwise deficient in or that underexpress the gene. Successful HO gene transfer requires two essential elements to produce functional HO activity. Firstly, the HO gene must be delivered in a safe vector, e.g., adenoviral, retroviral or leptosome based vectors, currently being used in clinical trials. Secondly, with the exception of HO gene delivery to either ocular or cardiovascular tissue via catheter-based delivery systems, HO delivery must be site and organ specific. This has been achieved in rabbit ocular tissues, rat liver, kidney and vasculature, SHR kidney, and endothelial cells [Abraham et al., 1995a; Abraham et al., 1995b; Abraham et al., 2002c; Quan et al., 2004; Sabaawy et al., 2000; Sabaawy et al., 2001; Yang et al., 2004]. In this review, we discuss the functional significance of the HO system in various pathophysiological conditions and the beneficial therapeutic applications of human HO gene transfer and gene therapy in a variety of clinical circumstances.     

Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus

Psychoactive effects of cannabinoids are thought to be mediated, at least in part, by suppression of both glutamate and GABA release via CB1 cannabinoid receptor. Two types of cannabinoid receptor (CB1 and CB2) have been cloned so far. The CB1 receptors are abundantly expressed in the nervous system, whereas CB2 receptors are limited to lymphoid organs (Matsuda et al., 1990; Munro et al., 1993). Immunocytochemical and electrophysiological studies revealed that in the hippocampus CB1 receptors are expressed on axon terminals of GABAergic inhibitory interneurons (Tsou et al., 1999; Katona et al., 1999) and activation of these receptors decreases GABA release (Hájos et al., 2000). Other physiological studies pointed out the involvement of CB1 receptors in the modulation of hippocampal glutamatergic synaptic transmission and long-term potentiation (Stella et al., 1997; Misner and Sullivan, 1999), but anatomical studies could not confirm the existence of CB1 receptors on glutamatergic terminals. Here we examined cannabinoid actions on both glutamatergic and GABAergic synaptic transmission in the hippocampus of wild type (CB1+/+) and CB1 receptor knockout mice (CB1-/-). The synthetic cannabinoid agonist WIN55,212-2 reduced the amplitudes of excitatory postsynaptic currents in both wild type and CB1-/- mice, while inhibitory postsynaptic currents were decreased only in wild type mice, but not in CB1-/- animals. Our findings are consistent with a CB1 cannabinoid receptor-dependent modulation of GABAergic postsynaptic currents, but a novel cannabinoid-sensitive receptor must be responsible for the inhibition of glutamatergic neurotransmission.     

Ethics, transplantation, and the changing role of anatomists

Anatomists are regarded as custodians of cadaveric material donated to science. Almost every facet of medical science has experienced explosive advances. This has impacted directly on anatomists and their role. Increasingly, anatomists are raising concerns with regard to the treatment of human tissue (Jones,2002, Clin. Anat. 15:436-440). The Korperwelten (Bodyworlds) of Gunther von Hagens et al. (1987, Anat. Embryol. 175:411-421) has evoked considerable debate about the treatment of human cadavers. Thus far clinical anatomists have had little role to play in policy formulation, legislation, and ethical imperatives as applied to cadaveric donation for organ transplantation. Anatomists play an even more negligible role in the raging ethical controversy around live related/unrelated organ transplantation. Due to the critical international shortage of cadaveric donors, boundaries are being pushed to meet the needs of potential recipients (Ohler,2001, Prog. Transplant. 11:160-161). Constant reappraisal of these ethical and moral issues is therefore appropriate. Issues that relate to cultural and economic imperialism and pronouncements of international transplant societies may also require re-evaluation. The legislature governing the donation of human tissue in various countries is usually governed by a Human Tissue Act or its equivalent. In general, such acts are congruent with the Human Tissue Act (South Africa: Government Gazette 9, November 2001; No. 22824) that states "It is an offense to charge a fee in relation to the donation of human organs." In many countries, however, various lay press report that "the sale of body parts is now coming of age." Terms such as "rewarded gifting" and "donors" being transformed into "vendors" are opening a Pandora's Box (Nelson et al.,1993, "Financial incentives for organ donation: a report on the UNOS ethics committee payment subcommittee"). Cameron and Hoffenberg (1999, Kidney Int. 55:724-732) feel strongly that arguments in favour of the sale of organs are sufficiently cogent to warrant further discussion. Equally disturbing is the use of executed prisoners as organ donors. In the developing world there are additional socio-economic, indigenous and cultural, religious, and ethical issues to consider. In addition, strategies that are ethically sound and morally acceptable to expand the pool of living donors must keep pace with recent advances in medicine. A paradigm shift is required for anatomists to contribute to the international ethical debate, not only as custodians of the dead but also as protectors of the living. Their voices should be heard in transplantation and other forums, and contribute to the ethical debate as well as relevant evolving legislature.     

Molecular biology and pathogenesis of the human T-cell leukaemia/lymphotropic virus Type-1 (HTLV-1)

Retroviruses are associated with a variety of diseases, including immunological and neurological disorders, and various forms of cancer. In humans, the Human T-cell Leukaemia/Lymphotropic virus type 1 (HTLV-1), which belongs to the Oncovirus family, is the aetiological agent of two diverse diseases: Adult T-cell leukaemia/lymphoma (ATLL) (Poiesz et al. 1980; Hinuma et al. 1981; Yoshida et al. 1982), as well as the neurological disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (Gessain et al. 1985; Rodgers-Johnson et al. 1985; Osame et al. 1986). HTLV-1 is the only human retrovirus known to be the aetiological agent of cancer. A genetically related virus, HTLV-2, has been identified and isolated (Kalyanaraman et al. 1982). However, there has been no demonstration of a definitive aetiological role for HTLV-2 in human disease to date. Simian T-cell lymphotropic viruses types 1 and 2 (STLV-1 and -2) and bovine leukaemia virus (BLV) have also been classified in same group, Oncoviridae, based upon their similarities in genetic sequence and structure to HTLV-1 and -2 (Burny et al. 1988; Dekaban et al. 1995; Slattery et al. 1999). This article will focus on HTLV-1, reviewing its discovery, molecular biology, and its role in disease pathogenesis.     

Mosaic trisomy 4: Long-term outcome on the first reported liveborn

In a previous report, we described the first liveborn with trisomy 4 mosaicism [Marion et al. (1990) Am J Med Genet 37:362-365]. To our knowledge, since our original report, there have been only four additional reports of a prenatal diagnosis of mosaic trisomy 4 resulting in a liveborn child [Hsu et al. (1997) Prenat Diag 17:201-242; Kuchinka et al. (2001) Prenat Diag 21:36-39; Wieczorek et al. (2003) Prenat Diag 23:128-133; Zaslav et al. (2000) Am J Med Genet 95:381-384]. Three of the more recent reports lacked confirmation of the mosaicism in tissue samples collected from the child after delivery, and likely represent cases of confined placental mosaicism. We recently examined our original patient, N.J., in an effort to provide long-term follow-up. N.J. is currently 14-years-old, and is enrolled in both special education and mainstream eighth grade classes at a local public middle school. Although she generally scores below average on standardized intellectual tests, her verbal skills and social interactions are more age appropriate. Our initial report described abnormalities of N.J.'s right hand and right ear, for which several reconstructive surgeries have been performed. A current medical concern is her entrance into puberty, as menarche has not yet occurred, and asymmetrical breast development is present. Overall, N.J. has developed into a generally healthy adolescent with low-normal intellect. This report demonstrates the importance of long-term follow-up in providing accurate counseling for rare chromosomal disorders.     

Tuftelin mRNA is expressed in a human ameloblastoma tumor

RT-PCR, Southern blotting and DNA sequencing have established for the first time that tuftelin mRNA is expressed in human ameloblastoma tumor. The expression of amelogenin mRNA in ameloblastoma was also established, confirming earlier reports by Snead et al. These results corroborate, on a molecular level, the enamel organ epithelial origin of ameloblastoma. In view of the present results, it is interesting that previous studies have indicated that although ameloblastoma, a non-mineralized odontogenic tumor, transcribes amelogenin mRNA, amelogenin (and enamelin) proteins are not expressed in this tissue. However, in mineralizing odontogenic tumors, both these classes of proteins are expressed.     

Organ and effective doses in newborns and infants undergoing voiding cystourethrograms (VCUG): a comparison of stylized and tomographic phantoms

The time-sequence videotape-analysis methodology, developed [Sulieman et al., Radiology 178, 653-658 (1991)] for use in tissue dose estimations in adult fluoroscopy examinations and utilized [Bolch et al., Med. Phys. 30, 667-680 (2003)] for analog fluoroscopy in newborn patients, has been extended to the study of digital fluoroscopic examinations of the urinary bladder in newborn and infant female patients. Individual frames of the fluoroscopic and radiographic video were analyzed with respect to unique combinations of field size, field center, projection, tube potential, and tube current (mA), and integral tube current (mAs), respectively. The dosimetry study was conducted on five female patients of ages ranging from four-days to 66 days. For each patient, three different phantoms were utilized: a stylized computational phantom of the reference newborn (3.5 kg), a tomographic computational phantom of the reference newborn (3.5 kg), and (3) a tomographic computational phantom uniformly rescaled to match patient total-body mass. The latter phantom set circumvented the need for mass-dependent rescaling of recorded technique factors (kVp, mA, mAs, etc.), and thus represented the highest degree of patient specificity in the individual organ dose assessment. Effective dose values for the voiding cystourethrogram examination ranged from 0.6 to 3.2 mSv, with a mean and standard deviation of 1.8+/-0.9 mSv. The ovary and colon equivalent doses contributed in total approximately 65%-80% of the effective dose in these fluoroscopy studies. Percent differences in the effective dose assessed using the two tomographic phantoms (one fixed at 3.5 kg with rescaled technique factors rescaled and one physically rescaled to individual patient masses with no adjustment of recorded technique factors) ranged for -49% to +15%. Percent differences in effective dose found using the 3.5 kg stylized phantom and the 3.5 kg tomographic phantom, both with patient-specific rescaling of technique factors, ranged from -10% to +17%. These differences are due in part to a reduced ovary dose in the tomographic phantom for right posterior oblique (RPO) views when compared to those seen in the stylized phantom.     

Structural variants are a major source of gene expression differences in humans and often affect multiple nearby genes

Structural variants (SVs) are an important source of human genome diversity, but their functional effects are poorly understood. We mapped 61,668 SVs in 613 individuals from the GTEx project and measured their effects on gene expression. We estimate that common SVs are causal at 2.66% of eQTLs, a 10.5-fold enrichment relative to their abundance in the genome. Duplications and deletions were the most impactful variant types, whereas the contribution of mobile element insertions was small (0.12% of eQTLs, 1.9-fold enriched). Multitissue analysis of eQTLs revealed that gene-altering SVs show more constitutive effects than other variant types, with 62.09% of coding SV-eQTLs active in all tissues with eQTL activity compared with 23.08% of coding SNV- and indel-eQTLs. Noncoding SVs, SNVs and indels show broadly similar patterns. We also identified 539 rare SVs associated with nearby gene expression outliers. Of these, 62.34% are noncoding SVs that affect gene expression but have modest enrichment at regulatory elements, showing that rare noncoding SVs are a major source of gene expression differences but remain difficult to predict from current annotations. Both common and rare SVs often affect the expression of multiple genes: SV-eQTLs affect an average of 1.82 nearby genes, whereas SNV- and indel-eQTLs affect an average of 1.09 genes, and 21.34% of rare expression-altering SVs show effects on two to nine different genes. We also observe significant effects on rare gene expression changes extending 1 Mb from the SV. This provides a mechanism by which individual SVs may have strong or pleiotropic effects on phenotypic variation.

Structural variants (SVs) are a diverse class of genetic variation that include copy number variants (CNVs), mobile element insertions (MEIs), and balanced rearrangements at least 50 bp in length. Although SVs are relatively rare compared with single-nucleotide variants (SNVs) and small insertion or deletion (indel) variants, their size and diversity mean that SVs can disrupt protein-coding genes and genomic regulatory elements through diverse mechanisms. Furthermore, SVs often have more severe consequences compared with smaller variants, and previous studies have found that SVs have an outsized impact on human gene expression compared with their relative abundance in the genome (Stranger et al. 2007; Sudmant et al. 2015; Chiang et al. 2017). SVs have also been implicated in the biology of human diseases such as autism spectrum disorder (Sebat et al. 2007; Weiss et al. 2008; Turner et al. 2017; Brandler et al. 2018) and schizophrenia (International Schizophrenia Consortium 2008; Walsh et al. 2008; McCarthy et al. 2009; Marshall et al. 2017). However, SVs are difficult to detect from short-read DNA sequencing data and are often excluded from complex trait association studies.Advances in high-throughput sequencing technologies that have allowed for widespread use of whole-genome sequencing (WGS), combined with advances in scaling SV detection algorithms, mean that comprehensive studies of all forms of genetic variation are now possible for large human cohorts. Recent studies of SV in large, deeply sequenced human cohorts have found that SVs account for 4.0%–11.2% of rare high-impact coding alleles (Abel et al. 2020) and are responsible for 25%–29% of rare protein-truncating events per genome (Collins et al. 2020). However, few studies to date have examined the functional effects of SV on gene expression, and these studies are limited to relatively small cohort sizes or only a few tissue types with available gene expression data (Sudmant et al. 2015; Chiang et al. 2017; Han et al. 2020; Jakubosky et al. 2020).Here, we use deep WGS data and multitissue RNA-seq expression data from 613 individuals in the Genotype-Tissue Expression (GTEx) project to comprehensively map SVs and to evaluate their impact on both common and rare gene expression changes in up to 48 tissue types (Supplemental Table S1). This study expands on our prior analysis of SV in 147 human samples from the GTEx cohort with RNA-seq expression data from 13 different tissues (Chiang et al. 2017) and is the most comprehensive study of SV-eQTLs to date. The expanded cohort size provides greater power to evaluate the impact and mechanisms of SV-associated gene expression changes, particularly for rare SVs.     

探讨调强放疗计划中并行器官腮腺的优化方法

目的：在鼻咽癌调强计划设计中,尝试克服物理约束的局限性,通过改变腮腺的优化条件,使腮腺受照量达到RTOG规定的要求且既不影响靶区剂量。方法：对12例已实施调强放疗的鼻咽癌患者的腮腺进行全部（包括被靶区包绕的深叶腮腺组织）和部分（指靶区外的腮腺组织）勾画,在30%、50%和75%腮腺体积处设置目标剂量和不同权重,对优化计算过的靶区和腮腺所产生的剂量分布,通过结构评估和DVH直方图,定量分析腮腺受照剂量及对靶区的影响。结果：同样的优化条件对部分腮腺体积和全部腮腺优化时,部分腮腺体积优化的D50、MD均大于按全部体积优化的结果。对全部腮腺按不同权重优化得出的结果显示,各靶区98%的体积基本达到98%的处方剂量,但在腮腺优化权重增加到2倍时,CTV2的剂量会降低2%左右,靶区外热点会转移至上颌骨处,靶区适形度略差。但可以使得腮腺MD≤26 Gy;而把权重增加到1.2和1.6倍优化时,都可以使腮腺D50〈28 Gy,MD≤30 Gy,V20都大于70%以上。结论：要按全部腮腺体积优化,加大无重叠区腮腺的剂量权重1.2～1.6倍左右,既可保证靶区剂量符合要求又可使得腮腺D50≤28 Gy（符合RTOG一个标准）,MD≤30 Gy。     

Pseudomonas aeruginosa exoenzyme S, a bifunctional type-III secreted cytotoxin

Our recent studies have shown ExoS to be a bifunctional type-III secreted cytotoxin. Intracellular expression of the amino terminus of ExoS (C234) in eukaryotic cells stimulates actin reorganization without cytotoxicity, which involves small-molecular-weight GTPases of the Rho subfamily. Expression of the carboxyl terminus of ExoS comprises an ADP-ribosyltransferase domain, which is cytotoxic when expressed in cultured cells (Pederson and Barbieri, 1998). Rho and Ras are molecular switches, which control numerous cellular processes. Recent signaling studies suggest that there is crosstalk between Rho and Ras (Keely et al, 1997). Ras and Rho also contribute to wound healing processes and tissue regeneration. Recent studies have shown that microinjection of endothelial cells with activated Ras stimulated their motility, while microinjection of Ras-blocking antibodies inhibited cellular motility that is a component of the wound healing process (Fox et al., 1994). In addition, hepatocyte growth factor/scatter factor (HGF/ SF) and epidermal growth factor stimulate cellular motility through the Ras signal transduction pathway (Ridley et al., 1995). Rac and Rho are also involved in motility and tissue regeneration, since dominant negative Rac inhibits the cellular motility stimulated by HGF/SF (Santos et al., 1997) and inhibition of Rho by either C. difficile ToxA and ToxB or the C. botulinum C3 transferase inhibits wound healing (Santos et al., 1997). Inhibition of tissue regeneration and wound healing appear to play a role in the pathogenesis of C. difficile, since treatment of gastrointestinal mucosa with C. difficile ToxA and ToxB alone inhibits regeneration of the gastric mucosa. Thus, ExoS may contribute to the establishment of P. aeruginosa infections by inhibiting wound healing and tissue regeneration by two mechanisms. The amino terminus of ExoS could inhibit Rho function and wound healing in a manner similar to C. difficile. Alternatively, ExoS could inhibit the cellular motility and angiogenesis required for wound healing by ADP-ribosylating Ras. Through the inhibition of tissue regeneration and wound healing, ExoS may play a pivotal role in chronic disease by maintaining sites of colonization. Inhibition of Ras or Rho signaling may also interfere with both innate and acquired immunity. Small-molecular-weight GTP-binding proteins of the Ras superfamily are required for cellular processes, such as phagocytosis, as Rho proteins contribute to phagocytosis (Caron and Hall, 1998). Since Ras functions upstream of Rho in cellular signaling processes (Ridley et al., 1995), ADP-ribosylation of Ras by ExoS or the inhibition of Rho function by C234 may inhibit phagocytosis of P. aeruginosa by macrophages. Other studies indicate that Ras plays a role in T cell activation (Cantrell, 1994). Thus, ExoS may inhibit acquired immunity by inhibiting T-cell activation.     

HLA-SB in the south of France. Correlation between locally derived and reference typing reagents

The HLA-D region of the Major Histocompatibility Complex has been subdivided since 1978 (Mawas et al. 1978) into two subregions separable by recombination: a telomeric subregion (closer to HLA-B), coding for the classical HLA-DR or Dw specificities (Mawas et al. 1980) as well as for the more recent MT series (Park et al. 1980); and a centromeric subregion (closer to GLO), coding for a new series of alleles provisionally named SB (for secondary B cell antigens) (Shaw et al. 1980, 1981a). Reagents allowing the identification of six independent alleles have been characterized in two laboratories (Charmot et al. 1980 and Shaw et al. 1980, 1981b) using the technology of primed lymphocytes typing (Sheehy et al. 1975; Mawas et al. 1975). The existence of this new locus is supported by the following arguments: population studies by Shaw demonstrating five traits distinct from DR behaving as alleles (Shaw et al. 1981b), analysis of two informative SB/DR recombinant families (Mawas et al. 1978; Mawas et al. 1980; Shaw et al. 1981a), and, finally, studies of mutants showing independent loss of DR expression without loss of SB expression (Kavathas et al. 1981). The present report summarizes the HLA-SB typing of 109 unrelated individuals from the South of France and segregation studies in 14 unrelated families; a first attempt to correlate local "SB" reagents with the NIH reference standards is presented.     

Antiendothelial cell antibodies (AECA) in patients with uveoretinitis

Summary AECAs have been found in 26% of patients with uveoretinitis in studies arising from three different laboratories, and their presence can-not simply be explained by coexisting extraocular disease. There is little correlation with ocular disease activity or other markers of systemic inflammation and vascular damage that can be found in this group of patients, but this lack of correlation has also been found in studies of more widespread inflammatory diseases. The changes found in the peripheral blood of patients with uveoretinitis are the result of a mixture of acute and chronic inflammation, reactions to coexisting tissue damage, as well as predisposing abnormalities of inflammation and hemostasis. Even patients with similar clinical appearances are unlikely to be pathologically homogeneous, and the reasons for the presence of AECA are likely to be various. Some patients may demonstrate a heightened antibody response to endothelium damaged by unknown mechanisms, whereas others may develop cytotoxic AECA as an integral part of the inflammatory process. The majority of serum samples with AECA demonstrated anti-body-dependent cell-mediated cytotoxicity, but this potentially patho-genetic mechanism was only demonstrable in a minority of patients. It is unlikely that IgM AECA or complement-mediated cytotoxicity is a relevant mechanism of vascular damage in this group of patients. A subgroup of patients may be genetically predisposed to produce excess autoantibodies in response to tissue damage caused by a wide variety of insults. Sawyerr et al. (36) has suggested that increased serum levels of agalactosyl IgG may account for some of the AECA binding found in chronic inflammatory diseases: we have also found changes in agalactosyl IgG in patients with active isolated uveoretinitis (40), but levels did not correlate with levels of IgG AECA (unpublished results). Further longitudinal studies will be necessary on each sub-group of patients in order to determine the true clinical significance of these findings.