T-cell growth, cell surface organization, and the galectin–glycoprotein lattice

Summary:  Basal, activation, and arrest signaling in T cells determines survival, coordinates responses to pathogens, and, when dysregulated, leads to loss of self-tolerance and autoimmunity. At the T-cell surface, transmembrane glycoproteins interact with galectins via their N -glycans, forming a molecular lattice that regulates membrane localization, clustering, and endocytosis of surface receptors. Galectin–T-cell receptor (TCR) binding prevents ligand-independent TCR signaling via Lck by blocking spontaneous clustering and CD4-Lck recruitment to TCR, and in turn F-actin transfer of TCR/CD4-Lck complexes to membrane microdomains. Peptide–major histocompatibility complexes overcome galectin–TCR binding to promote TCR clustering and signaling by Lck at the immune synapse. Galectin also localizes the tyrosine phosphatase CD45 to microdomains and the immune synapse, suppressing basal and activation signaling by Lck. Following activation, membrane turnover increases and galectin binding to cytotoxic T-lymphocyte antigen-4 (CTLA-4) enhances surface expression by inhibiting endocytosis, thereby promoting growth arrest. Galectins bind surface glycoproteins in proportion to the branching and number of N -glycans per protein, the latter an encoded feature of protein sequence. N -glycan branching is conditional to the activity of Golgi N -acetylglucosaminyl transferases I, II, IV and V (Mgat1, 2, 4, and 5) and metabolic supply of their donor substrate UDP-GlcNAc. Genetic and metabolic control of N -glycan branching co-regulate homeostatic set-points for basal, activation, and arrest signaling in T cells and, when disturbed, result in T-cell hyperactivity and autoimmunity.     

Olive oil intake and breast cancer risk in the Mediterranean countries of the European Prospective Investigation into Cancer and Nutrition study

Although there is some evidence suggesting that olive oil could reduce breast cancer (BC) risk, the epidemiological data are still relatively limited, not entirely consistent and mainly based on case-control studies. Therefore, we prospectively assessed the association between olive oil and BC risk in postmenopausal women from the Mediterranean cohorts within the European Prospective Investigation into Cancer and Nutrition. The analysis included 62,284 postmenopausal women recruited from Spain, Italy and Greece who had complete dietary data (collected from validated country-specific dietary questionnaires). The risk of BC (overall and by hormone receptor subtypes) was assessed using hazards ratios (HRs) obtained from Cox proportional hazards regression, while adjusting for known BC risk factors. After a mean follow-up of 9 years, 1,256 women were diagnosed with a primary incident invasive BC. The multivariate HRs for BC risk by olive oil intake (highest vs. lowest tertile of g/day/2,000 kcal) were 1.07 (95% CI = 0.91-1.25) in the adjusted model, 1.06 (95% CI = 0.91-1.24) in the model additionally adjusted for reproductive-related factors and 1.10 (95% CI = 0.92-1.31) for the model additionally adjusted for dietary factors. There was no association between olive oil and risk of estrogen or progesterone receptor-positive tumors, but a suggestion of a negative association with estrogens and progesterone receptor-negative tumors. The results from our prospective study showed that olive oil consumption during adult life was not associated with the risk of BC. However, larger prospective studies are still needed to explore possible differences related to hormone receptor status.     

Auditory nerve is affected in one of two different point mutations of the neurofilament light gene.

OBJECTIVE: To define auditory nerve and cochlear functions in two families with autosomal dominant axonal Charcot-Marie-Tooth (CMT). METHODS: Affected members in two families with different point mutations of NF-L gene were screened with auditory brainstem responses (ABRs). Those with abnormal ABRs were further investigated with clinical, neurophysiological and audiological procedures. The point mutations of NF-L gene involved were Glu397Lys in 8 affected members of the family with AN, and Pro22Ser in 9 affected members of the family without AN. RESULTS: ABRs and stapedial muscle reflexes were absent or abnormal in affected members of only one family consistent with auditory neuropathy (AN). In them, audiograms, otoacoustic emissions, and speech comprehension were normal. Absent or abnormal ABRs were consistent with slowing of conduction along auditory nerve and/or brainstem auditory pathway. Wave I when present was of normal latency. CONCLUSIONS: Auditory nerve involvement in the presence of normal cochlear outer hair cell activity is asymptomatic in one of two families with CMT disorder with different point mutations of the NF-L gene. The nerve disorder is consistent with altered synchrony and slowed conduction. SIGNIFICANCE: The absence of "deafness" may reflect the ability of central mechanisms to compensate for the slowly developing auditory nerve abnormalities.     

Pathological effects of pellagra on the esophagus

This study determined the pathological effects of niacin/tryptophan deficiency on the esophagus. Nine patients with severe clinical pellagra and 31 age‐ and sex‐matched controls were assessed. All pellagrins had an esophagitis varying from severe to mild. The esophagitis improved in five patients following six to seven days of vitamin therapy. The relationship between vitamin deficiencies and esophageal cancer is discussed.     

Glycerol suppresses proliferation of rat hepatocytes and human HepG2 cells

BACKGROUND: In fulminant hepatic failure (FHF), the ability of surviving hepatocytes to proliferate is diminished. Therefore, it is important that medical therapy cause no further impairment of liver regeneration. In FHF, intracranial hypertension secondary to brain edema is the most common cause of brain injury and death and glycerol is used in some countries to treat this complication. Glycerol has been long known to suppress the growth of various cell types. We therefore decided to examine the effect of glycerol on hepatocyte proliferation in vitro and in vivo in rats subjected to partial (2/3) hepatectomy. Additionally, we investigated the effect of glycerol on the proliferation of HepG2 cells. MATERIALS AND METHODS: Mitogen-induced primary rat hepatocytes were cultured in a hormonally defined Dulbecco's modified Eagle's medium containing increasing amounts of glycerol (0.5, 1.0, 2.0, 4.0%). HepG2 cells were cultured in minimal essential medium/10% FBS. After 2 days, HepG2 cells were exposed to glycerol (1.0-2.0-4.0%) and harvested after 48 h. Control dishes contained no glycerol. Cell proliferation was measured by the incorporation of [(3)H]thymidine and/or bromodeoxyuridine (BrdU). In vivo, Sprague-Dawley rats were subjected to standard partial 2/3 hepatectomy and assigned to intraportal administration of either 400 microl of glycerol or saline. Rats were killed after 1, 2, 3, 5, and 7 days. Liver weight/body weight ratio and BrdU uptake were measured. RESULTS: In all cultures tested, glycerol suppressed the growth of cells in a dose-dependent manner. In vivo, a single intraportal dose of glycerol slowed the liver regenerative response. CONCLUSIONS: This study demonstrated that glycerol has a potent growth-inhibitory effect on hepatocyte proliferation in vivo and in vitro. Remarkably, glycerol inhibited the proliferation of liver cancer cells as well. The results of this study have important clinical implications.     

Presymptomatic molecular diagnosis of autosomal dominant polycystic kidney disease using PKD1-and PKD2-linked markers in Cypriot families

Autosomal dominant polycystic kidney disease (ADPKD), is a heterogeneous disorder, primarily characterized by the formation of cysts in the kidneys, and the late development in life of progressive chronic kidney failure. Three genes are implicated in causing ADPKD. One on chromosome 16, PKD1, accounts for 85–90% of all cases, and the PKD2 gene on chromosome 4 accounts for the remainder. A very rare third locus is still of unknown location. We used PKD1-and PKD2-linked polymorphic markers to make the diagnosis of ADPKD in young presymptomatic members in affected families. We showed that in young members of families where clinical diagnosis cannot be definitively established, molecular linkage analysis can assist clinicians in the diagnosis. In one family a 24-year old had one cyst on the right kidney; however, molecular analysis showed clearly that he had inherited the normal haplotype. In another family, in one part of the pedigree there was co-inheritance of the disease with a PKD1-linked haplotype which originated in a non-affected 78-year-old father. Analysis with PKD2-linked markers excluded this locus. The data can be explained in one of two ways. Either this family phenotype is linked to a third locus, or the proband was the first affected person, most probably because of a novel mutation in one of her father's chromosomes. In conclusion, the combined use of markers around the PKD1 and the PKD2 locus provides more definitive answers in cases where presymptomatic diagnosis is requested by concerned families.     

Multiple complex coronary plaques in patients with acute myocardial infarction

BACKGROUND: Acute myocardial infarction is believed to be caused by rupture of an unstable coronary-artery plaque that appears as a single lesion on angiography. However, plaque instability might be caused by pathophysiologic processes, such as inflammation, that exert adverse effects throughout the coronary vasculature and that therefore result in multiple unstable lesions. METHODS: To document the presence of multiple unstable plaques in patients with acute myocardial infarction and determine their influence on outcome, we analyzed angiograms from 253 patients for complex coronary plaques characterized by thrombus, ulceration, plaque irregularity, and impaired flow. RESULTS: Single complex coronary plaques were identified in 153 patients (60.5 percent) and multiple complex plaques in the other 100 patients (39.5 percent). As compared with patients with single complex plaques, those with multiple complex plaques were less likely to undergo primary angioplasty (86.0 percent vs. 94.8 percent, P = 0.03) and more commonly required urgent bypass surgery (27.0 percent vs. 5.2 percent, P < or = 0.001). During the year after myocardial infarction, the presence of multiple complex plaques was associated with an increased incidence of recurrent acute coronary syndromes (19.0 percent vs. 2.6 percent, P < or = 0.001); repeated angioplasty (32.0 percent vs. 12.4 percent, P < or = 0.001), particularly of non-infarct-related lesions (17.0 percent vs. 4.6 percent, P < or = 0.001); and coronary-artery bypass graft surgery (35.0 percent vs. 11.1 percent, P < or = 0.001). CONCLUSIONS: Patients with acute myocardial infarction may harbor multiple complex coronary plaques that are associated with adverse clinical outcomes. Plaque instability may be due to a widespread process throughout the coronary vessels, which may have implications for the management of acute ischemic heart disease.     

Medullary cystic kidney disease with hyperuricemia and gout in a large Cypriot family: No allelism with nephronophthisis type 1

We describe a large Cypriot family with an interstitial type of nephropathy, inherited as an autosomal dominant trait that led to end stage renal failure between 51 to 78 years of age (mean 62.2 years). Twenty-three people are known to be affected, but several younger relatives with normal renal function may remain undiagnosed because of the absence of precise clinical and laboratory diagnostic criteria. This nephropathy is associated with medullary renal cysts, hypertension, hyperuricemia, and gout. Several relatives have typical medullary cystic disease (MCD), while in the others the findings are compatible with this diagnosis. Due to the similarity of clinical and pathologic findings, earlier reports had suggested that MCD may be allelic to autosomal recessive familial juvenile nephronophthisis, which was mapped recently to chromosome band 2q13. Linkage analysis of the present family with a closely linked marker excluded linkage to the above locus. Linkage was also excluded to the PKD1 locus of adult polycystic kidney disease type 1, and up to 5 cM on either side, on chromosome 16. We suggest that because of the element of hyperuricemia and gout found in this family, although with reduced penetrance, it may represent a variant of autosomal dominant MCD of the adult type. This variability may be the result of allelic or locus heterogeneity. Molecular genetic approaches including linkage analysis on appropriate families will certainly assist in classifying such related genetically heterogeneous disorders. Am. J. Med. Genet. 77:149–154, 1998. © 1998 Wiley-Liss, Inc.     

Malignant mutation in the lamin A/C gene causing progressive conduction system disease and early sudden death in a family with mild form of limb-girdle muscular dystrophy

Background Lamin proteins A and C are major functional and structural components of the nuclear lamina. Mutations of the LMNA gene have been associated with dilated cardiomyopathy, conduction system defects and skeletal muscle dystrophy simultaneously, in variable involvement. We report on a family with a mutation of the lamin A/C gene (c.908–909delCT). Methods Thirty five members of the family of a proband were studied and underwent clinical and genetic evaluation. Family members were considered to be affected if they demonstrated conduction system defects, limb-girdle muscular dystrophy, dilated cardiomyopathy, carried the lamin A/C mutation or suffered sudden death. Results Fifteen members of the family were considered to be affected. Conduction system defects were the major feature of the affected members (67%), with variable involvement of dilated cardiomyopathy (33%), and limb-girdle muscular dystrophy (53%). Sudden death occurred in four members (27%) and was the presenting feature in three (20%) of the affected members at an early age. Mutation c.908–909delCT was confirmed in 12 of the affected members. The pattern of inheritance was autosomal dominant. Conclusion Lamin c.908–909delCT mutation is malignant compared to other dilated cardiomyopathy—associated mutations of the Lamin A/C gene. Patients with this mutation have rapid progression of atrioventricular conduction abnormalities, and sudden death may be the presenting feature. Early identification of affected families and consideration of an implantable defibrillator is important in this setting. This study was supported by the Muscular Dystrophy Association of the USA (grant to Drs Theodoros Kyriakides and Kyproula Christodoulou).