An in vivo role for Trypanosoma cruzi calreticulin in antiangiogenesis

Angiogenesis leads to neovascularization from existing blood vessels. It is associated with tumor growth and metastasis and is regulated by pro- and antiangiogenic molecules, some of them currently under clinical trials for cancer treatment. During the last few years we have cloned, sequenced and expressed a Trypanosoma cruzi calreticulin gene (TcCRT). Its product, TcCRT, a 45 kDa protein, is more than 50% identical to human CRT (HuCRT). TcCRT, present on the surface of trypomastigotes, binds both C1q and mannan binding lectin and inhibits the classical activation pathway of human complement. Since TcCRT is highly homologous to a functional antiangiogenic fragment from HuCRT (aa 120–180), recombinant (r) and native (n) TcCRT were tested in their antiangiogenic effects, in the chick embryonic chorioallantoid membrane (CAM) assay. Both proteins mediated highly significant antiangiogenic effects in the in vivo CAM assay. This effect was further substantiated in experiments showing that the plasmid construct pSecTag/TcCRT also displayed significant antiangiogenic properties, as compared to the empty vector. Most likely, the fact that antiangiogenic substances act preferentially on growing neoplasic tissues, but not on already established tumors, is due to their effects on emerging blood vessels. The results shown here indicate that TcCRT, like its human counterpart, has antiangiogenic properties. These properties may explain, at least partly, the reported antineoplasic effect of experimental T. cruzi infection.     

Plasma protein haptoglobin modulates renal iron loading

Haptoglobin is the plasma protein with the highest binding affinity for hemoglobin. The strength of hemoglobin binding and the existence of a specific receptor for the haptoglobin-hemoglobin complex in the monocyte/macrophage system clearly suggest that haptoglobin may have a crucial role in heme-iron recovery. We used haptoglobin-null mice to evaluate the impact of haptoglobin gene inactivation on iron metabolism. Haptoglobin deficiency led to increased deposition of hemoglobin in proximal tubules of the kidney instead of the liver and the spleen as occurred in wild-type mice. This difference in organ distribution of hemoglobin in haptoglobin-deficient mice resulted in abnormal iron deposits in proximal tubules during aging. Moreover, iron also accumulated in proximal tubules after renal ischemia-reperfusion injury or after an acute plasma heme-protein overload caused by muscle injury, without affecting morphological and functional parameters of renal damage. These data demonstrate that haptoglobin crucially prevents glomerular filtration of hemoglobin and, consequently, renal iron loading during aging and following acute plasma heme-protein overload.     

Gastroesophageal reflux in asthmatic patients: an incidence study and clinical correlation

The prevalence of gastroesophageal reflux (GER) in asthmatic patients is elevated, but the exact frequency remains unknown. The relationship between GER and asthma has not been investigated in Mexico. The objective of this study is to know the frequency of GER in Mexican asthmatic patients and the possible relationship with the severity of asthma. Fifty patients with adult-onset asthma were studied. AII of them fulfill the diagnostic criteria of the National Institutes of Health, U.S. The evaluation included a symptoms questionnaire, spirometry, esophageal manometry, 24-h esophageal pH-recording, and an upper gastrointestinal endoscopy. Twenty-three patients had mild asthma (46%), 16 moderate (32%) and 11 had severe asthma (22%). Twenty-seven (54%) reported heartburn and regurgitation at least twice a week. The esophageal pH-recording showed pathologic GER in 37 subjects (74%) and endoscopic esophagitis was found in 7 cases (14%). The pH-recording showed pathologic GER in 13 patients with mild asthma (57%), in 13 with moderate asthma (81%) and in all patients with severe asthma (100%). The frequency of GER in Mexican asthmatic patients is high and increases proportionately with the severity of asthma. This factor must be considered in the integral evaluation of these patients.     

Secretion of growth hormone and thyroid-stimulating hormone in patients with dementia

We studied the growth hormone (GH) response to GH-releasing hormone (GHRH) and the thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in four groups of patients with dementia and examined whether GH and TSH secretion is altered in patients with Alzheimer's disease. The four groups included those with Alzheimer's disease (n=28), parkinsonism with dementia (n=10), progressive supranuclear palsy with dementia (n=10), and dementia of vascular origin (n=28). The results showed no differences among the four groups in GH response to GHRH (12.2 ± 2, 10.7 ± 2, 8.9 ±1.1, and 9.9 ± 1.9 g/ml, respectively); there was no correlation between GH response to GHRH and sex, stage of the disease, or cerebral atrophy. The proportion of patients with exaggerated, normal, or lower GH response was similar in the four groups. There were also no differences among the groups in terms of TSH response to TRH (9.2 ±0.9, 11.1 ± 1, 11.1 ± 1, and 10.3 ± 1 mU/ml, respectively), nor was there a correlation between TSH response to TRH and sex, stage of the disease, cerebral atrophy, or GH response to GHRH. The proportion of those with exaggerated, normal, or lower TSH response was similar in the four groups. Cerebrospinal somatostatin levels were similar in Alzheimer's disease and vascular dementia patients. These findings indicate that neither GH response to GHRH nor TSH response to TRH provides a useful diagnostic adjunt in Alzheimer's disease patients.Abbreviations AD Alzheimer's disease - PD parkinsonism with dementia - PSP progressive supranuclear palsy - VD dementia of vascular origin - GH growth hormone - GHRH growth hormone releasing hormone - TRH thyrotropin releasing hormone - TSH thyroid stimulating hormone Correspondence to: J.M. Gomez     

A new syndrome characterized by mental retardation, epilepsy, palpebral conjunctival telangiectasias and IgA deficiency

Mental retardation, epilepsy, palpebral conjunctival telangiectasias and diminished serum IgA, with a particular facies and shortened fifth finger were found in a 12-year-old Mexican girl. She has six siblings, of whom five have the same characteristics. The parents and the elder sister were not affected, and there was no history of consanguinity. This seems to be a new syndrome, and as both sexes are affected, the parents are normal and several siblings have the same syndrome, we postulate an autosomal recessive mode of inheritance.     

Autosomal trisomy and maternal use of multivitamin supplements

Recent reports suggest that women carrying certain polymorphisms of folate genes associated with suboptimal folate status might be at increased risk for having a child with Down syndrome or other autosomal trisomies, and hypothesized that maternal use of multivitamin supplements might reduce such risk. To evaluate this hypothesis, we examined data from a population-based case-control study, and contrasted cases of Down syndrome, trisomy 18, and trisomy 13, with unaffected controls. Periconceptional multivitamin use, compared to no such use, was associated with an odds ratio (OR) of 0.9 (95% confidence interval [CI], 0.6-1.3) for having a pregnancy affected by an autosomal trisomy. The OR was 0.8 (95% CI, 0.5-1.3) for Down syndrome and 1.4 (95% CI, 0.5-3.6) for trisomies 13 and 18, with little variation by maternal race or age. Periconceptional multivitamin use was not associated with a major reduction in the risk for common autosomal trisomies.     

T cell clones expressing the natural killer cell-related p58 receptor molecule display heterogeneity in phenotypic properties and p58 function

A new anti-p58 monoclonal antibody (mAb), termed CH-L, has been used to characterize a minor subset of T lymphocytes co-expressing p58 and CD3 molecules. In two-color immunofluorescence analysis, CH-L⁺CD3⁺ cells represented 0.5 to 6% of the peripheral blood lymphocytes (in 20 healthy donors). Clonal analysis showed that most CD3⁺CH-L⁺ T cell clones expressed the CD8⁺4^? T cell receptor (TcR) α/β⁺ phenotype, while only a few were CD8^?4⁺ TcR α/β⁺, CD8^?4^? TcR α/β⁺ or CD8^?4^? TcR γ/δ⁺. Western blot analysis indicated that the CH-L mAb identifies the same 56-58-kDa diffuse band in both T and natural killer cell (NK) clones. A minority of T cell clones also expressed other NK-related markers such as CD16, CD56 and CD94 and two clones also reacted with the anti-p58 mAb EB6. Interestingly, most clones displayed cytolytic activity in an anti-CD3 mAb-triggered redirected killing assay against the Fcδ receptor⁺ P815 target cells and NK-like activity against K562 and Raji cells. In contrast, the IGROV-1 ovarian carcinoma cell line was resistant to cytolysis by all of these clones. Since p58 molecules have previously been shown to exert regulatory functions on NK-mediated lysis, we investigated whether anti-p58 mAb could also influence cytotoxicity mediated by CD3⁺p58⁺ T lymphocytes. Lysis of P815 target cells, triggered by anti-CD3 mAb, could be inhibited by anti-p58 mAb in 8 out of 12 cytolytic clones tested, while 4 clones were not inhibited. In addition, anti-p58 mAb enhanced the cytolytic activity of 3 clones against IGROV-1 and of 4 other clones against Raji target cells. Taken together, these data indicate that p58⁺ T cells express heterogeneous phenotypes and different forms of TcR and, in most instances, display cytolytic functions. Perhaps more importantly, the p58 molecule appears to modulate the cytolytic activity triggered via the CD3/TcR complex.