Identification of DNA polymorphisms associated with the V type alpha1-antitrypsin gene.

alpha1-Antitrypsin (alpha1-AT) is a highly polymorphic protein. The V allele of alpha1-AT has been shown to be associated with focal glomerulosclerosis (FGS) in Negroid and mixed race South African patients. To identify mutations and polymorphisms in the gene for the V allele of alpha1-AT in five South African patients with FGS nephrotic syndrome DNA sequence analysis and restriction fragment length polymorphisms of the coding exons were carried out. Four of the patients were heterozygous for the BstEII RFLP in exon III [M1(Val213)(Ala213)] and one patient was a M1(Ala213) homozygote. The mutation for the V allele was identified in exon II as Gly-148 (GGG)-->Arg (AGG) and in all patients was associated with a silent mutation at position 158 (AAC-->AAT). The patient who was homozygous for (Ala213) also had a silent mutation at position 256 in exon III (GAT-->GAC) which was not present in any of the other four patients. Although the V allele of alpha1-AT is not associated with severe plasma deficiency, it may be in linkage disequilibrium with other genes on chromosome 14 that predispose to FGS. Furthermore, the associated silent mutation at position 158 and the Ala213 polymorphism are of interest, as these could represent an evolutionary intermediate between the M1(Ala213) and M1(Val213) subtypes.

[Evisceration and secondary enucleation with implantation following endophthalmitis]. / Eviscération suivie d'énucléation avec implantation secondaire à la suite d'endophtalmie.

PURPOSE: Primary evisceration followed by secondary enucleation and implant placement makes it possible to use the sclera of a patient with endophthalmitis. This sclera will be used for secondary implantation. PATIENTS AND METHODS: Four patients with endophthalmitis and corneal perforation (bacterial infection in three cases and fungal infection in one case) underwent evisceration and, 4-6 weeks later, enucleation. During the secondary enucleation, the sclera was recovered and used as wrapping material for the alumina implant (Al2O3) (20 and 22 mm in diameter). Between the two operations, the patients were treated with systemic and topical antibiotics or antifungal agents. RESULTS: No complications were observed for both the first and the second operation. Enucleated sclera was crumpled and bent in all four cases. The sclera was spread out and used as wrapping material. Prosthetic fitting was performed 4-5 weeks after the second operation. No complications have been observed to date (10 to 32 months follow-up). CONCLUSION: Primary implantation following endophthalmitis is debatable because an infectious complication cannot be excluded. The use of sclera for implant wrapping decreases the risk of implant extrusion, especially when the conjunctiva and Tenon's facia have been weakened by previous surgery or infection. Primary evisceration with a conformer placement followed by enucleation and implantation is an ideal solution in endophthalmitis because this technique allows the use of patient's own sclera.

Elastase binding capacity of alpha 2-macroglobulin in plasma of patients with asthma or chronic obstructive pulmonary disease, without alpha 1-protease inhibitor deficiency.

The amidolytic activity of alpha 2-macroglobulin complexed with porcine pancreatic elastase (EC 3.4.21.11) was assayed using succinyl-trialanyl-p-nitroanilide. The levels of activity were compared in chronic obstructive pulmonary disease patients, asthma patients, and in healthy subjects with no record of lung disease. Levels of alpha 1-protease inhibitor were also determined and only those cases within the normal range for alpha 1-protease inhibitor were selected. Both the asthma cases and those with chronic obstructive pulmonary disease had levels of elastase-binding capacity related to alpha 2-macroglobulin which were significantly higher than the control groups.

Elastase binding capacity of alpha 2-macroglobulin and its association with glucocorticoid concentration in southern African black patients with hepatocellular carcinoma.

Thirty-three Southern African black patients with hepatocellular carcinoma (HCC) (7 women) and 43 black control individuals (14 women), all in the age group 18-45 years, were investigated for plasma alpha 2-macroglobulin (alpha 2M) elastase binding capacity (EBC). Cortisol levels were measured in 15 (3 women) of the HCC patients and 10 (5 women) of the control subjects. A significant difference in EBC was found between the HCC patients and the control subjects (P < 0.001). A significant difference was also found in cortisol levels between the two groups (P < 0.001). A significant correlation between EBC and cortisol levels was obtained (r = 0.57; P < 0.042). The significant increase in EBC of alpha 2M in HCC patients could be due to an increase in circulating cortisol.

[The concentration of fetal cells in maternal haematopoietic organs during pregnancy. An experimental study in mice (author's transl)]. / Concentration de cellules foetales dans les organes hématopoïétiques maternels au cours de la gestation. Etude expérimentale chez la souris.

We have been able to show that fetal cells are able to survive and multiply in the haematopoietic organs of the pregnant mouse. We have been able to label fetal cells with a chromosome marker (T6) which is clearly visible in the metaphase of mitosis. It is not only that there is a considerable concentration of fetal cells in the maternal spleen (3 to 6 per cent) but there are several factors that suggest that these fetal cells can multiply there. These are, the presence of mitoses, long survival, and a rise in numbers in the case of a new pregnancy. Thus pregnancy seems to bring about a physiological "microchimerism".

[Endometrectomy: comparison of Nd-Yag laser and resectoscope]. / Endométrectomie: comparaison laser Nd-Yag et résecteur.

Based on the current literature, comparative assessment of the advantages and disadvantages of the Nd-Yag laser versus the electro-surgical resector show both techniques to be similar with regard to efficiency, risk and security. However, regarding cost, there is no doubt that the resector is preferred which additionally allows histologic diagnosis and use in an emergency setting in spite of bleeding. Specific and rigorous hysteroscopic training, first diagnostic then operative, decreases the risk and complications of hysteroscopic procedures.

BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities.

The therapeutic activity of selective serotonin (5-HT) reuptake inhibitors (SSRIs) relies on long-term adaptation at pre- and post-synaptic levels. The sustained administration of SSRIs increases the serotonergic neurotransmission in response to a functional desensitization of the inhibitory 5-HT1A autoreceptor in the dorsal raphe. At nerve terminal such as the hippocampus, the enhancement of 5-HT availability increases brain-derived neurotrophic factor (BDNF) synthesis and signaling, a major event in the stimulation of adult neurogenesis. In physiological conditions, BDNF would be expressed at functionally relevant levels in neurons. However, the recent observation that SSRIs upregulate BDNF mRNA in primary cultures of astrocytes strongly suggest that the therapeutic activity of antidepressant drugs might result from an increase in BDNF synthesis in this cell type. In this study, by overexpressing BDNF in astrocytes, we balanced the ratio between astrocytic and neuronal BDNF raising the possibility that such manipulation could positively reverberate on anxiolytic-/antidepressant-like activities in transfected mice. Our results indicate that BDNF overexpression in hippocampal astrocytes produced anxiolytic-/antidepressant-like activity in the novelty suppressed feeding in relation with the stimulation of hippocampal neurogenesis whereas it did not potentiate the effects of the SSRI fluoxetine on these parameters. Moreover, overexpressing BDNF revealed the anxiolytic-like activity of fluoxetine in the elevated plus maze while attenuating 5-HT neurotransmission in response to a blunted downregulation of the 5-HT1A autoreceptor. These results emphasize an original role of hippocampal astrocytes in the synthesis of BDNF, which can act through neurogenesis-dependent and -independent mechanisms to regulate different facets of anxiolytic-like responses.

Retinal dysfunction in combined methylmalonic aciduria and homocystinuria (Cblc) disease: a spectrum of disorders.

BACKGROUND: Cobalamin C methylmalonic aciduria with homocystinuria (cblC disease) is a rare hereditary inborn error of cobalamin metabolism, characterised by neurological, haematological and ophthalmological abnormalities. PATIENTS AND METHODS: Three consecutive patients with Cblc disease were examined. Investigations included slit lamp and fundus examination and full-field ERG. RESULTS: A maculopathy associated with both photopic and scotopic abnormal ERG was present in two cases and a salt and pepper retinopathy with abnormal photopic ERG was detected in the third patient. CONCLUSIONS: Despite early treatment and regular metabolic controls, all our patients exhibited both retinal and ERG abnormalities. There was no correlation between funduscopic appearance and the type of photoreceptor dysfunction. A literature review disclosed a retinopathy in 29 / 70 cases with cblC disease, with an abnormal ERG in 8 of the 12 tested cases, most with retinopathy. Retinal dysfunction in cblC disease may be more frequent than previously thought, and can involve cones only or both rods and cones. We recommend a formal ocular examination with full-field ERG in patients with Cblc disease.

Capucin: a novel striatal marker down-regulated in rodent models of Huntington disease.

In an initial study, we compared quantitative transcriptome data across mouse brain territories using the serial analysis of gene expression method. Among the novel regional markers that we discovered, we focused on a striatum-enriched transcript with no available experimental cDNA sequence. Here, we report its cloning, gene structure, and detailed distribution in mouse brain. Quantitative RT-PCR and in situ hybridization demonstrated predominant expression in dorsolateral striatum. We therefore named it capucin for caudate-and putamen-enriched sequence. Mouse capucin is a 237-amino-acid protein, without any registered ortholog in mammalian species. It contains no recognizable motif other than two predicted carboxy-terminal transmembrane domains. When expressed in fusion with a fluorescent protein, it localized to the Golgi apparatus in two mammalian cell lines. Interestingly, we observed a significant down-regulation of capucin mRNA levels in two rodent models of Huntington disease, indicating a possible contribution to the pathogenesis of this disorder.

[Optical coherence tomography in Malattia Leventinese]. / Tomographie a coherence optique dans la Malattia leventinese.

BACKGROUND: Malattia Leventinese (ML) is a genetically homogeneous macular dystrophy with an autosomal dominant mode of inheritance. Ophthalmoscopically it is recognisable by a radial pattern of drusen-like deposits in the macula and by parapapillary deposits, named Forni's verrucosities. The aim of this study is to describe optical coherence tomographic (OCT) findings and to compare them with histological data. PATIENTS AND METHODS: Six patients underwent ophthalmological examination, angiography and OCT. Diagnosis was confirmed by genetic analysis of the R345W mutation. A histopathological study of an ML donor eye was performed. RESULTS: OCT revealed a diffuse RPE-choriocapillaris thickening with nodular features in the macular and parapapillary areas. The protrusions reached as far as the outer nuclear layer. CONCLUSIONS: OCT is a non-invasive technique that provides a cross-sectional picture of the retina comparable to a histological section. In ML, OCT revealed a diffuse alteration of the RPE-Bruch's membrane complex. The macular and parapapillary nodular lesions are the tomographic equivalents of drusen and Forni's verrucosities.

[Self-mutilation with crystalline lens dislocation in Gilles de la Tourette disease treated with retropupillary "iris claw" lens]. / Automutilation avec luxation cristallinienne dans la maladie de Gilles de la Tourette traitée par lentille "iris-claw" rétropupillaire.

BACKGROUND: Gilles de la Tourette syndrome is a neurological disorder characterized by motor and vocal tics. Extreme forms of this disease manifest themselves with self-mutilating behavior and foul language. HISTORY AND SIGNS: A 59-year-old man, treated for Gilles de la Tourette syndrome, presented with visual loss after an attack during which he punched his right eye with his fist. On examination visual acuity was decreased to finger counting but could be improved to 1.0 with an S + 13D lens. There was vitreous prolaps into the anterior chamber and pigment was noted in the vitreous cavity. The complete dislocated lens could be seen ophthalmoscopically in the inferior fundus of the eye. THERAPY AND OUTCOME: The patient was treated with vitrectomy and phacoemulsification through the pars plana. An additional encircling band was placed due to peripheral retinal tears in the inferior quadrants. Visual rehabilitation was achieved with a secondary implant of a retropupillary iris-claw lens nine months later. DISCUSSION: Self-inflicted injuries are common in Gilles de la Tourette syndrome. Ocular lesions described in the literature comprise isolated cases of orbital hemorrhage, retinal detachment and permanent severe visual loss. Lens luxation has not been described before, and is probably due to weakened zonulae induced by repeated trauma. Treatment with a retropupillary iris-claw lens is the preferred therapy as it reduces the risk of endothelial touch during repeated trauma on the eye.

Determination of functional activity of alpha 1-protease inhibitor and alpha 2-macroglobulin in human plasma using elastase.

The competitive binding of human alpha 1-antitrypsin and human alpha 2-macroglobulin to porcine pancreatic elastase was studied. Mixtures of these two protease inhibitors, when titrated against elastase give inhibition curves analogous to those obtained with human plasma. This is however not the case when the individual inhibitors are used. A theoretical treatment enabled us to devise an assay method to determine the amounts of functional activity of alpha 1-protease inhibitor and alpha 2-macroglobulin respectively in human plasma.

Functional levels of alpha 2-macroglobulin in plasma in relation to emphysema.

In most studies, concentrations of alpha 2-macroglobulin are determined by immunological techniques. In this study, the amidolytic activity of porcine pancreatic elastase complexed with alpha 2-macroglobulin was measured using an elastase-specific substrate, succinyl-trialanyl-p-nitroanilide. The activities of plasmas from 47 emphysema cases were compared with 39 normal subjects. The age ranges of both groups were from 50 to 84 years. The mean activity of bound elastase in emphysema cases was 2.48 +/- 0.03 kU/l of plasma. The mean for normal subjects was 1.48 +/- 0.11 kU/l of plasma. The difference was very significant (2P less than 0.001). All except 2 of the emphysema cases had smoked. The same results were obtained when only people who had smoked for 25 years or more were included in the analysis. All the plasma samples of people included in the study were assayed by an immunological method for absolute level (in g/l) of alpha 1-proteinase inhibitor. The levels of alpha 1-proteinase inhibitor for all the persons studied fell within the normal range for MM-phenotypes (2 to 4 g/l).

Posterior ischemic optic neuropathy: case report of a rare complication after general surgery.

BACKGROUND: Posterior ischemic optic neuropathy (PION) is a rare cause of bilateral severe and bilateral visual loss. Three mechanisms for posterior ischemic optic neuropathy are recognized: arteritic, non-arteritic, and peri- or postoperative. We report a case of bilateral postoperative posterior ischemic optic neuropathy. HISTORY AND SIGNS: A previously healthy 51-year-old man complained of the sudden onset of visual loss and unformed visual hallucinations in both eyes, 24 hours after an uneventful lumbar spine surgery. Duration of surgery was 12 hours with 2.5 liters of blood loss. At the time of visual loss, anemia was 74 g/L. Ophthalmic examination revealed decreased visual acuity to count fingers and normal optic disc without swelling or hemorrhages in both eyes. THERAPY AND OUTCOME: Despite blood transfusion 2 days after visual loss, evolution was stable. One month later, visual acuity was 0.15 RE and 0.2 LE with severe dyschromatopsia. Pupils reacted sluggishly to light but briskly to convergence. Optic discs were diffusely pale. DISCUSSION: Peri- and postoperative posterior ischemic optic neuropathy is a rare but devastating complication of surgery performed at distance from the visual pathways and its vascularization. Risk factors include: spine surgery, peri-operative hypotension, anemia, facial edema. Early recognition of posterior ischemic optic neuropathy and rapid correction of hypotension and/or anemia might improve outcome of posterior ischemic optic neuropathy, which usually is poor.

[The syndrome of ovarian hyperstimulation]. / Syndrome d'hyperstimulation ovarienne.

The ovarian hyperstimulation syndrome (SHO) can be defined as an iatrogenic pathology induced by active substances administered for controlling follicular maturation and ovulation. The etiology, the physiopathology, the diagnostic and therapeutic methods available are discussed. A theoretical model, based on clinical data, allows identification of a set of criteria which should help determining prospectively the chances of development of such a pathology.

Differences in the genotypes and plasma concentrations of the INTERLEUKIN-1 receptor antagonist in black and white South African asthmatics and control subjects.

The allelic frequency of a variable tandem repeat (VNTR) polymorphism in intron 2 of the IL-1 Ra gene was studied in black and white patients with asthma as well as control individuals. The plasma IL-1 Ra concentration was also determined in asthmatics and compared to control individuals. The 410-bp allele of the IL-1 Ra was significantly increased in all black subjects (90%) as compared to all white subjects (74%, P<0.0001), while the 240-bp allele was significantly reduced in all black subjects (11%) as compared to all white subjects (27%, P<0.0001). There was no difference in the frequency of the VNTR of the IL-1 Ra between black asthmatics and black controls and between white asthmatics and white controls. The IL-1 Ra levels were significantly increased in black and white patients with severe or moderate asthma as compared to patients with mild asthma. Increased plasma concentrations of the IL-1 Ra was found to be associated with disease severity in all asthmatic patients.