[Magnetic resonance imaging for delineation of prostate in radiotherapy: monocentric experience and review of literature]. / Imagerie par résonance magnétique et délinéation de la prostate en radiothérapie : expérience monocentrique et revue de la littérature.

PURPOSE: To assess the benefits of magnetic resonance imaging (MRI) in the dosimetric treatment planning for prostate radiotherapy. PATIENTS AND METHODS: Ten consecutive patients have been enrolled. They were treated for a low risk prostate adenocarcinoma. A rigid superimposition was performed between MRI and scan slides obtained at time of virtual simulation, then prostate volume was delineated by four to five physicians, on TDM slides and on MRI/TDM superimposition. For each treatment plan, we assessed the impact of MRI in terms of planned treatment volume (PTV) position, individual variability of prostate delineation and doses delivered to the critical organs. The prescribed dose was 74 Gy in 37 fractions to the PTV. RESULTS: PTV delineated on TDM (V(TDM)) were 1.15 (SD 3.71) larger than volumes delineated on MRI. Prostate apex was 4.6 mm (SD 2.87) lower on TDM than on MRI. Posterior limit of the prostate was in mean 4 mm more posterior on TDM. The variability between physicians in terms of prostate delineation was lower using MRI. For apex, these variations were 6.8 mm using TDM, versus 3.3 mm using MRI. Mean rectal dose was 8 % lower with MRI, compared to delineation using TDM. CONCLUSION: Superimposition TDM/MRI improves accuracy, decreases delineation variability, and allows to spare anterior part of the rectum from irradiation. It remains unknown whether this strategy translates into clinical benefit.

The presence of ancient human T-cell lymphotropic virus type I provirus DNA in an Andean mummy.

The worldwide geographic and ethnic clustering of patients with diseases related to human T-cell lymphotropic virus type I (HTLV-I) may be explained by the natural history of HTLV-I infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-I is generally detected in both groups. To clarify the common origin of HTLV-I in Asia and the Andes, we analyzed HTLV-I provirus DNA from Andean mummies about 1,500 years old. Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-I-pX (open reading frame encoding p40x, p27x) and HTLV-I-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-I-pX and HTLV-I-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-I was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-I sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.

[Causes, diagnosis and treatments of circulatory shocks]. / États de choc : grands cadres étiologiques, prise en charge initiale.

Shock states are the leading causes of intensive care admission and are nowadays associated with high morbidity and mortality. They are driven by a complex physiopathology and most frequently a multifactorial mechanism. They can be separated in whether a decrease of oxygen delivery (quantitative shock) or an abnormal cell distribution of cardiac output (distributive shock). Septic, cardiogenic and hypovolemic shocks represent more than 80% of shock etiologies. Clinical presentation is mostly characterized by frequent arterial hypotension and sign of poor clinical perfusion. Hyperlactatemia occurs in most of shock states. The diagnostic of shock or earlier reversible "pre-shock" states is urgent in order to initiate adequate therapy. Therefore, orientation and therapies must be discussed with intensive care physiologists in a multidisciplinary approach. Etiologic investigation and correction is a primary concern. Hemodynamic and respiratory support reflect another part of initial therapy toward normalization of cell oxygenation. Fluid resuscitation is the corner stone part of initial therapy of any form of shock. Vasoconstrictive drugs or inotropic support still often remain necessary. The primary goal of initial resuscitation should be not only to restore blood arterial pressure but also to improve clinical perfusion markers. On the biological side, decrease of lactate concentration is associated with better outcome.

Potentiation of thyroxine 5-deiodination by aminotriazole.

Aminotriazole, a goitrogen, in addition to its known inhibitory effects on the thyroid, demonstrated a unique effect on peripheral deiodination of thyroxine (T4). In contrast to the well-known peripheral effects of goitrogens such as propylthiouracil in inhibiting 5'-deiodinase activity, i.e., to effect a decrease in T4 to triiodothyronine (T3) conversion, aminotriazole had no effect on the 5'-deiodinative pathway. Rather, this goitrogen appeared to stimulate the alternative pathway, viz. T4 5-deiodination, resulting in an increased reverse triiodothyronine (rT3) serum concentration. This was shown in comparisons of serum T4, T3 and rT3 concentrations and serum T3/T4 and rT3/T4 ratios between rats treated with aminotriazole and T4, and rats treated with T4 alone. The finding that aminotriazole may specifically enhance T4 5-deiodination, independently of T4 5'-deiodination, is novel, as this has not been observed in the case of other goitrogens. It is of interest that this goitrogen is devoid of sulphur, which is a prominent constituent of thiourylene compounds which have been noted to affect 5'-deiodination. The potentiating effect of aminotriazole on 5-deiodination of T4 was not attributable to dietary factors.

Simultaneous adult T-cell leukemia/lymphoma and sub-acute polyneuropathy in a patient from Chile.

This paper reports a case of adult T-cell leukemia/lymphoma associated with human T-cell lymphotropic virus type I (HTLV-I) diagnosed in a Chilean patient who developed after 1 1/2 years a crisis with a progressive sensorimotor polyneuropathy. Serum and cerebrospinal fluid HTLV-I antibody tests were positive and HTLV-I DNA was clonally integrated in peripheral lymphocytes. This case is unusual in having simultaneous neurological disease. Along with other recent data from South America, this suggests that the endemic area of HTLV-I may spread far beyond the Caribbean area.

Clinical and neuropathological study of six patients with spastic paraparesis associated with HTLV-I: an axomyelinic degeneration of the central nervous system.

Between 1990 to 1994, 6 TSP/HAM patients, 3 women and 3 men with an average age of 57.1 years (39 to 76 years old), who died in the Salvador Hospital were submitted to postmortem examination. The mean time of paraparesis was 7 years (3 to 17 years), and 2 patients had pseudobulbar signs. Three cases had macroscopic atrophy of the spinal cord. Histologically, all cases had lesions in the pyramidal tracts and 4 cases showed somatotopic lesions of the Goll's tracts which followed a "dying back" ascendant and descendant distribution, respectively. In 2 cases, both of which had intellectual impairment, demyelination of the subcortical and parathalamic areas was observed without U fiber involvement. Abnormal vessels with gross thickening of the adventitia, many of them with lymphocytic cuffs, were seen everywhere, especially in the spinal cord, brain stem, midbrain and meninges, but no relation between these findings and the parenchymal lesions was observed. Also, in the cases with posterior column involvement, neuronal changes and proliferation of satellite cells in the dorsal ganglia were found. All cases showed histological sialoadenitis and none had inflammatory muscle changes. We conclude that the lesions affected the neuraxis in a systemic axial fashion as in degenerative diseases, and did not seem to be secondary to vascular or inflammatory abnormalities.

Genetic characterization and phylogeny of human T-cell lymphotropic virus type I from Chile.

Infection with Human T-Cell Lymphotropic Virus type I (HTLV-I) have been associated with the development of the HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Phylogenetic analyses of HTLV-I isolates have revealed that HTLV-I can be classified into three major groups: the Cosmopolitan, Central African and Melanesian. In the present study, we analyzed the tax, 5' ltr, gag, pol, and env sequences of proviruses of PBMC from ten HAM/TSP patients to investigate the phylogenetic characterization of HTLV-I in Chilean patients. HTLV-I provirus in PBMC from ten Chilean patients with HAM/TSP were amplified by PCR using primers of tax, 5' ltr, gag, pol, and env genes. Amplified products of the five genes were purified and nucleotide sequence was determined by the dideoxy termination procedure. DNA sequences were aligned with the CLUSTAL W program. The results of this study showed that the tax, 5' ltr, gag, pol, and env gene of the Chilean HTLV-I strains had a nucleotide homology ranged from 98.1 to 100%, 95 to 97%, 98.9 to 100%, 94 to 98%, and 94.2 to 98.5% respect to ATK-1 clone, respectively. According to molecular phylogeny with 5' ltr gene, the Chilean HTLV-I strains were grouped with each other suggesting one cluster included in Transcontinental subgroup.

Defective human T-cell lymphotropic virus type I (HTLV-I) provirus in seronegative tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM) patients.

Infection with human T-cell lymphotropic virus type I (HTLV-I) have been associated with the development of the tropical spastic paraparesis/HTLV-I-associated myelopathy (TSP/HAM). We studied the presence of HTLV-I provirus in peripheral blood mononuclear cells (PBMC) from 72 Chilean patients with progressive spastic paraparesis by polymerase chain reaction: 32 seropositive and 40 seronegative cases. We amplified different genomic regions of HTLV-I using primers of 5' ltr, tax, env/tax, pX, pol and env genes. These genes were detected from all seropositive patients. The seronegative patients were negative with 5' ltr, pol, env, and pX primers. However, amplified product of tax and env/tax genes was detected from 16 and four seronegative patients, respectively. Three of them were positive with both genetic regions. The results of this study show that the complete HTLV-I provirus is found in 100% of seropositive cases. In seronegative cases, clinically very similar of seropositive cases, was found only tax gene in 42.5% (17/40) of patients. These results suggest the presence of a defective HTLV-I provirus in some seronegative patients with progressive spastic paraparesis, and suggest a pathogenic role of this truncate provirus for a group of TSP/HAM.

Ancient HTLV type 1 provirus DNA of Andean mummy.

The worldwide geographic and ethnic clustering of patients with diseases related to human T cell lymphotropic virus type 1 (HTLV-1) may be explained by the natural history of HTLV-1 infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-1 is generally detected in both groups. To clarify the common origin of HTLV-1 in Asia and the Andes, we analyzed HTLV-1 provirus DNA from Andean mummies about 1500 years old. Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-1-pX (open reading frame encoding p(40x), p(27x)) and HTLV-1-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-1-pX and HTLV-1-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-1 was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-1 sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.

Characteristic distribution of HTLV type I and HTLV type II carriers among native ethnic groups in South America.

To confirm the geographic and ethnic segregation of HTLV-I and HTLV-II carriers in native populations in South America, we have conducted a seroepidemiological study of native populations in South America, including HTLV-I carriers distributed among seven ethnic groups in the Andes highlands of Colombia, Peru, Bolivia, Argentina, and Chile, and two ethnic groups on Chiloe Island and Easter Island; and HTLV-II carriers distributed among seven ethnic groups of the lowlands along the Atlantic coast of Colombia, Orinoco, Amazon, and Patagonia, and one ethnic group on Chiloe Island. The incidence rate of HTLV-I and HTLV-II carriers varied among the ethnic groups, ranging from 0.8 to 6.8% for HTLV-I seropositivity and from 1.4 to 57.9% for HTLV-II seropositivity. A new HTLV-I focus was found among the Peruvian Aymara (1.6%), the Bolivian Aymara (5.3%) and Quechua (4.5%), the Argentine Puna (2.3%), and the Chilean Atacama (4.1%), while on HTLV-II focus was found among the Brazilian Kayapo (57.9%), the Paraguayan Chaco (16.4%), and the Chilean Alacalf (34.8%) and Yahgan (9.1%). The distribution of HTLV-I/II foci showed a geographic clustering of HTLV-I foci in the Andes highlands and of HTLV-II foci in the lowlands of South America. It was thus suggested that South American natives might be divided into two major ethnic groups by HTLV-I and HTLV-II carrier state.

A private view of heterozygosity: eight-year follow-up study on carriers of the Tay-Sachs gene detected by high school screening in Montreal.

We surveyed 264 persons (132 carriers, 132 matched noncarriers) screened for Tay-Sachs heterozygosity during 1974-76 in a program directed at senior high school students in Montreal. Among 198 who apparently received the questionnaire in 1982, the response rate was 42% (38 carriers, 45 noncarriers; age range 21-26 yr). Respondents and nonrespondents had no apparent demographic differences. Of eight unable to remember their genotype only one was a carrier (these persons were excluded from the study). The subjects were: single (75%), married (20%), engaged (3%), divorced (1%); 32% of carriers were engaged or married vs 16% of noncarriers. (There were no carrier couples in our sample, but one such couple, who married after being screened in the high school program, requested amniocentesis in 1981.) Only three of the 12 spouses or fiancé(s) of carriers have not been tested (vs 3 of 6 noncarrier partners). Only 19% of carriers now attach any "worry" to heterozygosity (vs 46% at the earlier time of test disclosure, P = 0.001); carriers with spouses or fiancé(e)s are less "worried" than unattached carriers. Only 3% of carriers claim they would change marriage plans if their fiancé(e) was also a carrier. Carriers and noncarriers uniformly approve (96%) genetic screening for themselves and for other mutant genotypes; 92% of carriers and 95% of noncarriers approve being screened in high school. These findings indicate that Canadians screened in high school: 1) have largely positive attitudes toward genetic screening long after the experience, and 2) are making appropriate use of the test result.

Chorionic villi sampling: women's attitudes.

To determine the acceptability of chorionic villi sampling (CVS) to women eligible for prenatal diagnosis, we undertook a survey to identify aspects of this new procedure that made it more or less preferable than amniocentesis. All women greater than or equal to 35 years scheduled for amniocentesis were asked to read some detailed descriptive material about amniocentesis and CVS, to rate the importance of the specific differences between procedures, and to indicate which procedure they would prefer, first considering each difference between them independently and then considering all the factors jointly. In the absence of precise estimates of CVS-associated risk at the time of the survey, almost equal proportions preferred amniocentesis and CVS (50.2 and 45.1%, respectively). Risk information was the most important factor to women preferring amniocentesis; the timing of the test or nature of the termination procedure was most important to those preferring CVS. In the hypothetical case where CVS was stipulated to have the same attributable risk as amniocentesis, 82% of respondents would prefer it. However, if the spontaneous abortion rate following CVS was stipulated to be 5% more than the amniocentesis risk, preferences reversed and only 22% would still prefer it. Thus, the data suggest that the ultimate acceptability of the new procedure for women over 35 years seeking prenatal diagnosis will depend on the risk associated with it and underscore the importance of ongoing trials aimed at establishing this risk.

New form of bone dysplasia with multiple fractures associated with monosomy X.

We report on the clinical, radiologic, and pathologic findings in a 20-week-old fetus with monosomy X and severe hydrops associated with fetal dwarfism. The fetus presented with osteoporosis, bent bones, multiple fractures, and distinctive symmetric submetaphyseal transverse bone interruptions or pseudofractures. We excluded by radiologic and histopathologic examination the diagnoses of osteogenesis imperfecta, hypophosphatasia, campomelic dysplasia, achondrogenesis, hypochondrogenesis, and other types of bone dysplasia. To our knowledge, this is a previously undescribed bone dysplasia associated with monosomy X. This bone dysplasia may be inherited as an X-linked recessive disorder.

Sympathoadrenal system and activation of glycogenolysis during muscular activity.

Comparisons were made of the appearance of phosphorylase (PHOS) a and lactate (LA) during electrical stimulation of the gastrocnemius (GM) and soleus (SM) muscles of normal and sympathectomized (SYMPX) rats. Ten-second stimulation at 3 Hz increased PHOS a approximately fourfold in the GM of normal rats, whereafter it declined during stimulation until at 60 s it was similar to rest. The increase in PHOS a of GM from SYMPX rats after 10 s of stimulation was approximately 50% that of normal rats. Stimulation of the SM produced smaller and slower increases in PHOS a with the peak occurring after 60 s, which remained constant to 90 s. SYMPX did not alter this effect in the SM. LA production and creatine phosphate depletion in the GM were continuous throughout stimulation and uninfluenced by SYMPX. This was true for the SM with the exception of LA production being greater after SYMPX. [ATP] was unchanged by electrical stimulation. The rate and magnitude of the PHOS a appearance was a function of stimulation frequency. Reversion of PHOS to the b form after stimulation was rapid, with approximately 50% of the peak value being attained in 2.5 s, and at 5 s the values were those of rest. These data demonstrate that an intact sympathoadrenal system is not obligatory for the initiation of glycogenolysis in skeletal muscle.

Neuropathological changes in the rat brain cortex in vitro: effects of kainic acid and of ion substitutions.

The ionic mechanisms that may contribute to the neurotoxicity of kainic acid, were studied in a system of rat thin neocortical slices superfused in vitro. Slices superfused for 3 h under control conditions showed an essentially normal aspect when studied by light microscopy. Presence of 30 microM kainate in the superfusion fluid induced neuronal swelling, nuclear condensation and signs of necrosis in some cells, while other neurons, especially in deeper layers, appeared dark and condensed, with microvacuolation. The neuropil presented numerous profiles of swollen dendrites. When the slices were superfused with chloride-free medium, a large number of pyknotic neurons was seen. This was further enhanced by 30 microM kainate, which produced no swelling in this medium. These effects of Cl-free medium were almost entirely prevented in Cl-free medium without calcium and with 0.1 mM of EGTA. Sodium-free medium induced a marked neuronal swelling that was not much changed by kainate. When calcium in an otherwise normal superfusion fluid was reduced to 0.1 mM, a large number of pyknotic neurons, some with incrustations, were seen. Kainate (30 microM) in this low calcium medium led to a very large swelling and destruction of neurons, and to a spongy neuropil. These effects of kainate were greatly intensified in calcium-free-EGTA (0.1 mM) medium. Ca-free-EGTA medium by itself induced considerable neuronal and neuropil swelling. It is concluded that kainate induces neuronal swelling by a sodium- and chloride-dependent mechanism, and the enhancement of swelling in low calcium is due to an increased sodium uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

HTLV-I positive progressive spastic paraparesis (TSP) associated with a lymphoid disorder in three Chilean patients.

We describe the clinical and laboratory features in three Caucasian Chilean patients with tropical spastic paraparesis (TSP) associated with/or preceded by a lymphoproliferative disorder involving cutaneous lesions and localised lymphadenopathy. The neurological symptoms and signs were characteristic of TSP and CSF examination revealed the presence of oligoclonal bands. All three patients had a moderate leucocytosis (10-14 x 10(9)/l) with eosinophilia and a minority (2-4%) of circulating atypical polylobed or ATLL-like lymphocytes. Lymph node histology showed a diffuse pattern of infiltration (1 case) and marked expansion of the paracortical zone with convoluted lymphocytes and immunoblasts (2 cases). Skin biopsy demonstrated a dermal lymphoid infiltration with epidermotropism. Antibodies to HTLV-I were detected in the serum and CSF in the three patients and Southern blot analysis of peripheral blood mononuclear cells showed a monoclonal integration of HTLV-I proviral DNA in one case whereas in the two others the pattern was indicative of low level polyclonal integration. All three patients were treated with prednisolone and one with PUVA with transient partial response on the skin and neurological manifestations. Two patients died months to 5 years from presentation and the other is alive 12 years from diagnosis with active neurological and skin disease. The simultaneous occurrence of HTLV-I associated TSP with smouldering ATLL and a cutaneous ATLL or pre-leukaemic form is discussed.

Segmental demyelination induced by cerebrospinal fluid of progressive spastic paraparesis: correlation with altered proteolytic parameters.

Progressive spastic paraparesis (PSP) is a demyelinating disease of the central nervous system. We studied the ability of the cerebrospinal fluid (CSF) of patients to induce alterations in rat peroneal nerves, and to modify the proteolytic activity of trypsin in vitro. Subperineurial injection of native or heated CSF of patients induced segmental demyelination and other cytological alterations 5-7 days later, in the infiltrated zone, while proximal and distal regions were normal. The CSF of normal subjects did not induce demyelination, but upon heating, it did so. Trypsin was strongly inhibited by the normal CSF but upon heating, its inhibitory activity was replaced by a strong potentiation. In contrast, native and heated CSF of patients potentiated trypsin. Our findings indicate that (1) the normal CSF contains a thermostable factor that potentiates trypsin whose function is overruled by thermolabile protease inhibitors; (2) the CSF of PSP patients has a reduced inhibitory activity and a conserved ability to potentiate trypsin; and (3) the CSF is endowed with a pathogenic power that correlates with an unchecked potentiating activity. We propose that the imbalance of a protease system may play a role in the pathogenesis of PSP lesions.

Familial Creutzfeldt-Jakob disease in Chile.

Of the 87 cases of Creutzfeldt-Jakob disease (CJD) ascertained in Chile since 1931, 39 are familial accounting for 45% of all cases, and 25% of the 51 definite cases. There are 11 affected families with an average of 3.5 affected members per family, and a rate of occurrence consistent with autosomal dominant transmission. There is no evidence for maternal lineage, and age at death is not significantly different from that of sporadic cases. About half of the cases died around the same age, suggesting some form of vertical transmission. Three pairs of affected members in 3 different families died at the same time, possibly indicating common exposure to CJD agent. The study of absolute death intervals and temporal and spatial separations between affected members suggests minimum incubation periods ranging from 2 to 37 years, assuming case-to-case transmission. CJD occurring in a woman related by marriage to one of the affected families strongly argues for horizontal transmission. The high proportion of familial CJD observed in Chile is probably the result of both a genetically determined susceptibility to the CJD virus, and a high degree of case ascertainment. However, the present study leaves unanswered the mode of transmission of the agent within the affected families.

Cerebrospinal fluid of HTLV-1 associated myelopathy patients induces axonal sproutings and Schwann cell proliferation in the rat sciatic nerve.

HTLV-1 (human T-cell leukemia virus type I) associated myelopathy (HAM) is a demyelinating disease. We showed that the CSF of patients and heated CSF of normal subjects induce a segmentary demyelination in rat nerves, and potentiate trypsin in vitro. Here we further characterize the neuropathy induced by the CSF of patients. Peroneal nerves injected 5-8 days before with native or heated CSF of patients, besides extensive demyelination, presented proliferation of myelinating and nonmyelinating Schwann cells, axonal sprouting, fine fibres with a few turns of myelin, disarray of nonmedullated bundles, desmosome-like junctions, and coated pits and vesicles in Schwann cells and axons. The normal CSF was innocuous to the nerve in its native form, but after heating, it induced a neuropathy in all, similar to that elicited by the CSF of patients. Our findings indicate that the CSF of HAM patients contains a thermostable pathogen for nerves of the rat; a thermostable pathogen also occurs in the normal CSF although its activity is checked by endogenous thermolabile factors. We suggest that the pathogen present in the CSF of HAM patients participates in the disease.

Familial Creutzfeldt-Jakob disease in Chile is associated with the codon 200 mutation of the PRNP amyloid precursor gene on chromosome 20.

We have found the codon 200Lys mutation in 6 Chilean CJD families, including a family in the rural case cluster in Chillán. Thus, all 3 of the known clusters of CJD, in Slovakia, Libyan-born Israeli Jews, and Chile, are linked to the presence of the same mutation. The phenotypic features of the disease in these families are similar to those reported for other clustered or individual families elsewhere in the world. The heterogeneous genetic composition of the Chilean population interpreted in light of historical migration patterns suggests that the mutation may have entered Chile by Jewish emigration from Spain.