Computed tomography of renal metastases

Since the advent of CT, secondary neoplastic lesions of the kidneys have been detected with increasing frequency. After reviewing a large series of cases of renal metastases, we have been able to classify the CT findings into seven major categories that are discussed and illustrated in this article. The differential diagnoses between metastatic disease of the kidneys and other lesions such as renal infarctions, renal lymphoma, and primary malignancies are also considered.     

Urinary mercapturic acid diastereoisomers in rats subchronically exposed to styrene and ethanol

 Styrene is stereoselectively oxidized by cytochrome P450 to its reactive metabolite, styrene oxide. The (R)- and (S)-enantiomers of styrene oxide can be conjugated with glutathione (GSH) to both (R)- and (S)-diastereoisomers of the specific mercapturic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). Several investigations have indicated different toxic potential of the (R)- and (S)-configurations of styrene oxide and its GSH- and N-acetyl-conjugates. In this study the mercapturic acid diastereoisomers were measured in the urine of rats exposed to styrene in combination with ethanol, a good inducer of styrene metabolism. Male Sprague-Dawley rats were given an isocaloric liquid diet containing ethanol (5% w/v) for 3 weeks. Starting from the 2nd week, the animals were also exposed to styrene vapours (300 ppm, 6 h/day, 5 days/week) in a dynamic exposure chamber. Both the (R)- and (S)-diastereoisomers of the M1 and M2 as well as the conventional biomarkers, mandelic acid (MA) and phenylglyoxylic acid (PGA) were measured in urinary samples. Approximately 30 and 25% reduction of the levels of brain non-protein sulfhydryls (NPS) was observed in the animals given styrene and ethanol, respectively, while the combined ethanol and styrene treatment resulted in a 60% decrease. Ethanol consumption also resulted in higher urinary levels of the M1-R, M1-S and M2 metabolites associated with increased M1-R/S ratio and higher urinary MA excretion compared to animals treated with styrene. These results suggest that the urinary mercapturic acid diastereoisomers may be used as a noninvasive tool to examine stereoselective patterns of styrene metabolism in vivo, as well as their alterations caused by ethanol. These compound-specific mercapturic acids may also be valuable indicators of styrene-induced disorders of GSH homeostasis in nonaccessible organs. Received: 19 December 1995/Accepted: 10 May 1996     

Role of vasopressin on excitatory amino acids mediated pressor responses in the periaqueductal gray area

In order to evaluate the role played by vasopressin on pressor responses elicited by stimulation of the periaqueductal gray (PAG) area by excitatory amino acids we carried out in vivo studies in genetically vasopressin deficient rats (Brattleboro). Microinjections of l-glutamic acid (glutamate, 0.6 to 60 nmol/rat) or N-methyl-d-aspartic acid (NMDA, 0.07 to 7 nmol/rat) into the PAG area of freely moving Brattleboro rats induced increases of arterial blood pressure values significantly lower than those obtained in Long Evans rats (control) (glutamate in Brattleboro rats: from +2±1 mmHg to 16±3 mmHg; glutamate in Long Evans rats: from +16±2 mmHg to +36±4 mmHg; NMDA in Brattleboro rats: from +5±2 mmHg to +34 ±8 mmHg; NMDA in Long Evans rats: from +18±7 mmHg to 80±9 mmHg; n=5). Similarly, in anaesthetized Brattleboro rats (urethane 1.2 g/kg i.p.) pressor responses to NMDA microinjections (0.7 nmol/rat) into the PAG area were significantly lower than in Long Evans rats (controls) (+15±3 mmHg vs +24±4 mmHg). In Long Evans rats NMDA injection also reversed blood pressure decrease induced by ganglionic blocker, hexamethonium and/or losartan (3 mg/kg i.v.), an AT1 receptor antagonist. In Brattleboro rats, NMDA injection did not reverse blood pressure decreases induced by hexamethonium (5 mg/kg i.v.). Moreover, hexamethonium induced blood pressure decrease was not reversed by acetylcholine injection (137 nmol/rat) into the PAG area of anaesthetized Long Evans rats, but if injected before hexamethonium, acetylcholine was able to increase blood pressure (+25±3 mmHg). Our results document: i) the importance of the PAG area in the control of cardiovascular system; ii) the involvement of excitatory amino acids in the neural control of vasopressin release; iii) the close relationship between glutamate and vasopressin in the central blood pressure regulation. Received: 1 April 1997 / Accepted: 2 February 1998     

The role of hyperthermic perfusion as a first step in the treatment of soft tissue sarcoma of the extremities

Eighty-six patients with locally advanced, high-grade soft tissue sarcomas of the extremities were studied prospectively in order to determine the efficacy of hyperthermic perfusion (HP) or hyperthermic antiblastic perfusion (HAP) as the first step of a combined multimodality therapy. The immediate response was evaluated in terms of tumor regression, and results confirmed the in vivo sensitivity of human sarcomas to the selective antineoplastic action of heat alone or combined with drugs (melphalan, actinomycin D, and cis-platinum). HAP has been shown to be simpler and safer than HP, and it is now currently routinely employed. As far as the long-term cure is concerned, all the patients have been evaluated for functional results, locoregional control, and survival, according to the different treatment schedules. The first clinical trials employed HP or HAP followed by delayed surgery alone. In 11 of 17 evaluable patients treated with HP, and in 17 of 29 treated with HAP, conservative surgery could be performed. A high incidence of locoregional relapse (24%) occurred, with low overall survival rates: 50.1% and 31.7% at 5 and 10 years after HP plus surgery, and 47.9% after HAP plus surgery at both 5 and 10 years. The protocol was, therefore, modified to include continuous intraarterial infusion of Adriamycin® (ADR) (17 patients) or radiotherapy (9 patients) before surgery. The results obtained thus far may be summarized as follows: (a) conservative surgery with functional limb-salvage was possible in all patients; (b) the percentage of locoregional failure decreased to approximately 12% after HAP + ADR infusion + excision, the 5- and 10-year overall survival rates both being 77.6 %, and the 5- and 10-year disease-free rates both being 57.8%; (c) no local recurrences occurred in the group treated with HAP + radiotherapy + excision with a 5-year overall survival rate of 71.5% and a 5-year disease-free rate of 50.4%. In conclusion, the combined multimodality approaches employed appear to have improved both functional results and long-term cure, even though these must be further confirmed on a larger series of patients.

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Resumen Ochenta y seis pacientes con sarcomas de los tejidos blandos de las extremidades, de alto grado histológico, e invasión local avanzada fueron estudiados en forma prospectiva con el objeto de determinar la eficacia de la perfusión hipertérmica (PH) o la perfusión hipertérmica antiblástica (PHA) como primer paso dentro de una terapia combinada multimodal.La respuesta inmediata fue valorada en términos de la regresión tumoral, y los resultados confirmaron la sensibilidad in vivo de los sarcomas humanos a la acción antineoplásica selectiva del calor sólo o combinado con drogas (melfalán, actinomicina D, y cis-platino). La PHA ha demostrado ser más sencilla y más segura que la PH y actualmente es utilizada en forma rutinaria.En lo referente a curación a largo plazo, todos los pacientes han sido evaluados en cuanto a resultados funcionales, control locorregional, y supervivencia, de acuerdo a los diferentes programas terapéuticos.En los primeros ensayos clínicos se utilizó PH o PHA seguida de cirugía solamente. En 11 de 17 pacientes valorables tratados con PH y 17 con PHA, fue posible realizar cirugía conservadora. Se presentó una incidencia alta de relapso locorregional (24%), con tasas bajas de supervivencia global: 50.1% y 31.7% a 5 y 10 años con PH y cirugía, y 47.9% con PHA y cirugía tanto a 5 como a 10 años.El protocolo fue consecuentemente modificado para incluir una infusión intraarterial continua de Adriamicina® (ADR) (17 pacientes) o radioterapia (9 pacientes) antes de la cirugía.Los resultados logrados hasta el momento pueden ser resumidos así: (a) la cirugía conservadora con salvamento del miembro fue posible en la totalidad de los pacientes; (b) el porcentaje de falla locorregional disminuyó aproximadamente 12% después de PHA + infusión de ADR + resección, con supervivencias globales a 5 y 10 años de 77.6%, y tasas de estado libre de enfermedad a 5 y 10 años de 57.8%; (c) no se presentaron recurrencias locales en el grupo tratado con PHA + radioterapia + resección, con una tasa de supervivencia global a 5 años de 71.5% y una tasa de estado libre de enfermedad a 5 años de 50.4%.En conclusión, los aproches con terapia combinada multimodal empleados parecen haber mejorado tanto los resultados funcionales como las tasas de curación a largo plazo, aunque estos resultados aún deben ser reconfirmados en una serie mayor de pacientes.

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Résumé Une étude prospective concernant 86 malades qui présentaient un sarcome des parties molles des membres de stade évolutif avancé a été entreprise pour déterminer l'efficacité de la perfusion hyperthermique ou de la perfusion hyperthermique antiblastique en tant que première étape d'un traitement à modalités multiples.La réponse immédiate a été appréciée en fonction de la régression tumorale. Les résultats ont confirmé la sensibilité in vivo des sarcomes humains à l'action antinéoplasique sélective de la chaleur employée isolemment ou combinée avec des drogues (melphalan, actinomycine D, et cis-platinum). La perfusion hyperthermique antiblastique s'est montrée plus simple et plus sûre que la perfusion hyperthermique, et de ce fait est devenue une méthode thérapeutique normalement employée.Pour apprécier l'action thérapeutique à long terme tous les malades ont été étudiés en tenant compte des résultats fonctionnels, du contrôle loco-régional, et de la survie obtenus selon les différentes thérapeutiques appliquées.Les premiers essais ont eu recours à l'hyperthermie thermique ou à l'hyperthermie thermique antiblastique suivie d'une intervention chirurgicale. Chez 11 des 17 malades traités par l'hyperthermie thermique, et chez 17 des 29 malades soumis à l'hyperthermie antiblastique le traitement chirurgical conservateur a pu être réalisé. Les résultats furent les suivants: fréquence importante des récidives loco-régionales (24%); taux global de survie bas: 50.1% et 31.7% à 5 ans et 10 ans après perfusion hyperthermique suivie de chirurgie, ce taux étant de 47.9% après perfusion hyperthermique antiblastique suivie de chirurgie à 5 ans et 10 ans.En fonction de ces résultats le protocole thérapeutique fut modifié en y ajoutant une transfusion intra-artérielle continue d'Adriamycine® (17 malades) ou de la radiothérapie (9 malades) avant l'intervention.Les résultats obtenus à ce jour peuvent se résumer ainsi: (a) la chirurgie conservatrice permettant de sauver un membre fonctionnel est toujours possible; (b) la poucentage d'échec régional décroit environ jusqu' à 12% après perfusion hyperthermique antiblastique associée à la perfusion d'Adriamycine® et l'excision, le taux global de survie à 5 ans et 10 ans étant de 77.6%, le taux d'absence de la maladie à 5 ans et 10 ans étant de 57.8%; (c) aucune récidive locale n'est survenue dans le groupe traité par perfusion hyperthermique antiblastique associé à la radiothérapie et à l'exérèse, le taux global de survie à 5 ans étant de 71.5% et le taux d'absence de la maladie à 5 ans étant de 50.4%.En conclusion le traitement qui a été employé associant plusieurs modalités thérapeutiques a entrainé une amélioration des résultats fonctionnels et de la cure à long terme encore que ce fait demande a été confirmé par une étude étendue à un plus grand mombre de malades.

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Supported by Special Project Hyperthermia from the Italian Ministry of Health.     

Prevalence of hereditary ataxias and spastic paraplegias in Molise,a region of Italy

Summary An epidemiological survey of hereditary ataxias and paraplegias was conducted in Molise, a region of Italy (335, 211 inhabitants on 1 January 1989). Total prevalence was 7.5 x 10^–5 inhabitants (95% confidence limits 4.8–11.1). There were 7 patients with Friedreich's disease, 5 with early onset cerebellar ataxia with retained tendon reflexes, 4 with ataxia-telangiectasia, 9 with hereditary spastic paraplegias (2 autosomal dominant and 7 autosomal recessive cases). There was no patient with autosomal dominant cerebellar ataxia.     

Searching for archaic contribution in Africa

Abstract

Context: Africa’s role in the narrative of human evolution is indisputably emphasised in the emergence of Homo sapiens. However, once humans dispersed beyond Africa, the history of those who stayed remains vastly under-studied, lacking the proper attention the birthplace of both modern and archaic humans deserves. The sequencing of Neanderthal and Denisovan genomes has elucidated evidence of admixture between archaic and modern humans outside of Africa, but has not aided efforts in answering whether archaic admixture happened within Africa.

Objectives: This article reviews the state of research for archaic introgression in African populations and discusses recent insights into this topic.

Methods: Gathering published sources and recently released preprints, this review reports on the different methods developed for detecting archaic introgression. Particularly it discusses how relevant these are when implemented on African populations and what findings these studies have shown so far.

Results: Methods for detecting archaic introgression have been predominantly developed and implemented on non-African populations. Recent preprints present new methods considering African populations. While a number of studies using these methods suggest archaic introgression in Africa, without an African archaic genome to validate these results, such findings remain as putative archaic introgression.

Conclusion: In light of the caveats with implementing current archaic introgression detection methods in Africa, we recommend future studies to concentrate on unravelling the complicated demographic history of Africa through means of ancient DNA where possible and through more focused efforts to sequence modern DNA from more representative populations across the African continent.     

Administration of tibolone decreases 24 h heart rate but not blood pressure of post-menopausal women

OBJECTIVE: Elevation of blood pressure and heart rate increase the risk of cardiovascular disease. Administration of estrogens does not affect heart rate but may decrease 24 h blood pressure. In this study, we tested the effect of the estro-progestogenic compound tibolone. METHODS: Thirty healthy, post-menopausal women were randomized to receive placebo (n = 15) or tibolone, at the commonly prescribed dose of 2.5 mg per day (n = 15). Before and after 6 months of treatment, in each woman blood pressure and heart rate were monitored every 30 min for 41 h by an ambulatory device. Valuable readings were those collected from 8:00 a.m. of the second day to 8:00 a.m. of third day. Analyses were performed of 24 h, day-time (7:00 a.m.-11:00 p.m.) and night-time (11:00 p.m.-7:00 a.m.) values. Day to night difference was also calculated. Results: Placebo did not modify 24h, day-time, and night-time blood pressure or heart rate values. Day-night differences were also not affected by placebo. Similarly to placebo, tibolone administration did not modify any of the blood pressure parameters taken into consideration. By contrast, a significant decline of 24 h heart rate (73.2 +/- 2.3 beats/min versus 69.3 +/- 1.7 beats/min; P < 0.0008) was observed. The effect was significant both at day (76.6 +/- 2.4 beats/min versus 72.1 +/- 1.9 beats/min; P < 0.0001) and night (65.8 +/ 2.6 beats/min versus 62.4 +/- 1.9 beats/min; P < 0.05). Day-night blood pressure and heart rate differences were not affected by tibolone. CONCLUSIONS: In post-menopausal women, administration of tibolone does not influence 24 h blood pressure but reduces heart rate.     

Cellular and subcellular localization of the small G protein RhoA in the human and rat embryonic and adult kidney

Rho proteins, a subgroup of the Ras GTPase superfamily, control many cellular processes and morphogenetic events by acting as signaling molecules in the transduction pathways of various receptors. Among the "Rho-dependent" receptors are the extracellular matrix- and growth factor-binding sites; these are particularly involved in the modulation of renal development since they control the epithelial-mesenchymal interactions that drive kidney organogenesis. The present study has addressed the immunohistochemical localization of RhoA in developing and adult kidneys of rats and humans because: a) Rho proteins are known to have a morphogenetic role, b) data in the literature on expression of Rho GTPases during mammalian histogenesis and organogenesis are scarce, and c) their involvement in the transduction pathways of receptors is implicated in kidney development. In particular, RhoA peptide was found to be localized in the mesonephric duct and vesicles in both rats and humans; metanephric anlagen were mainly stained in ampullar-derived cells. Periglomerular tubules of fetal and adult kidneys as well as collecting ducts of adult kidneys showed intense staining. Therefore, the present study provides new information on the distribution patterns of RhoA during early stages of mammalian kidney development suggesting that this signaling molecule may take part in epithelial-mesenchymal induction processes that control kidney organogenesis. RhoA expression in adult structures may be linked with renewal of renal epithelial cells and the maintenance of their morphology and polarity.     

Colorectal polyposis with mixed juvenile and adenomatous patterns

Summary An unusual form of colorectal polyposis is described displaying juvenile, adenomatous and mixed patterns in a 17-year-old girl. Although juvenile polyposis is generally considered to be non-neoplastic in nature, in both the present and in other case reports histological findings support a neoplastic nature. Since an increase in the incidence of large bowel carcinomas has been found in subjects with a previous diagnosis of juvenile polyposis, these patients should be considered to be at risk, and submitted to follow up.