Strain-dependent effects of post-training GABA receptor agonists and antagonists on memory storage in mice

Post-training administration of the GABA-A and GABA-B receptor agonists muscimol and baclofen dose-dependently impaired retention of an inhibitory avoidance response in C57 mice, while improving memory consolidation in the DBA strain. By contrast, picrotoxin (blocker of GABA-activated ionophores), bicuculline (GABA-A antagonist) and CGP 35348 (GABA-B antagonist) dose-dependently improved retention in C57 mice and impaired it in DBA mice. These effects cannot be ascribed to non-specific actions of the drugs on retention performance, as the latencies during the retention test of those mice that had not received footshock during the training were not lengthened by the post-training drug administration. The effects on retention performance induced by GABA agonists and antagonists are probably due to an effect on memory consolidation, since they are observed when the drugs are given at short, but not at long, intervals after training. These results are discussed in terms of possible interaction of GABA systems with endogenous opioid and dopamine systems, whose activation has been shown to produce strain-dependent effects on memory processes. The possible utilization of these results for a genetic behavioral approach with recombinant inbred (RI) mice is also considered.     

Intralesional ethanol in the treatment of unresectable liver cancer

Percutaneous ethanol injection (PEI) under ultrasonography guidance has been widely tried in not advanced hepatocellular carcinoma (HCC). Ten years after the introduction of PEI, some conclusions of its indications can be drawn. In our series, 210 cirrhotic patients were treated; 141 with multisession PEI in an outpatient clinic, 57 with single session PEI under general anesthesia, and 12 with both. The 1-, 3-, and 5-year survival rates (by Kaplan-Meier method) were 93%, 65%, and 41% for Child class A patients with single HCC 5 cm, and 88%, 47%, and 33% for patients with multiple HCC up to five lesions 5 cm. In these patients the local recurrence rate was 15% and the new lesion rate at the 5-year follow-up was 74%. One death due to hemorrhage from esophageal varices in a Child class C patient treated by single session PEI occurred. The large number of cirrhotic patients enrolled in ultrasonography screening programs has created a large demand for effective, safe, repeatable, low-cost treatment that can be offered at many centers. PEI meets all these requirements. PEI is proposed as the treatment of choice for the mentioned patients, excluding candidates for liver transplantation and surgical resection according to the predictive adverse factors currently in use. Single session technique widened the indications of traditional PEI to larger lesions.

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Resumen La inyección percutánea de etanol (IPE) bajo guía ultrasonográfica ha sido ampliamente ensayada en carcinoma hepatocelular (CHC) no avanzado. Transcurridos diez años luego luego de la introducción de la IPE, se pueden sacar conclusiones pertinentes a su indicación: En nuestra serie, se trataron 200 pacientes cirróticos, 141 de ellos con IPE en múltiples sesiones en forma ambulatoria, 57 con una sesión única de IPE bajo anestesia generaly y 12 con ambas modalidades. Las tasas de sobrevida a 1, 3 y 5 años (por el método de Kaplan-Meier) fueron 93%, 65%, 41% en los pacientes en clase Child-A con CHC único de 5 cm, y 88%, 47% 33% en CHC múltiple de hasta 5 lesiones de 5 cm. En estos pacientes la tasa de recurrencia local fue 15% y la tasa de nuevas lesiones a los 5 años de seguimiento fue de 54%. Se presentó una muerte por hemorragia de várices esofágicas en un paciente en clase Child-C tratado con una sesión única de IPE. El gran número de pacientes cirróticos incorporados a programas de tamizaje con ultrasonido ha creado una gran demanda por tratamientos eficaces, seguros, reproducibles y de bajo costo. El IPE llena todos estos requerimientos. Se propone el IPE como el tratamiento de escogencia para los pacientes arriba mencionados, haciendo exclusión de los candidatos para transplante hepático y para resección quirúrgica de acuerdo con los factores adversos de pronóstico actualmente en uso. La técnica de une sesión única ha ampliado las significaciones tradicionales del IPE para ser aplicada a lesiones de mayor tamaño.

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Résumé L'alcoolisation par injection percutanée (APC) sous échographie est utilisée pour traiter des carcinomes hépatocellulaires (CHC) peu volumineux. Dix ans après l'introduction de la technique d'APC, on peut tirer des conclusions quant à es indications. Dans notre expérience, 210 patients cirrhotiques ont été traités: 141 ont été traités par APC en ambulatoire, 57 en «séance unique» sous anesthésie et 12 par les deux. La survie à 1, 3 et 5 ans (méthode de Kaplan-Meier) était respectivement de 93, de 65 et de 41 % pour les patients ayant une lésion unique 5 cm, classés Child A, et de 88, de 47 et de 33% chez les patients ayant des lésions multiples mais inférieures au nombre de 5, toujours 5 cm. Chez ces patients, le taux de récidive locale était de 15% et le taux de nouvelles lésions à 5 ans, de 74%. Il y a eu un décès par hémorragie en rapport avec une rupture de varices oesophagiennes chez un patient Child C traité en une seule séance d'APC. Le nombre croissant de patients actuellement soumis, à une surveillance par échographie va de paire avec un traitement efficace, sûr, de coût réduit, et facilement disponible dans de nombreux centres. L'APC répond à toutes ces conditions. L'APC peut être proposée comme traitement de choix pour des patients répondant aux critères suscités, en excluant les candidats à la transplantation ou ceux qui peuvent être traités chirurgicalement. Les indications de la technique préconisée ici, en une seule séance, s'élargissent actuellement à des lésions plus volumineuses.

     

Traumatic rupture of the thoracic aorta: Should one always operate immediately?

Although the traditional therapy for blunt traumatic rupture of the thoracic aorta (TRA) is immediate operative repair, there may be a selective role for delayed repair, particularly in patients with head trauma, respiratory failure, or cardiac dysfunction. The present study examines the hypothesis that TRA can be managed by selective delayed operative repair. Clinical data were collected from 59 consecutive patients with TRA at a regional trauma unit. All TRAs were at the aortic isthmus. Patients were retrospectively classified into three groups: group I (n=12) included patients who either arrived in extremis or rapidly became unstable during triage; group II (n=3) included patients who had no contraindications to early repair and underwent repair at the time of diagnosis; and group III (n=44) consisted of patients who because of concomitant injuries or sepsis required initial admission and management in the intensive care unit until their clinical status had improved sufficiently to allow for deliberate delayed operative repair of the TRA. The delay ranged from 1 day to 7 months. Eight patients have yet to undergo repair and remain well at follow-up from 1 to 4 years. Overall survival rates in groups I, II, and III were 17%, 100%, and 82%, respectively. The surgery-related mortality rate in group III was 10% (three patients). Only two (4.5%) patients in group III died as a result of a ruptured aorta within 72 hours of admission. In conclusion, contrary to surgical doctrine, TRA may not require immediate operative repair in all cases, but may instead be managed selectively depending on the patient's clinical status.     

The challenge for Cuba

The restrictions of a U.S. trade embargo and the collapse of the Soviet Union marked the beginning of a period of extreme economic hardship in Cuba. Economic adversity has had tremendous effects, both positive and negative, on all aspects of life on the Island, including environmental and public health.     

The role of pRb2/p130 protein in diagnosing lung carcinoma on fine needle aspiration biopsies

The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most studied tumor suppressor genes, and two related genes: p107 and pRb2/p130. These proteins are also known as the pocket proteins due to a unique structural and functional domain composed of subdomains A and B separated by a spacer region that is highly conserved among each of the proteins. These proteins exhibit unique growth suppressive properties that are cell type specific, suggesting that although the pocket proteins may complement each other, they are not fully functionally redundant. With the development of antibodies recognizing these three proteins it is now possible to detect expression in formalin-embedded specimens. Recent studies on 235 lung cancers, using immunohistochemical techniques, suggested an independent role for Rb2/p130 in the development and/or progression of human lung carcinoma. We found a statistically significant inverse relationship between the histological grading (degree of malignant potential) and the expression of pRb/p105, p107 and pRb2/p130 in squamous cell carcinomas, meaning that an increase in grading resulted in a significant decrease in protein expression. This phenomenon was particularly evident for pRb2/p130 (p < .0001) which had the highest percentage of undetectable levels in all the specimens examined and the tightest inverse correlation (p value) with both the histological grading and PCNA expression in the most aggressive tumor types, suggesting an important role for pRb2/p130 in the pathogenesis and progression of certain lung cancers. We further explored the expression of pRb2/p130 protein in routine archival FNAB cytological material from 30 Patients with lung cancer using immunocytochemical techniques, comparing protein expression with tumor type. Two pathologists evaluated the staining pattern and scored the percentage of positive cells. Of the 30 neoplasms, 27 displayed a positive staining for pRb2/p130. In particular, we detected pRb2/p130 in 9 (100%) squamous carcinomas, 11 (84%) adenocarcinomas, 5 (100%) BAC, and 2 (66%) SCC. The percentage of positive nuclei varied in different tumors with the highest expression level in adenocarcinomas. Immunocytochemistry represents a sensitive method for detection of pRb2/p130 expression in cytological or archival specimens, and the level of detection seems to be comparable to paraffin sections. Therefore, this methodology could be used in the preoperative evaluation of routine cytological specimens in order to improve the diagnostic and prognostic evaluation of lung cancer patients.     

Potential of Gene Therapy in Bone Marrow Transplantation

Gene therapy, initiated as a treatment for inherited disorders such as adenosine deaminase deficiency, is now a promising therapeutic strategy for malignancies and other acquired diseases. In particular, in the field of bone marrow transplantation (BMT) for haematological malignancies, the gene transfer of the suicide gene HSV-TK into donor lymphocytes allows control of the severe complication graft-versus-host disease (GvHD). The transfer of the HSV-TK suicide gene confers selective sensitivity to the drug ganciclovir, allowing in vivo elimination of the donor T-cells if severe GvHD occurs. In Italy, the first pilot study on delayed infusion of genetically engineered donor lymphocytes after T-depleted allogeneic BMT documented efficacy of engineered donor lymphocytes in terms of anti-tumour activity and efficiency of the suicide system. GvHD developed in 3 out of 8 patients and was successfully treated by ganciclovir administration.     

Antihypertensive drug therapy and hypoglycemia in elderly diabetic patients treated with insulin and/or sulfonylureas

We performed this case–control study to evaluate the risk of hypoglycemia associated with the use of antihypertensive drugs in older hospitalized diabetic patients treated with sulfonylureas and/or insulin. All diabetic patients admitted during 4 months in 1988, 1 month in 1991, 4 months in 1993 and 4 months in 1995 (n = 3477, mean age 71.4 ± 0.2 years, 1542 males and 1935 females) were enrolled in the study. During the four annual surveys 86 patients (mean age 71.1 ± 1.4 years, 33 males and 53 females) presented hypoglycemia during hospital stay. The patients who presented hypoglycemia were less frequently users of sulfonylureas and more frequently users of a combination of insulin and sulfonylureas. Use of antihypertensive drugs was similar in the two groups studied, and among potentially interacting drugs considered in the analysis, sulfonamides were more frequently used in patients who experienced hypoglycemia. Moreover, patients with hypoglycemia used a higher number of drugs, had a longer length of stay and had a greater prevalence of hypoglycemia as admission problem. Finally, although not significant, liver and renal diseases were more frequent among patients with hypoglycemia. In the multivariate analysis, contemporary use of insulin and sulfonylureas, liver disease and length of stay were significantly associated with hypoglycemia, while none of the antihypertensive drugs showed a significant association with the occurrence of hypoglycemia during hospital stay. Our results indicate that antihypertensive drugs do not increase the risk of hypoglycemia in elderly diabetic patients.     

Bilateral macular hemorrhage after laser in situ keratomileusis

· Background: This is the first report of a bilateral submacular hemorrhage after LASIK surgery in an extreme myo pic patient. A 31-year-old man underwent bilateral surgery for correction of –16.75+0.75×70° and –16.50+0.50×55°. · Methods: Case report. · Results: One day after surgery the patient’s uncorrected visual acuity was in the 20/50 range OU and by 17 days after surgery his visual acuity had declined to 20/200 range. Fundus examination showed multifocal subretinal macular and posterior pole hemorrhages. Fluorescein angiography showed some macular lesions compatible with lacquer cracks. · Conclusions: Preoperative and postoperative fundus examination is important to detect this phenomenon. Patients should be informed of this rare complication. Received: 2 June 1998 Revised version received: 16 November 1998 Accepted: 17 November 1998     

Clinicopathological study of familial late infantile Hallervorden-Spatz disease: a particular form of neuroacanthocytosis

The cases of two sisters with late infantile Hallervorden-Spatz disease are reported, one of whom has died. Autopsy of the deceased patient showed typical pallidal lesions, such as axonal spheroids and iron deposits, without involvement of the substantia nigra. Ultrastructural examination revealed that pallidal axonal enlargements consisted of collecition of mitochondria, dense bodies, vesicles and amorphous material. In the living patient, brain MRI showed the classical tiger's eye appearance of the globus pallidus. Retinitis pigmentosa, acanthocytosis and slight neuromuscular involvement with an increase in serum creatine kinase were observed in both subjects. The appearance of the globus pallidus on MRI was in line with the pathological abnormalities. Ultrastructural differences between the principal disorders characterized by neuroaxonal dystrophy are compared and the clinical spectrum and similarities of the different forms of neuroacanthocytosis analysed.     

The effects of cyclosporin A,tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells

Summary Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resistant, Pgp+, ER-MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.