Histomorphometric and immunohistochemical evaluation of the frontal cerebral cortex in diabetic rats after treatment with melatonin / Avaliação histomorfométrica e imuno-histoquímica do córtex cerebral frontal em ratos diabéticos após o tratamento com melatonina

The central nervous system is vulnerable to complications caused by diabetes. These complications lead to increased oxidative stress in the brain, resulting in damage to the cerebral cortex, among other regions. Insulin and hypoglycemic agents are still the most widely used treatments. However, current research with an experimental model of diabetes suggests the use of antioxidants, such as melatonin. Thus, we tested the hypothesis that exogenous melatonin may decrease or prevent the effects of diabetes in the frontal cortex of the rat brain. Fifty albino rats were allocated into five groups: GC = rats without diabetes induction, GD = diabetic rats induced by streptozotocin, GDM = streptozotocin-induced and melatonin-treated diabetic rats, GDI = diabetic rats induced by streptozotocin and treated with insulin, GDMI = diabetic rats induced by streptozotocin and treated with melatonin and insulin simultaneously. Diabetes was induced by intraperitoneal administration of streptozotocin (60mg/kg). Insulin (5U/day) was administered subcutaneously and melatonin (10mg/kg) by drinking water; both treatments last days after. We analyzed animals' weight, the cytokines IL-6 and TNF-α, apoptosis, glycogen, and did morphometry and histopathology of the frontal cortex were analyzed. The results showed that the cerebral cortex of the diabetic animals presented axonal degeneration, reduced number of neurons in the cortex, reduced glycogen, increased IL-6 and TNF-α expression, high apoptotic index, and reduced animal weight and the brain. Treatment with melatonin associated or not with insulin prevented such effects. Thus, we conclude that melatonin associated with insulin may be an alternative for avoiding the impact of diabetes in the brain's frontal cortex.(AU)

O sistema nervoso central é vulnerável a complicações originadas pelo diabetes estresse oxidativo no cérebro e resultando em lesões no córtex cerebral, dentre outras regiões. A insulina e hipoglicemiantes ainda são os tratamentos mais utilizados, entretanto, pesquisas atuais com modelo experimental do diabetes sugerem a utilização de antioxidantes como, por exemplo, a melatonina. Assim, testamos a hipótese de que a melatonina exógena pode diminuir ou prevenir os efeitos do diabetes no córtex frontal do cérebro de ratos. Foram utilizados 50 ratos albinos, divididos em 5 grupos: GC = ratos sem indução ao diabetes, GD = ratos induzidos ao diabetes pela estreptozotocina, GDM = ratos induzidos ao diabetes pela estreptozotocina e tratados com melatonina, GDI = ratos induzidos ao diabetes pela estreptozotocina e tratados com insulina, GDMI = ratos induzidos ao diabetes pela estreptozotocina e tratados com melatonina e insulina simultaneamente. O diabetes foi induzido pela administração intraperitoneal de estreptozotocina (60mg/kg). A insulina (5U/dia) foi administrada por via subcutânea e a melatonina (10mg/kg) pela água de beber. Ambos tratamentos foram realizados durante 30 dias após a indução. Foram analisados o peso dos animais, do cerebro, as citocinas IL-6 e TNF-α, apoptose, glicogênio, além da morfometria e histopatologia do córtex frontal. Os resultados mostraram que o córtex cerebral dos animais diabéticos apresentou degeneração axonal, redução do número de neurônios no córtex, redução do glicogênio, aumento da expressão do IL-6 e TNF-α, elevação do índice apoptótico, além da redução do peso dos animais e do cérebro. O tratamento com melatonina associada ou não a insulina preveniu tais efeitos. Assim, concluímos que a melatonina associada ou não a insulina pode ser uma alternativa na prevenção dos efeitos do diabetes no córtex frontal do cérebro.(AU)

Anabolic-androgenic steroids cycle administration decreases anxious-like behavior but does not affect long-term memory acquisition in rats

The steroid hormones are lipids in nature, which play crucial roles in several metabolic and behavioral pathways in mammals. Drug therapy uses sterol hormones for treating some disturbances linked with its deficiency; however, the illicit use of these hormones by amateur and elite athletes to enhance performance or body appearance may lead to several health issues. In this study we evaluated the anxious-like behavior and the long-term memory acquisition of male rats undergoing sedentary life-style or physical effort, with or without anabolic-androgenic steroids (ASC) treatment. The results showed a decrease in anxious-like behavioral levels in rats that received ASC treatment associated or not with physical effort, but this treatment did not affect the acquisition of long-term memory at the dose and experimental model assessed.

Tityus serrulatus envenoming in non-obese diabetic mice: a risk factor for severity

In Brazil, accidents with venomous animals are considered a public health problem. Tityus serrulatus (Ts), popularly known as the yellow scorpion, is most frequently responsible for the severe accidents in the country. Ts envenoming can cause several signs and symptoms classified according to their clinical manifestations as mild, moderate or severe. Furthermore, the victims usually present biochemical alterations, including hyperglycemia. Nevertheless, Ts envenoming and its induced hyperglycemia were never studied or documented in a patient with diabetes mellitus (DM). Therefore, this is the first study to evaluate the glycemia during Ts envenoming using a diabetic animal model (NOD, non-obese diabetic). Methods Female mice (BALB/c or NOD) were challenged with a non-lethal dose of Ts venom. Blood glucose level was measured (tail blood using a glucose meter) over a 24-h period. The total glycosylated hemoglobin (HbA1c) levels were measured 30 days after Ts venom injection. Moreover, the insulin levels were analyzed at the glycemia peak. Results The results demonstrated that the envenomed NOD animals presented a significant increase of glycemia, glycosylated hemoglobin (HbA1c) and insulin levels compared to the envenomed BALB/c control group, corroborating that DM victims present great risk of developing severe envenoming. Moreover, the envenomed NOD animals presented highest risk of death and sequelae. Conclusions This study demonstrated that the diabetic victims stung by Ts scorpion should be always considered a risk group for scorpion envenoming severity.

Behavioral alterations induced by repeated saxitoxin exposure in drinking water

Blooms of the saxitoxin-producing cyanobacterium Cylindrospermopsis raciborskii have been contaminating drinking water reservoirs in Brazil for many years. Although acute effects of saxitoxin intoxication are well known, chronic deleterious outcomes caused by repeated saxitoxin exposure still require further investigation. The aim of the present work is to investigate the effects of consumption of drinking water contaminated with C. raciborskii for 30 days on learning and memory processes in rats. Methods The effects of saxitoxin (3 or 9 g/L STX equivalents) or cyanobacteria on behavior was determined using the open field habituation task, elevated plus maze anxiety model task, inhibitory avoidance task, and referential Morris water maze task. Results No effects of saxitoxin consumption was observed on anxiety and motor exploratory parameters in the elevated plus maze and open field habituation tasks, respectively. However, groups treated with 9 g/L STX equivalents displayed a decreased memory performance in the inhibitory avoidance and Morris water maze tasks. Conclusions These results suggest an amnesic effect of saxitoxin on aversive and spatial memories.

Lipídios estruturados obtidos por interesterificação da tributirina com óleo de linhaça e seu potencial quimiopreventivo durante a fase de promoção inicial da hepatocarcinogênese experimental em ratos / Structured lipids obtained from intersterification of tributyrin and flax seed oil and their chemopreventive potential during early promotion phase of experimental hepatocarcinogenesis in rats

A combinação de agentes quimiopreventivos com diferentes mecanismos de ação tem sido considerada uma estratégia promissora para a prevenção do câncer. Dentre os diversos compostos bioativos em alimentos, destacam-se a tributirina, um pró-fármaco do ácido butírico presente em laticínios e produzido pela fermentação de fibras dietéticas, e o óleo de linhaça, fonte de ácido alfa linolênico. Nesse contexto, foi avaliada a atividade quimiopreventiva de lipídios estruturados obtidos a partir da interesterificação enzimática de tributirina e óleo de linhaça durante a fase de promoção inicial da hepatocarcinogênese experimental. Ratos Wistar machos submetidos ao modelo do hepatócito resistente receberam diariamente, por via intragástrica (i.g), maltodextrina, óleo de linhaça, tributirina, a mistura não esterificada ou lipídios estruturados durante a fase de promoção inicial. O tratamento com lipídios estruturados demonstrou atividade quimiopreventiva comparável à da tributirina, mesmo resultando em menor concentração hepática de ácido butírico. Tanto a tributirina quanto os lipídios estruturados não inibiram a proliferação celular em lesões preneoplásicas, mas induziram a apoptose naquelas em remodelação. Os efeitos inibitórios da tributirina em fases iniciais da hepatocarcinogênese experimental estão relacionados ao aumento da acetilação de histonas e à modulação de processos de translocação nuclear da p53. No presente estudo, foi observado aumento substancial da razão nuclear/citoplasmática de p53 e importina-alfa em fígados de animais submetidos ao modelo e tratados com tributirina, mas não nos tratados com lipídios estruturados. Por outro lado, o tratamento com lipídios estruturados reduziu a expressão dos oncogenes Bcl2, Ccnd2, Pdgfa, Vegfa e aumentou a expressão dos genes supressores de tumor Cdh13, Fhit e Socs3. Assim, embora o potencial quimiopreventivo dos lipídios estruturados seja comparável ao da tributirina, os resultados sugerem que o novo composto não exibe atividade de HDACi, e que seus efeitos inibitórios na hepatocarcinogênese possam ser atribuídos à modulação da expressão de oncogenes e genes supressores de tumor

Combination of chemopreventive agents with different mechanisms of action has been considered a promising strategy to cancer prevention. Among several bioactive food compounds, tributyrin, a butyric acid prodrug obtained from dairy products and dietetic fiber fermentation, and flax seed oil, a rich source of alpha linolenic acid have shown chemopreventive potential. Here, we evaluated the chemopreventive activity of structured lipids obtained by enzymatic interesterification of tributyrin and flax seed oil during the early promotion phase of experimental hepatocarcinogenesis. Male Wistar rats subjected to the resistant hepatocyte model were treated daily, i.g, with maltodextrin, flax seed oil, tributyrin, non-sterified blend, or structured lipids. Treatment structured lipids showed similar chemopreventive activity compared to tributyrin, even when structured lipids yielded lower concentrations of butyric in the liver. Tributyrin and structured lipids did not inhibit cell proliferation in preneoplastic lesions, but both of them induced apoptosis in remodeling preneoplastic lesions. In addition, histone acetylation and p21 restored expression tributyrin molecular mechanisms were related to modulation of p53 nuclear shuttling mechanisms. In the present study, it was observed a substantial increase in p53 nuclear/cytoplasmic ratio and importin-alpha in preneoplastic livers of tributyrin treated rats, but not in those treated with structured lipids. In contrast, treatment structured lipids downregulated expression of major oncogenes Bcl2, Ccnd2, Pdgfa, and Vegfa; and upregulated expression of critical tumor suppressor genes, Cdh13, Socs3 and Fhit. Hence, although structured lipids and tributyrin show similar chemopreventive potential, the results suggest that the new compound does not exhibit HDACi activity, and that its inhibitory effects may be attributed to the modulation of oncogenes and tumor suppressor genes expression

Investigação dos efeitos do ácido 2, 4 diclorofenoxiacético sobre diferentes populações de neurônios mioentéricos do duodeno de ratos / Investigation of 2, 4 dichlorophenoxyacetic acid effects in different population of rat duodenum myenteric neurons / Investigación de los efectos del ácido 2, 4 diclorofenoxiacético sobre diferentes poblaciones de neuronas mioentéricas del duodeno de ratones

O herbicida mais usado, tanto em pequenas como em grandes propriedades, por isso mais amplamente estudado é o 2,4-D. Os estudos de toxicidade têm se concentrado sobre as alterações do sistema nervoso central, e por isto pouco se conhece sobre seus efeitos no sistema nervoso entérico. Com o objetivo de avaliar os efeitos do 2,4-D sobre os neurônios mioentéricos do duodeno de ratos foi fornecido durante 60 dias doses de 2,4-D na concentração de 5mg/kg de peso de corpóreo para ratosWistarde dois grupos experimentais (n=5). Os animais dos grupos controle permaneceram o mesmo período sem receber 2,4-D. Ao final do período experimental os animais foram mortos, os duodenos foram coletados e processados por meio das técnicas histoquímicas de NADH-diaforase e NADPH-diaforase. Os neurônios foram quantificados e os resultados foram analisados estatisticamente. A densidade dos neurônios NADHd diferiu estatisticamente (P?0,05) entre os grupos experimental e controle, sendo maior no grupo controle. Já os neurônios NADPHd foram encontrados em maior quantidade no grupo experimental. Estes resultados sugerem que o 2,4-D possui ação neurotóxica sobre os neurônios do plexo mioentérico, interferindo na densidade neuronal mioentérica, quando se compara diferentes populações destes neurônios...

The 2,4-D herbicide is the most widely used, both in small and in large properties. Therefore, it is also the one that is most broadly studied. Toxicity studies have been focused on changes in the central nervous system, and for this reason, little is known about its effect in the enteric nervous system. With the objective of measuring the effects of 2,4-D on the myenteric neurons in the duodenum of rats, doses of 2,4-D were supplied for 60 days at a concentration of 5mg/kg of body weight to Wistar rats divided into two different experimental groups (n=5). The animals in the control groups remained without 2,4-D doses for the same period. At the end of the experimental period, the animals were euthanized and their duodenum were collected and processed through NADH-diaphorase and NADPH-diaphorase histochemical techniques. The neurons were quantified and the results were statistically analyzed. The density of NADHd neurons differed statistically (P< 0,05) between the experimental and control groups, being higher in the control group. However, NADPHd neurons were found in a greater quantity in the experimental group. These results suggest that the 2,4-D has a neurotoxic action in the neurons from the myenteric plexus, interfering in the myenteric neuronal density, when different population of these neurons are compared...

El herbicida más utilizado, tanto en pequeñas como en grandes propiedades es el 2,4-D, por eso lo más estudiado. Los estudios de toxicidad se han centrado sobre las alteraciones del sistema nervioso central, y por lo tanto, poco se sabe sobre sus efectos en el sistema nervioso entérico. Con el objetivo de evaluar los efectos del 2,4-D sobre las neuronas mioentéricas del duodeno de ratas se ha administrado durante 60 días dosis de 2,4-D en la concentración de 5mg/kg de peso corporal para ratones Wistarde, dos grupos experimentales (n = 5). Los animales de los grupos control permanecieron el mismo período sin recibir el 2,4-D. Al final del periodo experimental los animales fueron sacrificados, los duodenos fueron recogidos y procesados a través de las técnicas de histoquímicas de NADH-diaforasa y NADPH-diaforasa. Las neuronas fueron cuantificadas y los resultados analizados estadísticamente. La densidad de las neuronas NADHd difirió estadísticamente (P?0,05) entre los grupos experimental y control, siendo mayor en el grupo control. Ya las neuronas NADPHd se encontraron en mayor cantidad en el grupo experimental. Estos resultados sugieren que el 2,4-D tiene una acción neurotóxica sobre las neuronas del plexo mioentérico, lo que interfiere en la densidad neuronal mioentérica al comparar diferentes poblaciones de estas neuronas...

Malformaciones congénitas en la descendencia de ratas diabéticas / Congenital malformations in diabetic rat’s offspring

Se realizó una investigación experimental en ratas hembras de la cepa Wistar criolla, mediante un modelo de diabetes mellitus de hiperglucemia aguda, con el objetivo de identificar las malformaciones congénitas más frecuentes en los fetos de ratas diabéticas tratadas o no con vitamina E, con respecto a un grupo control. Los fetos se extrajeron el día antes de llegar al término de la gestación y sometidos a un estudio morfológico. Se estudiaron 198 fetos procedentes de madres diabéticas y 53 del grupo control para un total de 251. Se utilizaron variables como: presencia de malformaciones músculo-esqueléticas, alteraciones craneofaciales, cardiovasculares, del sistema nervioso central, renal y digestivo. Para el análisis descriptivo se construyeron distribuciones de frecuencias bivariadas absolutas y porcentuales de las variables en escalas nominales. Sólo hubo malformaciones congénitas en los grupos de fetos en cuyas madres fue inducida la diabetes. En los fetos de ratas diabéticas tratadas con vitamina E no se produjo una disminución de las malformaciones con respecto a aquellos no tratados. Se concluye que las malformaciones congénitas sólo se identificaron en los fetos de ratas diabéticas y las más frecuentes fueron las cardiovasculares. La vitamina E no logró proteger a los fetos de la cepa Wistar criolla de la ocurrencia de malformaciones congénitas, pero si disminuyó su mortalidad

An experimental research was conducted in female rats of Creole Wistar stump, through an acute hyperglycemia diabetes mellitus model, with the aim of identifying the most common congenital malformations in fetuses of diabetic rats treated or not with vitamin E, with respect to a control group. Fetuses were removed the day before reaching the end of gestation and undergone a morphological study. It was studied 198 fetuses from diabetic mothers and 53 from the control group for a total of 251. It was used variables such as presence of musculoskeletal malformations, craniofacial alterations, cardiovascular, of the central nervous system, renal and digestive. For the descriptive analysis it was constructed absolute and percentage bivariate frequency distributions on nominal scales. There were only congenital malformations in fetuses groups whose mothers were induced diabetes. A decrease of malformations was not produced in fetuses of diabetic rats treated with vitamin E in relation to those untreated. In conclusion, congenital malformations were identified only in fetuses of diabetic rats, and the most frequent were cardiovascular. Vitamin E could not protect fetuses of Creole Wistar stump from the occurrence of congenital malformations, but it did decrease mortality

Mielograma de ratas com disfunção tireoidiana / Bone marrow examination in rats with thyroid dysfunction

The cells of the myelo id, lymphoid , and erythroid lineage s of the bone marrow were quantified in rats with hypo and hyperthyroidism. Fifteen Wistar rats were divided into three groups: hypothyroid (n=5), hyperthyroid (n=5) , and control (n=5). Three months after the onset of the treatment s, euthanasia was performed . Bone marrow was aspirated from femurs of each animal to perform smear s that were stained with Quick Panoptic. T he percentage s of rubroblast, prorubrocyte, metarubrocyte, myeloblast, promyelocytes, metamyelocytes, myel ocytes, segmented, eosinophils, basophils, lymphocytes, plasma cells and monocytes in were determined a total of 500 cells. The bone marrow of animals with hypothyroidism had hypoplasia. The myeloid:erythroid ratio was higher in animals with thyroid dysfun ction. In hypo and hyperthyroidism, there was a significant reduction of the percentage of rubrocyte, metarubrocyte , and lymphocytes and increase of myelocytes and segmented cells. In hypothyroidism, there was a significant increase in the percentage of me tamyelocytes. It is c oncluded that both hypo and hyperfunction of thyroid increase the myeloid:erythroid ratio by increasing the number of cells of the myeloid lineage and reducing the cells of the erythroid lineage.

Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)-HSP20 complex attenuates the ß-agonist induced hypertrophic response in cardiac myocytes.

The small heat shock protein HSP20 is known to be cardioprotective during times of stress and the mechanism underlying its protective abilities depends on its phosphorylation on Ser16 by PKA (protein kinase A). Although the external stimuli that trigger Ser16 phosphorylation have been well studied, the events that modulate spatial and temporal control of this modification remain to be clarified. Here, we report that inhibition of cAMP phosphodiesterase-4 (PDE4) induces the phosphorylation of HSP20 in resting cardiac myocytes and augments its phosphorylation by PKA following ß-adrenergic stimulation. Moreover, using peptide array technology, in vitro binding studies, co-immunoprecipitation techniques and immunocytochemistry, we show that HSP20 binds directly to PDE4 within a region of the conserved catalytic domain. We also show that FRET-based, genetically-encoded cAMP reporters anchored to HSP20 exhibit a larger response to PDE4 inhibition compared to free cytosolic cAMP reporters, suggesting that the interaction with PDE4 is crucial in modulating the highly localised pool of cAMP to which HSP20 is exposed. Using information gleaned from peptide array analyses, we developed a cell-permeable peptide that serves to inhibit the interaction of PDE4 with HSP20. Disruption of the HSP20-PDE4 complex, using this peptide, suffices to induce phosphorylation of HSP20 by PKA and to protect against the hypertrophic response measured in neonatal cardiac myocytes following chronic ß-adrenergic stimulation.

Normal and abnormal embryonic development of the anorectum in rats.

BACKGROUND: The embryologic and pathologic aspect of anorectal malformation (ARM) remains poorly understood. There is no universally accepted theory to explain anorectal embryology and the abnormal development that produces ARM. The aim of this study was to observe the developmental processes of anorectum in rats and to explore the abnormal embryonic development that leads to ARM. METHODS: Rat embryos with ARM were obtained by treating pregnant rats with administration of ethylenethiourea (ETU). Normal rat embryos and embryos with ARM from gestational days 12.5 to 20 were sectioned serially and sagittally and stained with H & E. The relevant structure including cloaca and urorectal septum (URS) were examined in a temporospatial sequence. RESULTS: Characteristics of anorectum development in ARM rat embryos treated by ETU were as follows: (1) URS never fused with cloaca membrane. (2) Dorsal cloacal membrane was maldeveloped. (3) Cloacal configuration was abnormal. (4) Tail groove never appeared. All type of ARM was the rectourethal fistula and common cloaca in ETU-treated rat embryos and was discernible on gestation day 16. CONCLUSIONS: Absence of the tail groove and maldevelopment of the dorsal cloacal membrane, cloacal configuration, and urorectal septum are likely to be responsible for the formation of ARM. Failure of fusion of the URS with cloacal membrane is the immediate reason for rectourethral fistula or common cloaca in ETU-treated rats.

Estudio morfológico y morfométrico del epitelio lingual de fetos de ratas intoxicadas con cobre durante la preñez / Morphologic and morphometric study of the tongue epithelium of rat fetuses after copper intoxication during pregnancy

En ratas grávidas se estudiaron los efectos de la administración intravenosa de sulfato de cobre (4 mg/kg de peso) sobre la estructura del epitelio de la mucosa lingual de sus fetos. Los exámenes histopatológicos y morfométrico revelaron, en los animales del grupo intoxicado, un epitelio más delgado debido, principalmente, a la ausencia de los estratos granuloso y córneo en las regiones dorsal posterior y ventral de la mucosa lingual

Influência da diabete experimental na atividade exploratória de ratos no labirinto em cruz elevado / Influence of experimental diabetes in the exploratory activity of rats in high cross labirinth

Indivíduos portadores de diabetes mellitus apresentam um elevado nível de ansiedade. Há também relatos a respeito de alterações de sua função cognitiva, porém esses sáo conflitantes. Neste estudo, investigamos se a indução de diabete experimental por estreptozotocina promove alterações de performance no teste do labirinto em cruz elevado (elevated plus-maze), empregado para avaliação da ansiedade e dos processos de aprendizagem e momória em animais de laboratório....

El receptor ETa media la conducta "Barrel-rolling" (vuelta en tonel) inducida por la administración central de endotelinas en ratas conscientes / The receptors ETa mean the behavior Barrel-rolling inducer by the administration central of endothelins in rats conscious

La administración intracerebroventricular (ICV) de endotelinas, en ratas conscientes, produce una conducta conocida como "baller-rolling" (B-R) y otros signos convulsivos parecidos a las convulciones generalizadas en algunos tipos de epilepsia. Mediante el uso de un antagonista del receptor ETa, BQ-123, un agonista del receptor ETb, IRL-1620, y un antagonista del receptor ETb, BQ-788, demostramos que el B-R inducido por ET-1 o ET-3, en ratas conscientes, es medida a través del receptor ETa

Alteraciones feto-placentarias inducidas en ratas por la cepa TC-83 del virus de la encefalitis equina venezolana / Fetal-placental alteration induced in rat by venezuelan equine encephalitis virus strain TC-83

El estudio macroscópico y microscópico de los fetos de ratas Sprague-Dawley inoculadas con el virus de la EEV, cepa Guajira y cepa atenuada TC-83 demostró, durante la primera semana de gestación, muerte y reabsorción de todos los fetos con cepa Guajira y una disminución considerable en el número de crías, cuando se inocularon con la cepa TC-83. El estudio histológico del sistema nervioso central de las crías nacidas vivas, no demostró lesiones. Ratas inoculadas al 4to y 7mo día de gestación con TC-83 y sacrificadas el día de la gestación mostraron lesiones placentarias, principalmente, en los vasos miometriales en los fetos de aspecto viable, así como fuerte necrosis de otros fetos. Se compara la patogenia de la infección con el virus de la EEV a las lesiones inducidas en humanos por el virus de la rubéola y con estudios previos sobre el efecto intrauterino de otros Togavirus, y se destaca la necesidad de examinar cuidadosamente a las mujeres embarazadas y a sus hijos en las áreas de riesgo epidémico así como proscribir el uso de la vacuna TC-83 durante la gestación

Persistent common atrioventricular canal of the complete form associated with anomalies of the aortic arch system in WKY/NCrj rat fetuses.

Atrioventricular (AV) septal defect with a common AV orifice was found in two near-term rat fetuses, which are descendants of an inbred strain, known to genetically develop tetralogy of Fallot, hypertrophic cardiomyopathy, etc. In one fetus the anterior bridging leaflet was almost entirely committed to the left ventricle but in the other it protruded slightly into the right also, coinciding with type A or type B in humans, respectively. The latter fetus had also a subaortic ventricular septal defect with overriding of the aorta and a double aortic arch. Both fetuses had a narrow pulmonary infundibulum with a muscular band, a dysplastic pulmonary valve, and a markedly hypoplastic ductus arteriosus. Complete AV septal defect and tetralogy of Fallot may be linked genetically, with some common underlying developmental processes.

"Wavy ribs". A reversible pathologic finding in rat fetuses.

A literature of 74 scientific papers addressing the occurrence of "wavy ribs" in fetuses of small rodents has been collected with the support of a computer-assisted search on MEDLINE, TOXLINE, BIOSIS and EXCERPTA MEDICA systems (1982-1993) and has been critically examined. Numerous compounds of a large variation in chemical structure and biological activity, if given to pregnant rats during the later period of organogenesis, are known to cause "wavy ribs" in their fetuses, a reversible pathologic finding which is rarely observed in untreated controls. According to literature, causative factors, like delayed development of alkaline phosphatase, decreased fetal protein, dietary contents, maternal toxicity, renal loop diuretics, myometrial constriction, endocrine disturbances and beta-adrenoceptor stimulation or blocking have been observed and discussed, but, a general explanation for the lesions is still missing. Therefore, the following hypothesis may be added: the high doses used in reproductive toxicology may induce maternal and placental circulatory disturbances leading to reductions in fetal serum proteins, with delayed development of osteoblast progenitors and low fetal serum alkaline phosphatase in the day 17-20 fetus. Normalization of the neonate's homeostasis (serum protein) leads to enhanced ossification and concomitant bone repair until weaning.

The asymmetrical genetic determination of laterality: flatfish, frogs and human handedness.

The determination of the left-right body axis is unlike that of the two other axes because left-right positional information is not required to specify mirror-image structures on the two sides. When the left and right sides of the body are not mirror symmetrical such positional information is required, as is a mechanism for reading that information. There are several possible gradient schemes for left-right information, including symmetrical gradients from which the information is extracted by spatial differentiation. The genetic mechanisms for the control of handedness are not known. There is no evidence for 'left-handed' and 'right-handed' genes, only for mutations that can interfere with handedness in a non-specific manner. Such mutations never produce situs inversus with a frequency greater than 50%. The situs of individual organs shows a strong correlation, suggesting a global mechanism such as a gradient of left-right positional information. Many asymmetries in vertebrates follow a pattern in which growth on the left is favoured over growth on the right. This may be related to the 'dexiothetism' of chordate ancestors postulated by Jefferies.

Development of handed body asymmetry in mammals.

We have proposed a three step model for the specification of left-right in mammalian embryos. The fundamental assumption is that handedness is imparted by an asymmetrical molecule. Conversion of molecular asymmetry to the cellular level gives a property to one side of the embryo to bias an otherwise random generation of an asymmetrical gradient which can be interpreted by developing organs. Rat embryos, treated at discrete stages, show a window of sensitivity for disruption of handedness, which may reflect the time of conversion/biasing. Heat shock and several chemicals cause left-right inversion in up to 50% of embryos exposed during neural groove formation. Earlier stages are less sensitive; no treatment begun after foregut pocket formation influences asymmetry. Evidence for cellular interactions in left-right specification comes from the apparent rescue of iv/iv mutant embryos in chimeras. We are looking for molecular left-right disparity before morphological asymmetry but detect no differences in two-dimensional protein profiles. Using an indirect measure, we find a right-left gradient of tissue oxygen in embryos at the 20-30 somite stage. This may reflect asymmetrical vasculature, as we have suggested to explain drug-induced asymmetrical limb malformations.