Altered bladder function in transgenic mice expressing rat elastin

The elasticity of tissues subjected to repeated deformation is provided by the presence of elastic fibers in the extracellular matrix (ECM). The most abundant component of elastic fibers is elastin, whose soluble precursor is tropoelastin. To establish the role elastin plays in the bladder, this study describes the biosynthetic, histologic, and physiologic consequences of expression of an isoform of rat tropoelastin in transgenic mouse bladder. The polymerase chain reaction (PCR) was used to determine expression of a rat tropoelastin minigene in transgenic mice. Histochemical methods were used to demonstrate changes in elastic fibers in frozen sections of bladder. Cystometric analysis was carried out in transgenic and non-transgenic mice, prior to and after 3 weeks of partial outlet obstruction. The PCR assay demonstrated that bladder tissue of transgenic mice expressed rat tropoelastin mRNA, whereas non-transgenes did not. Increased deposition of elastic fibers was demonstrated with the Verhoeff-van Gieson stain. Bladders of transgenic animals were more compliant than bladders of their non-transgenic littermates. Partial outlet obstruction resulted in increased bladder volume and more compliant bladders in non-transgenic mice. In contrast, the bladder volume and compliance in transgenes was almost unchanged by obstruction. This study demonstrates that normal elastic fiber assembly is prerequisite for the compliant properties of the bladder wall. Moreover, the response of the bladder to obstruction is critically influenced by elastin synthesis.     

Trends in prenatal diagnosis of Down syndrome and other autosomal trisomies in Scotland 1990 to 1994, with associated cytogenetic and epidemiological findings

The present report summarizes findings on 670 cases of autosomal trisomy diagnosed in Scotland, with actual or expected dates of delivery in 1990 to 1994 inclusive. Cases were notified by cytogenetic service laboratories. There were 277 prenatal and 369 postnatal diagnoses and 24 spontaneous losses. Excluding the latter, numbers diagnosed with trisomy 21, trisomy 18, trisomy 13, and other trisomies were, respectively, 470 (72.8%), 108 (16.7%), 36 (5.6%), and 32 (5.0%). Estimated maternal age-specific birth rates for trisomy 21 were close to published values from other jurisdictions. However, comparisons with a clinically based national register of congenital anomalies suggested that 3-4% of Down syndrome births were never karyotyped, most being early neonatal deaths. There was a striking increase over the period in the proportion of cases detected prenatally, associated with increased maternal serum screening in mothers <35 years old. Over the 3 final years (1992-1994), prenatal screening followed by elective termination was estimated to reduce the birth rate in trisomy 21 by 24% in mothers aged <35 years, by 57% in older mothers, and by 35% in all mothers. The crude incidence per 1,000 births fell from 1.08 in 1990-1991 to 0.77 in 1992-1994, in spite of an upward shift in the overall maternal age distribution. For trisomies 18 and 13, the estimated overall reductions in the birth rate over the whole 5-year period were respectively, 26 and 17%. In free trisomy 18, there was a significant reduction in the sex ratio (male/female) to 0.65, in line with earlier studies.     

Protection against ischemic damage by adenosine amine congener, a potent and selective adenosine A1 receptor agonist

Although the selectivity and potency of adenosine amine congener (ADAC) at adenosine A1 receptors are similar to other highly selective agonists at this receptor type, the chemical structure of the N6 substituent is completely different. We now demonstrate that the characteristics of the therapeutic profile of ADAC are distinct from those observed during our previous studies of adenosine A1 receptor agonist-mediated neuroprotection. Most significantly, chronic treatment with low microgram doses of ADAC (25-100 microg/kg) protects against both mortality and neuronal damage induced by 10 min bilateral carotid occlusion in gerbils. At higher chronic doses, the statistical significance of the protective effect is lost. Acute preischemic administration of the drug at 75-200 microg/kg also results in a statistically significant reduction of postischemic mortality and morbidity. These data indicate that, contrary to other adenosine A1 receptor agonists whose chronic administration enhances postocclusive brain damage, ADAC may be a promising agent in treatment of both acute (e.g., cerebral ischemia) and chronic (seizures) disorders of the central nervous system in which adenosine A receptors appear to be involved.     

Transitional Cell Carcinoma Involving the Prostate with a Proposed Staging Classification for Stromal Invasion

Purpose

We investigated the effect on survival of transitional cell carcinoma of the prostatic urethra, ducts and stroma, and determined the difference between prostatic stromal involvement occurring via direct extension through the bladder wall versus stromal invasion arising intraurethrally.

Materials and Methods

Between August 1971 and December 1989, 489 men underwent radical cystoprostatectomy for transitional cell carcinoma, including 143 (29.2 percent) identified with prostate involvement by transitional cell carcinoma in the cystectomy specimen. Patients were separated into 2 groups: 1–19 in whom the primary bladder tumor extended full thickness through the bladder wall to invade the prostate (classified as P4a) and 2–124 in whom prostate involvement arose from within the prostatic urethra.

Results

Five-year recurrence-free and overall survival rates were 25 and 21 percent, respectively, in group 1 versus 64 and 55 percent, respectively, in group 2. In the 124 patients in group 2 survival rates were similar for those with prostatic urethral tumors or carcinoma in situ and ductal tumors (no stromal invasion). Five-year overall survival rates without and with stromal invasion were 71 and 36 percent, respectively (p less than 0.0001). Transitional cell carcinoma of the prostatic urethra or ducts does not alter survival predicted by primary bladder stage alone. Prostatic stromal invasion arising intraurethrally significantly decreases survival, which varies based on primary bladder stage (64.6 percent in stage P1, 30.8 percent in stages P2/P3a and 13.6 percent in stage P3b, p = 0.0001). P1 bladder tumors with prostatic stromal invasion arising intraurethrally had a significantly higher survival rate than P4a tumors (64.6 versus 21 percent, p = 0.0001). P3b bladder tumors with stromal invasion had a survival rate similar to that of P4a tumors (p = 0.78).

Conclusions

Prostatic urethral or ductal transitional cell carcinoma does not alter survival determined by primary bladder stage alone and it should not be classified as P4a. Prostatic stromal involvement arising intraurethrally significantly decreases survival predicted by primary bladder stage alone. P1 bladder tumors with prostatic stromal invasion arising intraurethrally have a significantly higher survival rate than P4a tumors and they should be separately classified as P1str. Muscle invasive (P2/P3a) bladder tumors with stromal invasion have a higher survival rate than P4a tumors (no statistical significance) and they should be designated separately (that is P2str). P3b bladder tumors with prostatic stromal invasion arising intraurethrally are indistinguishable from P4a tumors.     

A case-control study of persons with elevated blood levels of dieldrin

Twenty-seven pesticide workers with elevated blood levels of dieldrin (15 ppb) were involved in a case-control study which included history and physical examination, comprehensive neurological evaluation, laboratory tests, and psychological and psychomotor testing. No clinically important differences were found on history, physical, specialized neurological tests, or laboratory examination. The exposed group showed a statistically significant difference in five out of 58 psychological (P) and psychomotor (PM) tests—at least three would be expected by chance (p .05). In only one of these tests was there any significant correlation with dieldrin levels. Even though the exposed group had worse scores than the control group in 47 of 58 P-PM tests, such scores were, with a few exceptions, in the normal range of values. Elevated blood levels of dieldrin encountered in this study do not appear to have any chronic deleterious effects on health, as measured by conventional medical work-up and extensive central nervous system testing.     

Cytogenetic studies of herbicide interactions in vitro and in vivo using atrazine and linuron

The herbicides atrazine and linuron, found in Wisconsin's groundwater, were tested alone and in combination, both in vivo and in vitro, to determine their individual and combined genotoxic effects. Human lymphocytes exposed in vitro to either 1 g/ml linuron or 0.001 g/ml atrazine showed little chromosome damage, whereas significant chromosome damage was observed in lymphocytes simultaneously exposed to 0.5 g/ml linuron and 0.0005 g/ml atrazine, suggesting at least an additive model. In another experiment, mice were fed 20 g/ml atrazine, 10 g/ml linuron, or a combination of 10 g/ml atrazine and 5 g/ml linuron in their drinking water for 90 days, after which bone marrow cells and cultured splenocytes were examined for chromosomal damage. None of the treatment groups showed chromosome damage in bone marrow, whereas the cultured splenocytes demonstrated damage in all treatment groups. These experiments suggest that, prior to assessing the risk of a herbicide, it may be necessary to test it in combinations which mimic the mixtures which would occur under field conditions, such as in contaminated groundwater.     

EEG features and their evolution in the acute phase of haemorrhagic shock and encephalopathy syndrome.

Serial EEGs have been carried out during the acute phase of haemorrhagic shock and encephalopathy syndrome (HS&E) in 22 infants and children aged 3 months to 14 years. Most patients presented with fits and coma and all had shock with bleeding and disseminated intravascular coagulation (DIC). The initial EEG showed prolonged runs of often rhythmic discharges which fluctuated in amount and amplitude with varying distribution and morphology ("electrical storms"). Over a period of days the "electrical storms" gradually decreased leaving only low amplitude EEG activities or evolving to electrocerebral silence (7 cases). Fifteen patients died and all five children with multifocal "electrical storms" who survived showed gross neurological handicap. The rather distinctive EEG pattern is unusual in the context of an acute encephalopathy outside the neonatal period although similar "electrical storms" may be seen in a less extreme form in infants and children with other conditions associated with DIC. This EEG pattern presumably reflects changes in the cerebral microcirculation which in HS&E are usually relentlessly progressive and associated with devastating cortical damage.     

The effect of hypothermic cardiopulmonary bypass and total circulatory arrest on cerebral metabolism in neonates, infants, and children

Cardiopulmonary bypass management in neonates, infants, and children often requires the use of deep hypothermia at 18 degrees C with occasional periods of circulatory arrest and represents marked physiologic extremes of temperature and perfusion. The safety of these techniques is largely dependent on the reduction of metabolism, particularly cerebral metabolism. We studied the effect of hypothermia on cerebral metabolism during cardiac surgery and quantified the changes. Cerebral metabolism was measured before, during, and after hypothermic cardiopulmonary bypass in 46 pediatric patients, aged 1 day to 14 years. Patients were grouped on the basis of the different bypass techniques commonly used in children: group A--moderate hypothermic bypass at 28 degrees C; group B--deep hypothermic bypass at 18 degrees to 20 degrees C with maintenance of continuous flow; and group C--deep hypothermic circulatory arrest at 18 degrees C. Cerebral metabolism significantly decreased under hypothermic conditions in all groups compared with control levels at normothermia, the data demonstrating an exponential relationship between temperature and cerebral metabolism and an average temperature coefficient of 3.65. There was no significant difference in the rate of metabolism reduction (temperature coefficient) in patients cooled to 28 degrees and 18 degrees C. From these data we were able to derive an equation that numerically expresses a hypothermic metabolic index, which quantitates duration of brain protection provided by reduction of cerebral metabolism owing to hypothermic bypass over any temperature range. Based on this index, patients cooled to 28 degrees C have a predicted ischemic tolerance of 11 to 19 minutes. The predicted duration that the brain can tolerate ischemia ("safe" period of deep hypothermic circulatory arrest) in patients cooled to 18 degrees C, based on our metabolic index, is 39 to 65 minutes, similar to the safe period of deep hypothermic circulatory arrest known to be tolerated clinically. In groups A and B (no circulatory arrest), cerebral metabolism returned to control in the rewarming phase of bypass and after bypass. In group C (circulatory arrest), cerebral metabolism and oxygen extraction remained significantly reduced during rewarming and after bypass, suggesting disordered cerebral metabolism and oxygen utilization after deep hypothermic circulatory arrest. The results of this study suggest that cerebral metabolism is exponentially related to temperature during hypothermic bypass with a temperature coefficient of 3.65 in neonates infants and children. Deep hypothermic circulatory arrest changes cerebral metabolism and blood flow after the arrest period despite adequate hypothermic suppression of metabolism.     

Effects of Δ 9-Tetrahydrocannabinol and pentobarbital on a cortical response evoked during conditioning

A surface-negative wave, evoked by tone cues, appeared in monkey post-arcuate cortex as the monkey learned that the cue signaled the availability of reward. This evoked activity was depressed, concomitantly with changes in the animal's behavioral responding, by doses of ⁹-tetrahydrocannabinol ( ⁹-Tetrahydrocannabinol-THC) as low as 0.032 mg/kg and of pentobarbital as low as 4 mg/kg. Pentobarbital tended to increase the latency of the evoked wave, an effect not seen with ⁹-THC.Supported by U.S. Public Health Service Grant no. DA 00015.