The nitric oxide pathway in pre-eclampsia: pathophysiological implications

Pre-eclampsia, one of the most significant health problems inhuman pregnancy, complicates 6-7% of all gestations and is theleading cause of fetal growth retardation, infant morbidityand mortality, premature birth and maternal death. Recent researchimplicates free radicals in the pathophysiology of pre-eclampsia.This review covers the biochemistry of nitric oxide (NO) andpossible interactions with other free radicals. Studies in therat show that pregnancy is associated with enhanced productionand responsiveness to NO in both reproductive tissues and bloodvessels. Rats infused with N^G-nitro-L-arginine methyl ester(L-NAME, a NO synthase inhibitor) have been used as an animalmodel of pre-eclampsia, and the effects of steroid hormoneson blood pressure in this model have been tested. Results suggestthat pre-eclampsia may be a state of NO deficiency. However,in humans there seem to be contradictions regarding the involvementof NO in maternal adaptation to pregnancy. It is suggested thatNO may be one of several systems that act in concert to maintaina symbiotic relationship between mother and fetus. However,the input of each system may be genetically determined.     

Surgical sperm retrieval and intracytoplasmic sperm injection as treatment of obstructive azoospermia

Male genital tract obstructions may result from infections, previous inguinal and scrotal surgery (vasectomy) and congenital bilateral absence of the vas deferens (CBAVD). Microsurgery can sometimes be successful in treating the obstruction. In other cases and in cases of failed surgical intervention, the patient can be treated by microsurgical or percutaneous epididymal sperm aspiration (MESA, PESA) or testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). We present the results of 39 ICSI procedures for obstructive azoospermia in 24 couples. The aetiology of the obstruction was failed microsurgery in 11 patients, CBAVD in nine and genital infections in four. Sperm retrieval was accomplished via MESA in four cases, PESA in 18 cases and via TESE in 11 cases. TESE was only applied when PESA failed to produce enough spermatozoa for simultaneous ICSI. In six patients, the ICSI procedure was performed with cryopreserved spermatozoa after an initial PESA procedure. Fertilization occurred in 47% of the metaphase II oocytes; embryo transfer was performed in 92% of procedures and resulted in a clinical pregnancy in 13/39 procedures. Ongoing pregnancy was achieved in 10/39 procedures. One pregnancy was terminated early after prenatal investigation showed a cytogenetic abnormality (47,XX+18, Edwards syndrome). The other nine pregnancies resulted in the live birth of 10 children, without any congenital abnormalities. Epididymal and testicular retrieved spermatozoa were successfully used for ICSI to treat obstructive azoospermia, and resulted in an ongoing pregnancy in 10 of 24 couples (41.6%) after 39 ICSI procedures, a success rate of 25.6% per treatment cycle and of 27.7% per embryo transfer.      

The role of diabetic control in diabetic retinopathy

In spite of the continuing debate, it is possible to summarize the present state of our knowledge and to draw the following conclusions: 1. Microangiopathy of diabetes can be produced by pure insulin-deficiency in human subjects and experimental animals. 2. Evidence supports the concept that the pathology is due mainly to the deranged metabolism following insulin deprivation. 3. Repair of the insulin deficiency in animals has been shown to prevent the vascular damage associated with insulin deficiency. 4. Present methods of therapy have not been successful in preventing vascular complications in the noninsulin-dependent middle-aged diabetic patient; and, based on the findings of the University Group Diabetes Program, there is reason to believe that new methods of therapy must be realized to improve this outlook. 5. The efficacy of "compulsive control" for prevention of microangiopathy in insulin-dependent diabetic patients has not been adequately studied. Based on the results of animal experiments, the prudent physician should make every attempt to restore a normal physiological cellular environment in these patients with the expectation that this will offer the patient the best opportunity to minimize degenerative complications. Prospective observations are needed on the effects of hypoglycemic episodes which may be inevitable under these circumstances, but there is no evidence at present to suggest that mild hypoglycemia is of itself detrimental. 6. All individuals interested in the prevention of the complications of diabetes using available therapeutic methods should work to encourage a prospective clinical trial carefully designed from both an ethical and scientific point of view to obtain answers to the questions raised here.     

Role of copper in mitochondrial iron metabolism

Heme synthesis by copper-deficient cells was investigated to elucidate the nature of the defect in intracellular iron metabolism. Iron uptake from transferrin by copper-deficient reticulocytes was 52% of normal, and the rate of heme synthesis was 33% of normal. Hepatic mitochondria isolated from copper-deficient animals were deficient in cytochrome oxidase activity and failed to synthesize heme from ferric iron (Fe III) and protoporphyrin at the normal rate. The rate of heme synthesis correlated with the cytochrome oxidase activity. Heme synthesis from Fe(III) and protoporphyrin by normal mitochondria was enhanced by succinate and inhibited by malonate, antimycin A, azide, and cyanide. It is proposed that an intact electron transport system is required for the reduction of Fe(III), thereby providing a pool of ferrous iron (Fe II) for protoheme and heme a synthesis.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

On-site screening sigmoidoscopy promotes long-term utilization but fails as a venue for training primary care endoscopists

BACKGROUND & AIMS: "Academic detailing" is an effective strategy for promoting the use of screening sigmoidoscopy by primary care physicians. The primary objectives of this study were to determine whether the sustained presence of an "outside" university-based gastroenterologist performing on-site screening sigmoidoscopy promoted long-term utilization and whether the provision for on-site sigmoidoscopy was an effective venue for training primary care endoscopists. METHODS: Nine urban community health centers, including 4 intervention and 5 control sites, participated in a nonrandomized controlled trial conducted over 3 years. RESULTS: By the end of year 3, overall self-reported use of screening sigmoidoscopy increased by 61% for the intervention group vs. only 25% for the comparison group (P = 0.001). Ninety-seven percent of those reporting compliance referred 1 or more asymptomatic average-risk patients for screening examinations. Only 2 of 83 (2.4%) eligible providers completed on-site training and continued performing screening examinations independently. The major barriers to participation included lack of interest, lack of time to learn or perform sigmoidoscopy, concerns about technical competence, and lack of need because of on-site availability. CONCLUSIONS: Maintenance of on-site screening sigmoidoscopy services performed by an outside gastroenterologist promotes long-term utilization but fails as venue for training primary care endoscopists. Alternative strategies for expanding capacity are needed.