The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection

In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a "healthy gut." Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.     

Rabbit antithymocyte globulin. A 10-year experience in cardiac transplantation

Rabbit antithymocyte globulin, a "custom-made" pan-anti-T-cell antibody produced in rabbits, is currently being evaluated in the United States and may, within several years, become approved by the Food and Drug Administration. Because we have used this agent for induction of immunosuppression for 10 years in cardiac recipients and because the results appear to be more favorable than those obtained with other agents (horse antithymocyte globulin, antilymphocyte globulin, OKT3), we have reviewed our experience. For the purpose of analysis, all non-bridge-to-transplant cardiac recipients have been divided into three groups on the basis of immunosuppression protocol: group I (March 1979 to January 1983), 28 patients treated with rabbit antithymocyte globulin, steroids, and azathioprine; group II (January 1983 to March 1985), 29 patients treated with rabbit antithymocyte globulin, cyclosporine, and steroids; and group III (March 1985 to January 1989), 98 patients treated with rabbit antithymocyte globulin, cyclosporine, steroids, and azathioprine. Actuarial data showed advantage for group III in survival rate (1 year 94%, 2 years 91%, 3 years 88%), freedom from rejection (30% free at 1 year), freedom from infection (50% free at 1 year), freedom from death from rejection (99% free at 1 year), and freedom from death from infection (97% freedom at 1 year). Actuarial survival rates and freedom from death from rejection and infection are comparable for any of our groups with contemporary published data. In the past 3 years, we have had no death from acute rejection or from posttransplant infection. Time-related rates of infection by etiologic agents have shown a significant reduction in early bacterial, viral, and nocardial infections between groups I and III. With rabbit antithymocyte globulin 200 mg intramuscularly every day for 3 days, our current protocol, T-cells are significantly reduced and local and systemic toxicity is almost unnoticeable. A progressively increasing cyclosporine dose along with rapid tapering steroid and maintenance azathioprine immunosuppressive induction appears to be the therapy of choice in cardiac transplantation.     

The tetracycline analogs minocycline and doxycycline inhibit angiogenesis in vitro by a non-metalloproteinase-dependent mechanism

The tetracycline analogs minocycline and doxycycline are inhibitors of metalloproteinases (MMPs) and have been shown to inhibit angiogenesis in vivo. To further study the mechanism of action of these compounds we tested them in an in vitro model of angiogenesis: aortic sprouting in fibrin gels. Angiogenesis was quantitated in this system by a unique application of planar morphometry. Both compounds were found to potently inhibit angiogenesis in this model. To further characterize the activity of these compounds against MMPs, we determined the IC₅₀s of both compounds against representatives of three classes of metalloproteinases: fibroblast collagenase, stromelysin, and gelatinase A. Doxycycline was found to inhibit collagenase, gelatinase A and stromelysin with IC₅₀s of 452 M, 56 M and 32 M, respectively. Minocycline was found to inhibit only stromelysin in the micromolar range with an IC₅₀ of 290 M. Since these results suggest that these compounds may not have been inhibiting in vitro angiogenesis by an MMP-dependent mechanism, we decided to test the effects of the potent MMP inhibitor BB-94. This compound failed to inhibit aortic sprouting in fibrin gels, thus strongly suggesting that both doxycycline and minocycline act by an MMP-independent mechanism. These results have implications for the mechanism of action of tetracycline analogs, particularly where they are being considered for the treatment of disorders of extracellular matrix degradation including periodontal disease, arthritis, and tumor angiogenesis.     

Calcium absorption and kinetics are similar in 7- and 8-year-old Mexican-American and Caucasian girls despite hormonal differences

To assess the possibility of ethnic differences in mineral metabolism in prepubertal children, we compared measures of calcium metabolism in 7- and 8-y-old Mexican-American (MA) and non-Hispanic Caucasian (CAU) girls (n = 38) living in southeastern Texas. We found similar fractional calcium absorption, urinary calcium excretion, calcium kinetic values and total-body bone mineral content in the MA and CAU girls. In contrast, parathyroid hormone (PTH) concentrations were greater in MA girls (4.01 +/- 0.47 vs. 1. 96 +/- 0.50 pmol/L, P = 0.005) than in CAU girls. Serum 25-hydroxyvitamin D concentrations were lower in MA girls (68.9 +/- 7.7 vs. 109.4 +/- 8.4 nmol/L, P = 0.001) than in CAU girls, but 1, 25-dihydroxyvitamin D concentrations did not differ between groups. Seasonal variability was seen for 25-hydroxyvitamin D concentrations in girls of both ethnic groups, but values in all of the girls were >30 nmol/L (12 ng/mL). We conclude the following: 1) greater PTH levels in MA girls than CAU girls are present without evidence of vitamin D deficiency; and 2) differences in 25-hydroxyvitamin D and PTH concentrations between MA and CAU girls do not have a large effect on calcium absorption, excretion or bone calcium kinetics. These data do not provide evidence for adjusting dietary recommendations for mineral or vitamin D intake by MA girls.     

Mos positively regulates Xe-Wee1 to lengthen the first mitotic cell cycle of Xenopus

Several key developmental events occur in the first mitotic cell cycle of Xenopus; consequently this cycle has two gap phases and is approximately 60-75 min in length. In contrast, embryonic cycles 2-12 consist only of S and M phases and are 30 min in length. Xe-Wee1 and Mos are translated and degraded in a developmentally regulated manner. Significantly, both proteins are present in the first cell cycle. We showed previously that the expression of nondegradable Mos, during early interphase, delays the onset of M phase in the early embryonic cell cycles. Here we report that Xe-Wee1 is required for the Mos-mediated M-phase delay. We find that Xe-Wee1 tyrosine autophosphorylation positively regulates Xe-Wee1 and is only detected in the first 30 min of the first cell cycle. The level and duration of Xe-Wee1 tyrosine phosphorylation is elevated significantly when the first cell cycle is elongated with nondegradable Mos. Importantly, we show that the tyrosine phosphorylation of Xe-Wee1 is required for the Mos-mediated M-phase delay. These findings indicate that Mos positively regulates Xe-Wee1 to generate the G2 phase in the first cell cycle and establish a direct link between the MAPK signal transduction pathway and Wee1 in vertebrates.     

Sources of information about cancer as perceived by adolescent patients, parents, and physicians

As survival time has been extended for young cancer patients, their informational needs have also increased. Using written questionnaires, we surveyed 63 adolescent patients, 60 parents, and 53 physicians to compare their perceptions of patient-communication patterns and current and preferred information sources. Physicians were the main current and preferred information sources noted by all three groups. Group discussions with patients the same age, films and television programs, and books were ranked as acceptable but less preferable sources by more than half of each group. More than 90% of the patients were usually accompanied by a parent. Patients most frequently sought their parents to discuss general concerns and cited parents as their second most frequently used source of disease-related information. Adolescents qualified their parental discussions more than was perceived by their parents (P less than 0.01) and viewed themselves as discussion initiators more frequently than did their parents (P less than 0.05). Parents were more likely than patients to prefer physicians as their child's information source (P less than 0.05). Physicians consistently underestimated their own and the parents' importance, believing instead that the patients relied more on peers. Fewer physicians than patients or parents favored including parents in discussion with health professionals (P less than 0.001).     

Superficially invasive squamous cell carcinoma of the cervix.

The microscopic pathologic features of early invasive squamous cell cervical carcinoma are used as determinants for the treatment of these lesions. This study is a retrospective review of 180 patients with squamous cell cervical carcinoma with invasion to a depth of 5 mm or less. Invasion of less than or equal to 1 mm, greater than 1 but less than or equal to 3 mm, greater than 3 but less than or equal to 5 mm was noted in 37, 84, and 59 patients, respectively. The median follow-up was 6.5 years. Four (2.2%) patients developed carcinoma in situ of the vagina and four (2.2%) patients progressed to invasive squamous carcinoma. Pelvic lymph node metastases were rare (1%). No patient has died from recurrent disease. Analysis of numerous clinical and pathological variables identified no risk factors for recurrence. Most (54/68) patients with tumor invading beyond 3 mm or with tumor demonstrating vascular invasion were treated by traditional "radical" methods. This limited a meaningful analysis of the risk of conservative treatment. The reliability of using the existing definitions of microinvasive disease for the guidance of treatment remains controversial. Further clarification may be rendered only with prospective clinical-pathologic studies performed by cooperative groups.     

Efficacy of "high-intensity" blue-light and "standard" daylight phototherapy for non-haemolytic hyperbilirubinaemia

We report our clinical experience with phototherapy in 3802 infants; 3629 were exposed to "standard" daylight phototherapy and 173 to "high-intensity" blue-light phototherapy. High-intensity blue-light phototherapy was twice as effective as standard daylight phototherapy in decreasing bilirubin concentrations. No failures occurred with high-intensity phototherapy compared with an overall failure rate of 1.84/1000 with daylight lamps; these cases were transferred to high-intensity phototherapy with prompt response. Rebound after cessation of phototherapy was greater in those exposed to high-intensity blue light with a significantly greater number requiring a second exposure. However, the incidence was still low. No third exposure was required in any infant. Nursing of infants under high-intensity blue light was more difficult and inconvenient as was clinical monitoring. The light also caused more stress on the nursing and medical personnel. However, the infants tolerated both types of phototherapy equally well. High-intensity blue-light phototherapy would seem to be the treatment of choice for infants with rapidly increasing or very high bilirubin levels, as well as in those not responding adequately to daylight phototherapy.