Sheep recombinant IGF-1 promotes organ-specific growth in fetal sheep.

IGF-1 is a critical fetal growth-promoting hormone. Experimental infusion of an IGF-1 analog, human recombinant LR3 IGF-1, into late gestation fetal sheep increased fetal organ growth and skeletal muscle myoblast proliferation. However, LR3 IGF-1 has a low affinity for IGF binding proteins (IGFBP), thus reducing physiologic regulation of IGF-1 bioavailability. The peptide sequences for LR3 IGF-1 and sheep IGF-1 also differ. To overcome these limitations with LR3 IGF-1, we developed an ovine (sheep) specific recombinant IGF-1 (oIGF-1) and tested its effect on growth in fetal sheep. First, we measured in vitro myoblast proliferation in response to oIGF-1. Second, we examined anabolic signaling pathways from serial skeletal muscle biopsies in fetal sheep that received oIGF-1 or saline infusion for 2 hours. Finally, we measured the effect of fetal oIGF-1 infusion versus saline infusion (SAL) for 1 week on fetal body and organ growth, in vivo myoblast proliferation, skeletal muscle fractional protein synthetic rate, IGFBP expression in skeletal muscle and liver, and IGF-1 signaling pathways in skeletal muscle. Using this approach, we showed that oIGF-1 stimulated myoblast proliferation in vitro. When infused for 1 week, oIGF-1 increased organ growth of the heart, kidney, spleen, and adrenal glands and stimulated skeletal myoblast proliferation compared to SAL without increasing muscle fractional synthetic rate or hindlimb muscle mass. Hepatic and muscular gene expression of IGFBPs one to three was similar between oIGF-1 and SAL. We conclude that oIGF-1 promotes tissue and organ-specific growth in the normal sheep fetus.

Pulsatile hyperglycemia increases insulin secretion but not pancreatic ß-cell mass in intrauterine growth-restricted fetal sheep.

Impaired ß-cell development and insulin secretion are characteristic of intrauterine growth-restricted (IUGR) fetuses. In normally grown late gestation fetal sheep pancreatic ß-cell numbers and insulin secretion are increased by 7-10 days of pulsatile hyperglycemia (PHG). Our objective was to determine if IUGR fetal sheep ß-cell numbers and insulin secretion could also be increased by PHG or if IUGR fetal ß-cells do not have the capacity to respond to PHG. Following chronic placental insufficiency producing IUGR in twin gestation pregnancies (n=7), fetuses were administered a PHG infusion, consisting of 60 min, high rate, pulsed infusions of dextrose three times a day with an additional continuous, low-rate infusion of dextrose to prevent a decrease in glucose concentrations between the pulses or a control saline infusion. PHG fetuses were compared with their twin IUGR fetus, which received a saline infusion for 7 days. The pulsed glucose infusion increased fetal arterial glucose concentrations an average of 83% during the infusion. Following the 7-day infusion, a square-wave fetal hyperglycemic clamp was performed in both groups to measure insulin secretion. The rate of increase in fetal insulin concentrations during the first 20 min of a square-wave hyperglycemic clamp was 44% faster in the PHG fetuses compared with saline fetuses (P0.23). Chronic PHG increases early phase insulin secretion in response to acute hyperglycemia, indicating that IUGR fetal ß-cells are functionally responsive to chronic PHG.

Neonatal outcomes after introduction of a national intrapartum fetal surveillance education program: a retrospective cohort study.

OBJECTIVE: To determine the impact of a multidisciplinary fetal surveillance education program (FSEP) on term neonatal outcomes. METHODS: A retrospective cohort study of term neonatal outcomes before (1998-2004) and after (2005-2010) introduction of a FSEP. Clinical data was collected for all term infants admitted to a neonatal intensive care unit (NICU) in Australia between 1998 and 2010. Infants with congenital abnormalities were excluded. Neonatal mortality and severe neonatal morbidity (admission to a NICU, respiratory support, hypoxic encephalopathy) were compared before and after the FSEP was introduced. The rates of operative delivery during this time were assessed. RESULTS: There were 3 512 596 live term births between 1998 and 2010. The intrapartum hypoxic death rate at term decreased from 2.02 to 1.07 per 10 000 total births. More neonates were admitted to NICU after 2005 (10.6 versus 14.6 per 10 000 live births), however fewer babies admitted to the neonatal unit had Apgar scores < 5 at five minutes (55.1-45.5%, RR 0.82, 95% CI 0.7-0.87); and rates of hypoxic ischemic encephalopathy fell from 36% to 30% (RR 0.83, 95% CI 0.76-0.90). There was no increase in rates of emergency in labour caesarean sections (11.7% pre versus 11.1% post, RR 0.95, 95% CI 0.95-0.96). CONCLUSIONS: Introduction of a national FSEP was associated with increased neonatal admissions but a reduction in intrapartum hypoxia, without increasing emergency caesarean section rates.

Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma.

PURPOSE: We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and PCNU with those of RT and carmustine (BCNU) in patients with malignant glioma. PATIENTS AND METHODS: A total of 346 patients with histologically verified supratentorial grade 3 and grade 4 astrocytoma were studied. After surgery, patients were randomly assigned to receive RT 60 Gy in 30 fractions and either PCNU 100 mg/m2 or BCNU 200 mg/m2 every 7 weeks for 1 year and every 10 weeks for the second year. RT and chemotherapy were started within 72 hours of randomization and usually on the same day. Of 334 assessable patients, 72% had partial or radical resection and 71% had grade 4 tumors. Median age was 59 years, and 85% had performance scores of 0 to 2 (Eastern Cooperative Oncology Group [ECOG]). The follow-up duration of 51 living patients ranged from 10.3 to 63.2 months, with a median of 36.2 months. RESULTS: The median survival duration in each group was 47 weeks, and median time to progression was 28 weeks. PCNU produced significantly more leukopenia and thrombocytopenia, whereas BCNU produced significantly more nausea, vomiting, and irritation. CONCLUSION: PCNU has no therapeutic advantage at this dose and schedule and does not warrant further study as a single agent for patients with high-grade glioma.

The consequences of treatment and disease in patients with primary CNS non-Hodgkin's lymphoma: cognitive function and performance status. North Central Cancer Treatment Group.

Per protocol, patients with primary CNS non-Hodgkin's lymphoma in an intergroup phase II trial conducted by the North Central Cancer Treatment Group and the Eastern Cooperative Oncology Group had their cognitive functions measured using the Folstein and Folstein Mini-Mental Status Examination (MMSE) and their physical functions measured using the Eastern Cooperative Oncology Group Performance Score (PS) at study entry, at each treatment evaluation, and at quarterly intervals thereafter until disease progression or death. Of the 53 eligible participants who began therapy, 46 (87%) had baseline MMSE scores recorded, 36 (68%) had at least one follow-up MMSE, and 32 (60%) had both, while 52 (98%) had baseline PS, 49 (92%) had at least one follow-up PS, and 48 (91%) had both. Patterns of MMSE and PS values over time were studied in each individual, in the group as a whole, in the 20 patients who completed the study regimen, in the 23 who survived more than a year, and in patients who were classified as nonprogressors at each key evaluation. For each patient, all recorded values were plotted versus time, with dates of disease progression and death included, to look for signs of decline in cognitive or physical function preceding adverse events. Long-term declines in scores of both cognitive and physical function were observed in many treated patients with primary CNS non-Hodgkin's lymphoma. Nearly all patients who were alive more than 52 weeks after study entry had a demonstrable decline in cognitive and physical functionality. Such declines may occur before disease progression is documented; they may also occur in some patients who have long-term follow-up without evidence of disease progression. Declining MMSE and PS was a poor predictor of disease progression. There was no association of PS and toxicity. The data from this study demonstrated the considerable difficulties we encountered conducting an ancillary study such as this within a multicenter clinical trial. Firstly, the test instruments written into the protocol were unable to tell if the declines seen were due to disease, treatment, co-morbidity, or other factors. Secondly, the missing data created difficulties in interpreting outcome.

Primary central nervous system non-Hodgkin's lymphoma: survival advantages with combined initial therapy?

PURPOSE: Results of multiple radiation, chemotherapy, and combined treatment trials have shown that the fate of primary central nervous system lymphoma (PCNSL) patients is very different from that of patients with similarly treated systemic IE non-Hodgkin's lymphoma. This study was designed to improve the survival of PCNSL patients by the use of combined initial therapy. METHODS AND MATERIALS: Forty-six eligible primary PCNSL patients were treated with whole brain irradiation and adjuvant chemotherapy consisting of preirradiation cyclophosphamide-adriamycin-vincristine-prednisone (CHOP) and postirradiation high-dose cytosine arabinoside (HDAC) as part of an ongoing Phase II Mayo/North Central Cancer Treatment Group/Eastern Cooperative Oncology Group (M/NCCTG/ECOG) intergroup effort, which opened in April 1986. RESULTS: This cohort consisted of 23 men and 23 women with median age 63.5 years (range 24 to 75 years). Only 5% were under age 40; 36% were age 40 to 59, 37% were age 60 to 69, and 22% were age 70 and over. Forty-six percent had good performance scores of ECOG 0-1 at time of study entry. Forty-six patients were evaluable for treatment outcome as of October 6, 1993. Of these, 10 were still alive. Estimated median survival and 21-month survival were 45.3 weeks and 29%, respectively. There were four early deaths ranging from Day 9 to Day 15 (three drug-related, one from other complications), and two CHOP responders died at 32 and 35 days, soon after Cycle 2 of CHOP (one probably drug-related, one from other complications). There was no significant difference in survival according to baseline performance status. However, survival was consistently worse for patients > 60 years old than for the younger patients (< or = 60 years). With deaths recorded for 21 of 21 older patients, but only 9 of the 14 younger patients, 21-month survival for older vs. younger was 14 vs. 50% based on the 35 patients who entered the study at least 21 months ago (p = 0.0365). Of the 46 patients evaluable for response, 63% had objective remissions on CHOP and another 20% remained stable. CONCLUSION: Combined modality therapy in this study did not produce an overall survival advantage in treating PCNSL. The 50% 21-month survival of younger patients may be a reflection of age only.

Primary central nervous system non-Hodgkin's lymphoma (PCNSL): survival advantages with combined initial therapy? A final report of the North Central Cancer Treatment Group (NCCTG) Study 86-72-52.

PURPOSE: We herein report updated survival and toxicity data on the entire cohort of 53 eligible patients treated on North Central Cancer Treatment Group (NCCTG) protocol 86-72-52, which is now closed. METHODS AND MATERIALS: An initial report was published in this journal in 1995. No substantive changes in the conclusions of that report were identified in this analysis. Median survival was 9.6 months for the entire cohort; median survival for the 20 patients who completed the prescribed protocol treatment was 20.7 months. The hematologic and non-hematologic toxicity distributions are virtually the same as those reported in the original paper. RESULTS: Results are given for the entire group and for subsets defined by age < or = 60 versus > 60 years, and < 70 versus > or = 70 years of age. CONCLUSIONS: No significant differences were observed in any of the outcome variables by age group. There was, however, a nonsignificant suggestion of poorer outcome in those who were > 60 years of age.

Using lot quality assurance sampling to assess measurements for growth monitoring in a developing country's primary health care system.

BACKGROUND: Local supervisors used lot quality assurance sampling (LQAS) during routine household visits to assess the technical quality of Costa Rican community-based health workers (CHW): measuring and recording weights of children, interpreting their growth trend and providing nutrition education to mothers. METHOD: Supervisors sampled 10 households in each of 12 Health Areas (4-8 hours per area). No more than two performance errors were allowed for each CHW. This LQAS decision rule resulted in judgments with a sensitivity and specificity of about 95 percent. RESULTS: Three categories of results are reported: (1) CHW adequately weighed children, calculated ages, identified children requiring nutritional services, and used the growth chart. (2) They needed to improve referral, education, and documentation skills. (3) The lack of system support to regularly provide growth cards, supplementary feeding to identified malnourished children, and other essential materials may have discouraged some CHW resulting in them not applying their skills. CONCLUSIONS: Supervisors regularly using LQAS should, by the sixth round of supervision, identify at least 90 percent of inadequately performing CHW. This paper demonstrates the strength of LQAS, namely, to be used easily by low level local health workers to identify poorly functioning components of growth monitoring and promotion.

PIP: Nurses and rural health supervisors used the Lot Quality Assurance Sampling (LQAS) technique to assess the quality of growth monitoring and promotion (GMP) conducted by community health workers (CHWs) in 12 health areas in Costa Rica. Each supervisor made 10 routine household visits and spent 4-8 hours in each area. The study allowed no more than two performance errors per CHW. CHWs could correctly identify children in need of the nutritional services of the primary health care (PHC) system. Yet they were weak in their referral, education, and documentation skills. The supply system and the documentation system that support growth monitoring did not work well. Perhaps the inadequate support system may have contributed to the CHWs' inferior use of their skills. The finding that there were inadequate supplies and poor documentation of required GMP data suggest that CHWs did not regularly conduct growth monitoring, perhaps due to a lack of scales and growth charts. The PHC system did not follow children with nutritional deficiencies, suggesting that health facilities did not keep a register and refer these children systematically. This would explain why CHWs did not refer malnourished children to health facilities. CHWs had significant time constraints that influenced their ability to perform regular growth monitoring. The evaluation team required 4-8 hours to observe growth monitoring in 10 households. The PHC system expects each CHW to conduct about 10 complete household visits/day, which includes growth monitoring, vaccinations, pre- and post-natal care, oral rehydration therapy training, and monitoring blood pressure. With each subsequent supervision visit, the misclassification error of substandard CHW (i.e., the probability of identifying an inadequate performer) decreases. By the sixth visit, supervisors could identify almost all CHWs with a performance quality of 80% or less. These findings suggest that supervisors use LQAS methods to regularly identify GMP problems.

The F1 genes of the F1F0 ATP synthase from the acidophilic bacterium Thiobacillus ferrooxidans complement Escherichia coli F1 unc mutants.

An atp gene cluster from the extreme acidophile Thiobacillus ferrooxidans was able to complement Escherichia coli F1 unc mutants for growth on minimal medium plus succinate. Complementation with all four E. coli F1 mutants tested was observed and subunits for the F1 portion of the T. ferrooxidans ATP synthase formed a functional association with the F0 subunits of the E. coli enzyme. In addition, a hybrid F1 enzyme in which some units were derived from E. coli and some from T. ferrooxidans was partially functional. No clones capable of complementing E. coli F0 unc mutants were isolated. The nucleotide sequence of the gene cluster was determined and the genes for the F0 and the F1 ATP synthase subunits were found to be physically linked.

Commissions, clubs, and consensus: Florida reorganizes for health reform.

This paper explores the political dynamics by which a health reform leader state--Florida--engineered an ambitious reorganization of state health agencies as an expected prelude to bolder policy measures before the end of 1994. Demographic and fiscal pressures spurred the state to action, but its success at innovation demands a political explanation. This narrative highlights Florida's patient quest, by means of commissions and task forces, for common ground among parties of diverse dispositions; the sagacity of would-be innovators in wielding a potent policy "club"--the prospect of a single-payer system--to encourage a search for common centrist ground; and the consensus- and coalition-building skills of the state's leading executive and legislative figures. Florida's political skill has sustained impressive departures, but the hardest questions--how to finance universal coverage, how to secure universal access, and how to keep it all affordable--remain to be answered.

Political evolution of federal health care regulation.

Although federal regulation of health care faces cultural obstacles and skepticism among policymakers, it has grown markedly over the past two decades. Beginning in the 1970s with decentralized programs aimed at regulating provider behavior (Health Systems Agencies and certificate of need) and budgets (state rate setting), health care regulation grew more centralized in the 1980s as federal policymakers expanded their influence on behavior (peer review organizations and medical practice guidelines) and budgets (Medicare prospective payment and the resource-based relative value scale). Behavioral regulation has increased the heavy micromanagement that providers face in the United States, while budgetary regulation falls well short of the fiscal macromanagement (global budgets, for example) that other Western nations use. As cost increases intensify, the coalitions that supported limited regulation as a compromise designed to forestall more threatening intrusions may yield to political pressure for firmer central budget controls.

Window shopping: state health reform politics in the 1990s.

Throughout the 1990s states sought politically acceptable policies to reduce the ranks of the uninsured. Visions of comprehensive health reform and universal coverage yielded by mid-decade to more modest measures to repair private health insurance markets, and to these enactments were added several new public programs (state and federal) to expand coverage for lower-income children and, in some cases, adults. Because governments remain ill equipped to counter the power of business, insurers, and providers in conflicts fought on private turf, reform agendas have been more readily set, moved, and cleared in public-sector arenas. Although the number of uninsured rose steadily until 1999, "catalytic federalism"--the accelerating interplay between state and federal reform forces and funds--may be putting the programmatic foundations for broader coverage incrementally into place.

Uneasy alliances: managed care plans formed by safety-net providers.

Health care providers that have traditionally served the poor are forming their own managed care plans, often in alliance with local safety-net peers. These alliances make it easier to raise needed capital, increase the pool of likely enrollees, and enable plans to benefit from efficiencies of scale. At the same time, however, the alliances often are undermined by conflicts of interest among the different sponsors and between the sponsors and the plan. This paper suggests that these plans are most likely to do well when the state makes special efforts to help and when plans have the leadership and financial reserves to take advantage of their supportive state policies.

'Manacled competition': market reforms in German health care.

In 1993 Germany joined the small but swelling ranks of societies determined to explore managed competition as a means of slowing the growth of health spending by giving stakeholders new incentives for efficiency. Realizing the benefits of competition, however, demands changes in institutional norms and regulatory practices that now largely handcuff those who would follow competitive logic into "managed care." In time Germany's system of "manacled competition" may evolve into a happy higher synthesis of managed care and managed competition. Or policymakers may conclude that the political price of installing workable market forces in health care is too high and reconcile themselves to more traditional applications of political pressure.

Modulation of nerve membrane sodium channel activation by deltamethrin.

Deltamethrin is a highly potent pyrethroid insecticide that causes hypersensitivity, choreoathetosis, tremors, and paralysis in mammals. It is known to modify the sodium channel in such a way as to prolong the tail current associated with step repolarization following a depolarizing pulse. Using the axial-wire voltage-clamp technique with the giant axon of the squid Loligo pealei, we have demonstrated that deltamethrin also greatly slows the opening of the sodium channel. This was first observed as a decrease, by as much as 80%, in the peak sodium current flowing during a short, 10 ms depolarization. Current flowing through these slowly opening deltamethrin modified sodium channels was observed during the first depolarizing pulse after deltamethrin exposure and developed with a time constant of 320 ms. This supports the idea that deltamethrin can modify sodium channels when they are in the closed or resting state. Further, evidence of this hypothesis was provided by experiments using 0.1 and 10 microM deltamethrin and measuring the tail current amplitude after depolarizing pulses of varying duration (1-1200 ms). The mean time constant for the increase in tail current amplitude was almost concentration independent; 253 ms at 0.1 microM and 193 ms at 10 microM. We conclude that deltamethrin modifies the activation kinetics of sodium channels in such a way as to slow opening and that this modification occurs predominantly when channels are in the closed or resting state.

Pyrethroid modifications of the activation and inactivation kinetics of the sodium channels in squid giant axons.

The kinetics of sodium channel activation and inactivation were analyzed in the squid giant axons internally treated with various pyrethroids. Pyrethroids increased the steady-state sodium current in squid giant axons by removing the inactivation. The steady-state sodium conductances in control and pyrethroid-treated axons showed the same voltage dependence, indicating that the removal of inactivation by pyrethroids did not lead to an alteration of gating charge transfer. The pyrethroid-modified sodium channels were activated with a biphasic time course involving the movement of at least two gating particles, and both components were voltage-dependent. The slower component was abolished by treatment with either pronase or N-bromoacetamide. The net elementary charges transported in the electric membrane field were reduced in the course of slow activation of the pyrethroid-induced sodium current. It appears that the 'immobilization' of gating charge is related to the slow activation rather than the inactivation of the sodium channel.

The role of G protein in muscarinic depolarization near resting potential in cultured hippocampal neurons.

Cultured neurons from the CA1 and CA3 regions of the rat hippocampus were studied by using the whole-cell version of patch clamp. Application of acetylcholine (5-10 microM) or muscarine (20 microM) to a neuron with a holding potential of approximately -70 mV produced a slow inward current. This inward current was inhibited by atropine (1-2 microM). Loading the cell with GTP gamma S caused a change in the muscarinic response. In the control cells the muscarine-induced inward current recovered by 89%. On the other hand, in the GTP gamma S-loaded cells the inward current recovered by only 30%, indicating some irreversibility. Pertussis toxin treatment did not change the muscarine-induced slow inward current. Loading the cells with cyclic AMP (100 microM) plus IBMX (1 mM) (an inhibitor of phosphodiesterase) did not occlude the effect of muscarine. We conclude that the slow inward current is mediated through a pertussis toxin-insensitive G protein, and that cyclic AMP is not a part of the signal transduction cascade. The finding that the GTP gamma S-loaded cells did not show complete irreversibility was discussed in relation to the results of Benson et al. (J. Physiol., 404 (1988) 479-496), which showed that there are two ionic mechanisms responsible for the muscarine-induced depolarization. Occasionally cells were encountered, in which muscarine (or acetylcholine) evoked a large and rapid inward current, followed by the usual slow inward current. The time course of this rapid response was not affected by GTP gamma S.

Management by objection? Public policies to protect choice in health plans.

Consumer choice is a watchword of the market reforms now sweeping the U.S. health care system. Policy makers, however, must grapple with an important ambiguity; is the objective to expand choice or protect choosers, and what should be done if the two goals conflict? Concerns about health care market malfunctions trigger a politics of consumer protection that may emphasize regulatory standards over market flexibility. To complicate matters further, hopes that deluging consumers with information can ensure that choices are at once ample and prudent are likely to be disappointed.

Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma.

The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-alpha) in patients with recurrent glioma. As single agents, both BCNU and IFN-alpha can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-alpha 2a (12 x 10(6) U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-alpha and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-alpha is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.

Evaluation of fludarabine phosphate in patients with recurrent glioma.

Fifteen patients with recurrent primary brain tumors were treated with fludarabine phosphate. There were no responses seen. Toxicity was mild and primarily hematological. Fludarabine phosphate would appear to be ineffective in recurrent gliomas.