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.

Elevated plasma norepinephrine inhibits insulin secretion, but adrenergic blockade reveals enhanced ß-cell responsiveness in an ovine model of placental insufficiency at 0.7 of gestation.

In pregnancies complicated by placental insufficiency (PI), fetal hypoglycemia and hypoxemia progressively worsen during the third trimester, which increases circulating norepinephrine (NE). Pharmacological adrenergic blockade (ADR-block) at 0.9 gestation revealed that NE inhibits insulin secretion and enhanced ß-cell responsiveness in fetuses with PI-induced intrauterine growth restriction (IUGR). NE concentrations in PI fetuses at 0.7 gestation were threefold greater compared with age-matched controls, but the levels were similar to near-term controls. Therefore, our objective was to determine whether elevations in plasma NE concentrations inhibit insulin secretion and produce compensatory ß-cell responsiveness in PI fetuses at 0.7 gestation. Fetal insulin was measured under basal, glucose-stimulated insulin secretion (GSIS) and glucose-potentiated arginine-stimulated insulin secretion (GPAIS) conditions in the absence and presence of an ADR-block. Placental weights were 38% lower (P < 0.05) in PI fetus than in controls, but fetal weights were not different. PI fetuses had lower (P < 0.05) basal blood oxygen content, plasma glucose, insulin-like growth factor-1 and insulin concentrations and greater plasma NE concentrations (891 ± 211 v. 292 ± 65 pg/ml; P < 0.05) than controls. GSIS was lower in PI fetuses than in controls (0.34 ± 0.03 v. 1.08 ± 0.06 ng/ml; P < 0.05). ADR-block increased GSIS in PI fetuses (1.19 ± 0.11 ng/ml; P < 0.05) but decreased GSIS in controls (0.86 ± 0.02 ng/ml; P < 0.05). Similarly, GPAIS was 44% lower (P < 0.05) in PI fetuses than in controls, and ADR-block increased (P < 0.05) GPAIS in PI fetuses but not in controls. Insulin content per islet was not different between treatments. We conclude that elevations in fetal plasma NE suppress insulin concentrations, and that compensatory ß-cell stimulus-secretion responsiveness is present before IUGR.

Delayed dedifferentiation and retention of properties in dissociated adult skeletal muscle fibers in vitro.

Adult skeletal muscle fibers can be isolated and cultured but tend to dedifferentiate and sprout with time in culture. We examined isolated adult mouse flexor digitorum brevis muscle fibers under various culture conditions by monitoring maintenance of the same fibers at 2-d intervals using survival analysis. Fibers plated on laminin and cultured in serum-free media did not show sprouting and exhibited significantly (P < 0.0001) longer survival (median survival time, T(50) = 10.2 d) than fibers in serum-containing media (T(50) = 3.3 d). Cell proliferation was markedly suppressed in serum-free cultures. Multiple or delayed Ca(2+) transients in response to brief field stimulation were often observed in dedifferentiated fibers after several d in serum-containing media but were not observed in fibers in serum-free media. The addition of cytosine arabinoside to serum-containing cultures did not prolong fiber survival (P = 0.39) and did not eliminate sprouting but did greatly suppress proliferation of nonmuscle cells. Fibers cultured in agarose gel with serum exhibited small, bud-like extensions but no sprouts and did not survive as long (T(50) = 6.2 d) as fibers plated on laminin and cultured in serum-free media (T(50) = 10.2 d) did. These results demonstrate that both morphological and physiological properties of fibers become modified in serum-containing media but can be retained by culturing without serum.

Nonuniform distribution of myosin light chains within the thick filaments of lobster slow muscle: Immunocytochemical study.

The in situ distribution of the alpha and beta myosin light chains was investigated at the subsarcomeric and subfilament levels in individual fibers of the superficial flexor muscle (SFM) of the lobster, Homarus americanus. Polyclonal antibodies were produced against the two classes of myosin light chains and used for subsequent immunolocalization on thin sections of sarcomeres and on isolated filaments from both the medial and lateral fiber bundles of the SFM. The beta myosin light chains were uniformly distributed within the crossbridge region of sarcomeres of both medial and lateral bundles. The alpha myosin light chains were uniformly distributed within the crossbridge region of sarcomeres from the medial bundle, but were nonuniformly distributed over the crossbridge region of lateral bundle sarcomeres. In the latter, the number of alpha myosin light chains was highest toward the center of the thick filaments, diminishing towards the ends. Similar distributions of alpha light chains were found in isolated myosin filaments. These data demonstrate that heterogeneity in protein composition extends to the level of the myosin filament and suggest that the myosin filament substructure in lobster may be different than that found in vertebrate skeletal muscle.

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.

An evaluation of the impact of training Honduran health care providers in interpersonal communication.

OBJECTIVE: To evaluate the impact of interpersonal communication (IPC) training on practice and patient satisfaction and to determine the acceptability of this training to providers in a developing country. DESIGN: The study used a pre-post design with treatment and control groups. Data collection methods included interaction analysis of audio-taped clinical encounters, patient exit interviews, and a self-administered questionnaire for health providers. STUDY PARTICIPANTS: Interaction analysis was based on an experimental group of 24 doctors and a control group of eight with multiple observations for each provider). Exit interviews were carried out with 220 pre-test patients and 218 post-test patients. All 87 health providers who received training responded to the self-administered questionnaire. INTERVENTION: A brief in-service training programme on interpersonal communications was presented in three half-day sessions; these focused on overall socio-emotional communication, problem solving skills and counselling. MAIN OUTCOME MEASURES AND RESULTS: The IPC intervention was associated with more communication by trained providers (mean scores of 136.6 versus 94.4; P = 0.001), more positive talk (15.93 versus 7.99; P = 0.001), less negative talk (0.11 versus 0.59; P = 0.018), more emotional talk (15.7 versus 5.5; P = 0.021), and more medical counselling (17.3 versus 11.3; P = 0.026). Patients responded by communicating more (mean scores of 113.8 versus 79.6; P = 0.011) and disclosing more medical information (54.7 versus 41.7; P = 0.002). Patient satisfaction ratings were higher for providers who had received the training and providers reported training to be relevant and useful. CONCLUSIONS: Further validation of IPC skills and simplification of assessment methods are needed if IPC is to be an area for routine monitoring and quality improvement.

A-band architecture in vertebrate skeletal muscle: polarity of the myosin head array.

Despite extensive knowledge of many muscle A-band proteins (myosin molecules, titin, C-protein (MyBP-C)), details of the organization of these molecules to form myosin filaments remain unclear. Recently the myosin head (crossbridge) configuration in a relaxed vertebrate muscle was determined from low-angle X-ray diffraction (Hudson et al. (1997), J Mol Biol 273: 440-455). This showed that, even without C-protein, the myosin head array displays a characteristic polar pattern with every third 143 A-spaced crossbridge level particularly prominent. However, X-ray diffraction cannot determine the polarity of the crossbridge array relative to the neighbouring actin filaments; information crucial to a proper understanding of the contractile event. Here, electron micrographs of negatively-stained goldfish A-segments and of fast-frozen, freeze-fractured plaice A-bands have been used to determine the resting myosin head polarity relative to the M-band. In agreement with the X-ray data, the prominent 429 A-spaced striations are seen outside the C-zone, where no non-myosin proteins apart from titin are thought to be located. The head orientation is with the concave side of the curved myosin heads (containing the entrance to the ATP-binding site) facing towards the M-band and the convex surface (containing the actin-binding region at one end) facing away from the M-band.

Implementing Medicaid managed care: the New York City story.

Across the nation, public officials are encouraging or requiring Medicaid beneficiaries to enroll in managed care. In this article, we report on a study of the implementation of Medicaid managed care in New York City. Several findings are clear. First, government officials need to treat health plans as partners rather than adversaries; in New York, the relationship between the state and the plans is far too adversarial. Second, effective managed care requires good management information systems; New York officials are collecting an enormous amount of data but not much useful information. Third, effective implementation of Medicaid managed care is slow going; New York's effort to dramatically accelerate the enrollment process did not work.

Nothing exceeds like success: managed care comes to Medicaid in New York City.

Nearly every state is encouraging or requiring Medicaid beneficiaries to enroll in managed care delivery systems. In New York City, Medicaid officials began with an incremental, but not insignificant, managed care initiative. Buoyed by its success, New York policy makers tried, and failed, to accelerate the transition to managed care. The legacy of that failure still plagues them. A comparison of such initiatives in other states indicates that most state officials have remembered what New York's leaders temporarily forgot, namely, that Medicaid managed care is a complex exercise that demands consultation and consensus building.

'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.

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.

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.

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.

Exceptionalism as the rule? U.S. health policy innovation and cross-national learning.

American health care reformers, who often look to other nations for models of desirable health systems, are often surprised nowadays by cross-national infatuation with health policy innovations minted in the United States. American innovations appeal to policy makers abroad as they struggle with cost pressures, distinguish knowledge about how health systems work, and deal with changing images of what constitutes good public policy. These strategems are adapted, not adopted; however, the premises and practices with which other nations follow American directions differ deeply from those in the United States. Ironically, even cross-national experiments may end up offering instructive policy "rules" to the exceptionalist United States.