Blockade of N-methyl-D-aspartate receptors may protect against ischemic damage in the brain.

In rats ischemia of the forebrain induced by a 30-minute occlusion of the carotid artery, followed by 120 minutes of arterial reperfusion, produced ischemic lesions of selectively vulnerable pyramidal cells in both hippocampi. Focal microinfusion into the dorsal hippocampus of 2-amino-7-phosphonoheptanoic acid, an antagonist of excitation at the N-methyl-D-aspartate-preferring receptor, before ischemia was induced protected against the development of ischemic damage. It is proposed that excitatory neurotransmission plays an important role in selective neuronal loss due to cerebral ischemia.

Smoking Predicting Physical Activity in an Aging America.

OBJECTIVES: Tobacco smoking and physical inactivity are among leading behavioral risk factors for ill health in older adults. This study considers how smoking is associated with physical activity. DESIGN: Using a Life-Course model, data are analyzed regarding this relationship, controlling for, and interacted with, life-course and other factors. Daily smokers and sometimes smokers were hypothesized to engage in less leisure-time physical activity than those who never smoked, while those who stopped smoking were expected to do more than never smokers. Analyses were performed using SAS-Callable SUDAAN. SETTING AND PARTICIPANTS: Secondary data from ten years of a national sample of adults aged 18 and over of the National Health Interview Survey, 2001-2010, are used (N = 264,945, missing data excluded, of 282,313 total cases). MEASUREMENTS: Daily smokers, occasional smokers, and smoking quitters are compared to never smokers with regard to requisite physical activity (150 minutes per week of moderate, 100 of vigorous, and/or 50 of strengthening activity). Life-course measures include birth cohorts, age, and year of survey, as well as gender, race/ethnicity, and education. RESULTS: Overall, hypotheses are supported regarding daily smokers and quitters; but the hypothesis is strongly rejected among sometimes smokers, who are much more likely to do requisite physical activity. Findings differ by age, sometimes smokers age 65 and over being less likely to do physical activity. Findings among all men are similar to the overall findings, while those among all women are similar to those for older respondents. Associations of smoking status with physical activity vary greatly by race/ethnicity. CONCLUSIONS: Daily smokers may be most in need of both smoking cessation and leisure-time physical activity interventions. Smoking-cessation efforts may pay greater physical activity benefits among women and the aged, while smoking-reduction efforts may provide better outcomes among men. Smoking reduction efforts may pay more exercise benefits among African-Americans and Hispanics.

Protection by NMDA antagonists against selective cell loss following transient ischaemia.

We have administered antagonists acting competitively or noncompetitively at the N-methyl-D-aspartate receptor after a short period of incomplete ischaemia and evaluated selective neuronal loss in the CA1 region of the rat hippocampus. The competitive antagonists D-(-)-2-amino-7-phosphonoheptanoate (2APH); 100 or 330 mg/kg; 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP); 3.3 or 10 mg/kg; and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) 3.3 or 10 mg/kg; and the noncompetitive antagonists MK801 [+)5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate), 0.3, 1, or 3 mg/kg, and dextrorphan, 2, 6, 18, or 54 mg/kg, were administered intraperitoneally 15 min and 5 h after a 10-min incomplete ischaemia period; additionally MK801 (1 or 3 mg/kg) and CGS 19755 (10 or 30 mg/kg) were administered 5 and 10 h postischaemia. Seven days after ischaemia, the brains were fixed by perfusion. CA1 pyramidal cell counts were performed on Nissl-stained sections using an ocular grid piece. Ventilated (no ischaemia) control animals had a mean of 406 +/- 13 CA1 neurones/3 grid lengths. Ischaemia reduced this mean to 157 +/- 23. A significant protective effect against this cell loss was seen after two injections (at 15 min and 5 h postischaemia) of 2APH, CPP (10 mg/kg), CGS 19755 (10 mg/kg), MK801 (1 mg/kg), and dextrophan (54 mg/kg). Delayed injection (5 and 10 h postischaemia) of CGS 19755 (10 and 30 mg/kg) and MK801 (1 and 3 mg/kg) did not provide any protection against pyramidal cell loss.

Long-term development of selective neuronal loss and the mechanism of protection by 2-amino-7-phosphonoheptanoate in a rat model of incomplete forebrain ischaemia.

Excitatory neurotransmission at the N-methyl-D-aspartate (NMDA) receptor is selectively blocked by 2-amino-7-phosphonoheptanoate acid (2-APH). Acute focal microinjection of 2-APH into the rat hippocampus partially protects against cytopathology developing in selectively vulnerable neurons after 30 min of ischaemia and 2 h of reperfusion. We show that this protective action of 2-APH does not involve alterations in local cerebral blood flow (CBF). Intermediate cytopathology and long-term neuronal survival has been assessed in rats receiving focal injections of (+/-) 2-APH, 20 micrograms in 1 microliter, into one dorsal hippocampus prior to and 4 and 10 h after a 10-min period of forebrain ischaemia. Cytopathology assessed 4 or 24 h after ischaemia shows no difference between the buffer and 2-APH-injected hippocampi. Assessment after 7 days survival shows a significant protection against neuronal loss in the CA1 zone of the 2-APH-injected hippocampus compared with the contralateral, buffer-injected hippocampus. Systemic injection of D(-)2-APH (675 mg/kg i.v. at 0 h, 4 h, and 10 h) affords significant protection to CA1 hippocampal neurones (as assessed after 7 days). These results suggest that maintained blockade of neurotransmission at the NMDA receptor in the postischaemic period can protect against delayed cell loss. The mechanism may be through antagonism of the excitotoxic action of an endogenous neurotransmitter acting in the postischaemic period.

Calcium overload in selectively vulnerable neurons of the hippocampus during and after ischemia: an electron microscopy study in the rat.

Light and electron microscopy has been used to study the cytopathological changes in the rat hippocampus directly after a 30-min period of forebrain ischemia and after 30 or 120 min of reperfusion. The fine structural localization of calcium has been demonstrated using the oxalate/pyroantimonate procedure. Cellular changes considered typical of ischemia (swelling of astrocytic processes, distention of mitochondria, condensation of cytoplasm, "ischemic cell change") are most prominent after 30 min of reperfusion. At this time, dense calcium pyroantimonate deposits are evident in swollen mitochondria in pyramidal and hilar neurons. After 120 min of reperfusion, substantial restitution has occurred; most mitochondria appear normal and there are few calcium deposits. However, a small number of selectively vulnerable neurons (hilar and pyramidal neurons) show dense condensation (ischemic cell change) with multiple vacuoles containing calcium deposits. The role of excessive calcium entry and mitochondrial calcium overload during the reperfusion period in determining the death of selectively vulnerable neurons is discussed.

Hyperglycemia does not augment neuronal damage in experimental status epilepticus.

The neuronal regions affected and the neuropathologic features of ischemia and status epilepticus are similar. Experimentally, elevated plasma glucose levels, increasing brain lactate, are associated with more severe neuropathologic damage from cerebral ischemia. We therefore studied the cytologic features and cerebral content of lactate and glucose in the selectively vulnerable neurons of rat hippocampus after 2 hours of L-allylglycine-induced status epilepticus in rats with mean plasma glucose concentrations of 65, 250, and 480 mg/100 ml. Brain lactate concentration was elevated in status and maximal in the high-glucose group, but the maximum levels (8 mumol/g) were less than those thought to augment cell death in ischemia. Using multiple linear regressions, only time-in-status predicted neuropathologic damage.

Redistribution of transmitter amino acids in rat hippocampus and cerebellum during seizures induced by L-allylglycine and bicuculline: an immunocytochemical study with antisera against conjugated GABA, glutamate and aspartate.

The effects of the convulsants L-allylglycine and bicuculline on the distribution of gamma-amino-butyric acid (GABA), glutamate and aspartate in rat brains were assessed immunocytochemically, using antisera raised against glutaraldehyde-protein conjugates of the respective amino acids. In accord with previous biochemical studies of GABA content, L-allylglycine treatment was followed by a decreased immunoreactivity for GABA in the hippocampus and cerebellum, whereas treatment with bicuculline led to an increased immunoreactivity in the hippocampus, but not in the cerebellum. Different cells and zones were affected differentially. With both convulsants the hippocampus showed the most pronounced changes in the neuropil of the pyramidal and granular cell layers. L-Allylglycine treatment led to a substantial decrease in the concentration of detectable GABA-immunoreactive bouton-like dots in the stratum oriens, radiatum and lacunosum-moleculare and in the deep hilar region, but did not produce statistically significant changes in this parameter in the outer and intermediate zones of the dentate molecular layer. In the cerebellum, the decrease in GABA immunoreactivity after L-allylglycine treatment was less in the basket cell terminals than in other GABA-containing elements. Neither convulsant altered the average staining intensity for aspartate or glutamate in the two regions studied, but L-allylglycine reduced the level of aspartate-like immunoreactivity in hippocampal hilar cells. All the changes described were evident after 20 min of seizure activity and were qualitatively similar after 60 min of seizure (animals paralysed and ventilated). Our results indicate that L-allylglycine or bicuculline given intravenously exerts specific effects on cerebral amino acid metabolism. The nature and magnitude of these effects show inter-regional variations and also differ among cellular compartments within each region. Amino acid immunocytochemistry may prove to be a valuable tool for the investigation of metabolic changes associated with epileptic seizures and should be particularly useful in regions showing heterogeneous changes that would tend to cancel each other in biochemical analyses.

Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87.

BW 1003C87, 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid, has been tested for its in vitro and in vivo effects on glutamate release in rat brain tissue, and for its cerebro-protective action in two rodent models of cerebral ischemia. In rat brain slices the release of glutamate evoked by veratrine is inhibited by BW 1003C87 (IC50 = 1.6 microM). In anaesthetised rats with microdialysis probes implanted in the dorsal hippocampus the increase in extracellular glutamate evoked by veratrine is markedly reduced by co-infusion of BW 1003C87, 100 microM. In anaesthetised rats with microdialysis probes implanted in the cortex and the caudate nucleus ipsilateral to a middle cerebral artery (MCA) occlusion the increase in dialysate glutamate concentration seen in the first 2 h following MCA occlusion is markedly attenuated by the prior administration of BW 1003C87, 20 mg/kg i.v. In rats subjected to 10 min of bilateral common carotid artery occlusion the loss of CA1 pyramidal neurons (assessed 7 days later) is reduced by administration of BW 1003C87 (20 mg/kg i.v., at the time of ischemia and 4 h later). The volume of cortex showing infarction 72 h after unilateral MCA occlusion is reduced by treatment with BW 1003C87 (20 mg/kg, i.v., beginning 5 min after occlusion). Inhibition of glutamate release may provide a therapeutic approach in cerebral ischemia as well as in epilepsy.

Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92.

202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine) is a novel compound in the same chemical series as the antiepileptic drug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantitatively assessed as a neuroprotective agent in focal cerebral ischaemia, and as an inhibitor of sodium and calcium channels and of synaptic transmission. In the rat permanent middle cerebral artery occlusion (MCAO) model of acute focal ischaemia, 202W92 reduced infarct volume by 75% in cortex and by 80% in basal ganglia, with ED(50) approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels (IC(50) 3 x 10(-6) M) in rat freshly-isolated cortical neurons and in the GH(3) pituitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (approximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC(50) 15 x 10(-6) M) and weakly inhibited low-voltage-activated (LVA) calcium currents of the recombinant alpha1I-mediated T-type (IC(50)>100 x 10(-6) M). The drug inhibited the amplitude and frequency of 4-aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs). In conclusion, 202W92 is an effective neuroprotective agent when administered post-ischaemia and a potent sodium channel inhibitor in vitro.

An adenosine analogue, 2-chloroadenosine, protects against long term development of ischaemic cell loss in the rat hippocampus.

Delayed ischaemic damage was assessed by light microscopy following 10 min of incomplete forebrain ischaemia and 7 days of reperfusion. Iterative focal injections of 2-chloroadenosine, a stable analogue of adenosine, protect against selective hippocampal CA1 loss (P less than 0.01), when given either immediately before ischaemia and after 4 and 10 h of reperfusion or after 1 min, 4 h and 10 h of reperfusion. Delayed focal injection of 2-chloroadenosine after 10 and 24 h of reperfusion fails to protect against CA1 cell loss. The mechanism of cerebroprotection may involve attenuation of excitatory neurotransmission.

Excitatory amino acid and calcium content of subarachnoid spinal fluid during hypoglycemia in the rat.

The concentrations of amino acids and calcium were measured in the subarachnoid cerebrospinal fluid (CSF) of rats prior to, and following, profound hypoglycemia. Calcium concentrations fell and amino acid changes were non-specific following hypoglycemia. In particular, elevations in excitatory amino acids did not occur, even though typical neuropathologic changes were found. These data do not support a role for excitatory amino acids or calcium as a 'CSF-borne toxin' in hypoglycemic brain injury. Moreover, the histopathological patterns of cell loss in the dentate gyrus often could not be reconciled with the concept of a CSF-borne toxin.

Medicaid nursing facility reimbursement methods: 1979-1997.

This article describes state Medicaid nursing facility reimbursement methods and rates in 1979-1997, using data derived from telephone surveys of state Medicaid reimbursement. The 1980s saw shifts toward prospective methodology. The late 1980s and early 1990s were characterized by adoption of casemix methods. The early 1990s also saw fewer changes in methodology with a hiatus in the mid-1990s followed recently by renewed changes to methodology. Medicaid per diem rates have increased faster than inflation but less rapidly than general health costs. The repeal of the Boren Amendment may now allow states to institute greater cost controls or moratoria on rate increases. Despite states' tendencies to follow one another's examples, Medicaid reimbursement remains diverse nationally, with wide differences in policies and rates.

Medicare home health utilization as a function of nursing home market factors.

Rapid increases in the size and costs of the home health market, unknown impacts of Medicare's DRG hospital reimbursement on the posthospital market, and general lack of knowledge about factors that explain interstate variation in home health utilization all suggest the importance of developing and testing models of Medicare home health use. This article proposes and tests a model of state home health utilization as a function of the nursing home market. This model proposes that home health utilization is a function of nursing home bed capacity, of the utilization of nursing home beds by Medicaid patients, of other demand factors, and of supply factors. This model is supported by the data. Specifically, Medicare home health use in the 1978-1984 period was found to be negatively related to nursing home bed stock, positively related to Medicaid nursing home utilization, and related to several other supply and demand factors, as hypothesized by the model. The further model assumption that home health utilization does not affect the nursing home market could not be tested in this analysis, but will be addressed in future research by the authors.

Estimating undersupply of nursing home beds in states.

This examination of nursing home bed supply estimates undersupply in each of the states for the purpose of identifying the states with the greatest undersupply of beds. New data on state nursing home bed supply for the period 1979-1982 are used. The study employs selected independent variables in two different types of analyses to estimate bed supply for each state. Where a state is found to have a bed shortage, state public policymakers may wish to employ policies that differ from those suitable for states with an adequate supply of beds. Because of limitations in the data, issues of oversupply and of the extent of undersupply could not be examined.

Medicaid nursing home reimbursement policies, rates, and expenditures.

Nursing home expenditures, along with those of hospitals, have been a target of cost containment efforts because they constitute a growing share of overall public expenditures for health. Of the total $287 billion spent on personal health care in 1982, $27 billion (9.5 percent) was spent on nursing home care (Gibson, Waldo, and Levit, 1983). Nationally, nursing home expenditures increased at a rate of 17.4 percent between 1980 and 1981 and 12.9 percent between 1981 and 1982, more rapidly than overall health care expenditures (Gibson, Waldo, and Levit, 1983).

State Medicaid reimbursement for nursing homes, 1978-86.

State Medicaid reimbursement methods and rates are reported for the period 1978-86 for skilled nursing and intermediate care facilities. A cross-sectional time series regression analysis of Medicaid reimbursement rates on methods showed that States using prospective class reimbursement had significantly lower rates for the period 1982-86. States using prospective facility-specific reimbursement methods had lower rates than retrospective methods in 1983-84.

Nursing home bed capacity in the States, 1978-86.

Trends in nursing home bed supply in the States show large variations in beds per population and a gradual decline in supply per aged population. A cross-sectional time-series regression analysis was used to examine some factors associated with nursing home bed supply. Variation was accounted for by economic factors, supply of alternative services, and climate. State Medicaid reimbursement rates had negative coefficients, with supply suggesting States may be increasing rates to improve access where supply is limited. Medicaid waiver policy was not found to be significant.

Trends in Medicaid nursing home reimbursement: 1978-89.

Medicaid nursing home reimbursement is of concern because of implications for nursing home expenditures. This article presents data on State Medicaid nursing home reimbursement methods, ratesetting methods, and average per diem rates, refining earlier data and updating through 1989. A trend in the early 1980s toward adopting prospective systems played out by the end of the decade. There were trends, however, toward casemix methods, which may increase access for high-need patients, and toward cost-center limits on nursing, which may provide incentives to lower quality care. Analysis supports previous findings that prospective systems allow greater control over increases in rates.

Ripple effects of PPS on nursing homes: swimming or drowning in the funding stream?

In a sample of 189 nursing homes, 83% reported that Medicare's hospital Prospective Payment System (PPS) impacts patient needs, 53% said it impacts both patients and services provided, and 25% said it impacts referrals to hospitals. The PPS effects were found to depend on the facility factors of size, Medicare certification, and tax status, and on the local market area factors of prevalence of PPS-nonexcluded hospital psychiatric units, competition, and levels of hospital discharges.

Changes in aged populations served by home health agencies.

This article examines changes in clients served by home health agencies, and how changes are related to recent health care trends and local market structure. Two types of explanatory factors are examined: organizational measures and market factors. A theoretical model of isomorphism is tested, considering the effects of privatization within the context of the growth of chains and multifacility systems. Findings show that (a) system members are more likely than nonmembers to show increases in clients of all ages; (b) for-profits that are not system members are more likely to have increases in total clientele and in clients age 65-74, whereas for-profits' changes in clientele age 85 or over depends on their system membership--increasing among nonmembers, decreasing among members; and (c) agencies in states with home health "certificate of need" (CON) are more likely to have increases in clients age 65-74 and 85 and over. The results for total clientele and those age 65-74 support an isomorphism hypothesis.