Localization of a heterotrimeric G protein gamma subunit to focal adhesions and associated stress fibers.

Signal transducing heterotrimeric G proteins are responsible for coupling a large number of cell surface receptors to the appropriate effector(s). Of the three subunits, 16 alpha, 4 beta, and 5 gamma subunits have been characterized, indicating a potential for over 300 unique combinations of heterotrimeric G proteins. To begin deciphering the unique G protein combinations that couple specific receptors with effectors, we examined the subcellular localization of the gamma subunits. Using anti-peptide antibodies specific for each of the known gamma subunits, neonatal cardiac fibroblasts were screened by standard immunocytochemistry. The anti-gamma 5 subunit antibody yielded a highly distinctive pattern of intensely fluorescent regions near the periphery of the cell that tended to protrude into the cell in a fibrous pattern. Dual staining with anti-vinculin antibody showed co-localization of the gamma 5 subunit with vinculin. In addition, the gamma 5 subunit staining extended a short distance out from the vinculin pattern along the protruding stress fiber, as revealed by double staining with phalloidin. These data indicated that the gamma 5 subunit was localized to areas of focal adhesion. Dual staining of rat aortic smooth muscle cells and Schwann cells also indicated co-localization of the gamma 5 subunit and vinculin, suggesting that the association of the gamma 5 subunit with areas of focal adhesion was wide-spread.

G-protein alpha subunit Gi(alpha)2 mediates erythropoietin signal transduction in human erythroid precursors.

Erythropoietin induces a dose-dependent increase in cytosolic calcium in human erythroblasts that is mediated by a voltage-independent Ca2+ channel. Inhibition of this response to erythropoietin by pertussis toxin suggests involvement of guanine nucleotide-binding regulatory proteins (G-proteins). The role of G-proteins in regulation of the erythropoietin-modulated Ca2+ channel was delineated here by microinjection of G-protein modulators or subunits into human erythroid precursors. This is the first report on the use of microinjection to study erythropoietin signal transduction in normal precursor cells. Fura-2 loaded day-10 burst-forming units-erythroid-derived erythroblasts were used for microinjection and free intracellular calcium concentration ([Ca(i)]) was measured with digital video imaging. BCECF (1,2',7'-bis(2-carboxyethyl)-5-(and -6-)-carboxyfluorescein) was included in microinjectate, and an increase in BCECF fluorescence was evidence of successful microinjection. Cells were microinjected with nonhydrolyzable analogues of GTP, GTPgammaS or GDPbetaS, which maintain the alpha subunit in an activated or inactivated state, respectively. [Ca(i)] increased significantly in a dose-dependent manner after microinjection of GTPgammaS. However, injection of GDPbetaS blocked the erythropoietin-induced calcium increase, providing direct evidence that activation of a G-protein is required. To delineate which G-protein subunits are involved, alpha or betagamma transducin subunits were purified and microinjected as a sink for betagamma or alpha subunits in the erythroblast, respectively. Transducin betagamma, but not alpha, subunits eliminated the calcium response to erythropoietin, demonstrating the primary role of the alpha subunit. Microinjected antibodies to Gi(alpha)2, but not Gi(alpha)1 or Gi(alpha)3, blocked the erythropoietin-stimulated [Ca(i)] rise, identifying Gi(alpha)2 as the subunit involved. This was confirmed by the ability of microinjected recombinant myristoylated Gi(alpha)2, but not Gi(alpha)1 or Gi(alpha)3 subunits, to reconstitute the response of pertussis toxin-treated erythroblasts to erythropoietin. These data directly demonstrate a physiologic function of G-proteins in hematopoietic cells and show that Gi(alpha)2 is required in erythropoietin modulation of [Ca(i)] via influx through calcium channels.

Ins 1,4,5-P3 and Ca2+ signaling in quiescent neonatal cardiac myocytes.

Activation of alpha 1-adrenergic receptors in neonatal cardiac myocytes results in changes in contractile activity and the induction of hypertrophic growth. The biochemical mechanisms responsible for these diverse effects are not yet established, but presumably involve the associated alpha 1-adrenergic stimulation of phosphatidylinositol (PI) hydrolysis, with concomitant generation of Ins 1,4,5-P3 and diacylglycerol. This study examined whether alpha 1-adrenergic generation of Ins 1,4,5-P3 in intact, quiescent, neonatal cardiac myocytes resulted in a Ca2+ signal. Stimulation of myocytes with norepinephrine in the presence of propranolol caused accumulation of inositol mono-, bis and trisphosphates. However, alpha 1-adrenergic stimulation did not alter cytosolic free Ca2+ levels in 85% of the myocytes examined. Direct generation of Ins 1,4,5-P3, by photolysis of microinjected caged Ins 1,4,5-P3, was also unable to alter cytosolic free Ca2+ levels, despite the presence of Ins 1,4,5-P3 receptors. Taken together, these data indicated that alpha 1-adrenergic stimulation did not initiate Ca2+ signaling because Ins 1,4,5-P3-induced Ca2+ mobilization was not operative in quiescent neonatal cardiac myocytes. Normal excitation-contraction Ca2+ handling mechanisms were present in these cells, as illustrated by depolarization- and caffeine-induced Ca2+ transients. Analysis of these same myocytes following 48 h in the presence of norepinephrine and propranolol showed a 40% increase in the ratio of protein to DNA and a 350% increase in release of atrial naturietic factor, compared to control cells, indicating the normal operation of alpha 1-adrenergic-induced hypertrophic growth. Therefore, the assumption that Ca(2+)-dependent processes will be activated by receptor signaling pathways coupled to enhanced phosphatidylinositol turnover in cardiac cells must be avoided. In addition, the data presented in this study clearly indicated that an increase in cytosolic free Ca2+ was not necessary for the induction of alpha 1-adrenergic-mediated cardiac hypertrophy.

Partial purification of inositol polyphosphate 1-phosphomonoesterase with characterization of its substrates and products by nuclear magnetic resonance spectroscopy.

A study of the enzyme activities that degrade Ins(1,3,4)P3 in rat brain showed that it was dephosphorylated primarily by a Mg2+-dependent inositol polyphosphate 1-phosphomonoesterase to Ins(3,4)P2 and then to Ins(3)P by a 4-phosphomonoesterase. A less active enzyme activity with the properties of a 4-phosphomonoesterase that converted Ins(1,3,4)P3 to Ins(1,3)P2 was also detected. The inositol polyphosphate 1-phosphomonoesterase was separated from the 4-phosphomonoesterase and the inositol monophosphate phosphomonoesterase by chromatography on phosphocellulose, DE-52 anion exchange and hydroxylapatite columns. Kinetic characterization of the partially purified inositol polyphosphate 1-phosphomonoesterase indicated that both Ins(1,3,4)P3 and Ins(1,4)P2 were substrates with apparent Km values of 0.9 microM and 0.7 microM, respectively. Either substrate was a competitive inhibitor of the other substrate and dephosphorylation of both substrates was directly inhibited by Li+ in an uncompetitive manner. These data strongly suggest that a single enzyme dephosphorylates both Ins(1,3,4)P3 and Ins(1,4)P2. The 4-phosphomonoesterase that dephosphorylated Ins(3,4)P2 to Ins(3)P was insensitive to Mg2+ and Li+ and was probably the same enzyme that degraded Ins(1,3,4)P3 to Ins(1,3)P2. The isomeric configurations of the major inositol polyphosphates formed from the degradation of Ins(1,3,4,5)P4 were determined using 1H- and 31P-NMR spectroscopy, and confirmation of the structures assigned to Ins(1,3,4,5)P4, Ins(1,3,4)P3 and Ins(3,4)P2 was obtained.

Gßγ-Mediated signaling in the heart: Implications of ß and γ subunit heterogeneity.

A family of G proteins, composed of α, ß, and γ subunits, plays a central role in coupling receptors to a variety of enzymes and ion channels. In the cardiovascular system, G proteins are involved in coupling receptors for epinephrine, norepinephrine, acetylcholine, adenosine, angiotensin II, and endothelin to regulation of adenylyl cyclases, phospholipases, and ion channels. For many years, the classic view has been that G protein α subunits provide the requisite specificity for receptor and effector interactions. Recent advances, however, have revealed that the ß and γ subunits also play prominent roles in transducing information from receptors to the appropriate effectors. With the identification of multiple subtypes of ß and γ subunits in the heart, questions are raised regarding their respective roles in signal transduction processes regulating cardiac function.

Psychological impact of islet cell-antibody screening. Preliminary results.

The identification of at-risk individuals before the onset of insulin-dependent diabetes mellitus with islet cell-antibody (ICA) screening programs could have significant psychological sequelae. We initiated a descriptive study of ICA+ subjects and their family members in which reactions to study participation, anxiety, and coping responses are monitored. Described here are preliminary results from 18 ICA+ youngsters, 6 ICA+ adults, and their family members. ICA+ identification resulted in clinically significant anxiety that dissipated to normal levels over time for all participants. Both ICA+ subjects and family members coped with the news in similar ways, relying primarily on problem-focused and social-support coping strategies. Few blamed themselves for their own or their loved one's ICA+ status. There was some evidence that the ICA+ participants may minimize the potential impact of their at-risk status. Compared with family members, ICA+ subjects used more avoidance coping strategies, and few believed they would ever develop diabetes. In contrast, many family members believed their loved one would ultimately develop diabetes. Although the initial findings support the resiliency of this population, the long-term effects of ICA screening remain to be seen.

Subjective symptoms, blood glucose estimation, and blood glucose concentrations in adolescents with diabetes.

Twenty-five adolescent campers with insulin-dependent diabetes mellitus (IDDM) completed a Symptom Rating Checklist and estimated their blood glucose (BG) immediately before having their BG assessed four times daily for 11 days. Consistent relationships between BG and symptoms were not identified when the data were analyzed for the group as a whole. However, when each camper's data were analyzed separately, 23 of the 25 adolescents had at least one significant glycemia-symptom (G-S) correlation. Each camper seemed to have a unique G-S pattern; only one symptom (hungry) was significantly related to BG for more than half of the youngsters studied. Almost all of the significant G-S correlations were indicative of low rather than high BG. However, when asked, few campers were able to accurately identify which symptoms were reliably associated with low or high BG. In this study, different measures of BG estimation error led to different results. The percent of estimates +/- 20% of the actual BG value (55% in this study) was strongly influenced by the actual BG reading because higher BG values have larger accuracy ranges than lower BG concentrations. When estimated BG was simply subtracted from actual BG, under- and overestimates canceled each other out, resulting in an unusually small estimated error (5 mg/dl in this investigation). The absolute difference score ignores the direction of estimation error, but may more accurately reflect patients' average estimation error (68 mg/dl in this study). When actual and estimated BG values were correlated for the group as a whole, the patients appeared to be highly accurate at estimating BG (r = .93, P less than .0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of inositol 1,3,4-trisphosphate phosphorylation in rat liver.

Liver homogenates phosphorylated Ins 1,3,4-P3 to an InsP4 isomer that was distinct from Ins 1,3,4,5-P4. This InsP4 isomer accumulated in vasopressin stimulated hepatocytes prelabeled with myo-[3H]inositol with a time course that lagged behind Ins 1,3,4-P3 formation. The Ins 1,3,4-P3 kinase responsible for its formation was partially purified from rat liver. The enzyme had a Km for Ins 1,3,4-P3 of 0.29 microM, a Km for ATP of 141 microM and was not affected by changes in free Ca2+ in the physiological range. The relationship of this new InsP4 isomer to the inositol phosphate signaling pathway is discussed.

Inositol 1,3,4,5-tetrakisphosphate increases the duration of the inositol 1,4,5-trisphosphate-mediated Ca2+ transient.

The effect of Ins 1,3,4,5-P4 on the intracellular Ca2+ mobilization produced by Ins 1,4,5-P3 has been examined in permeabilized hepatocytes. Ins 1,3,4,5-P4 did not affect the magnitude of the Ins 1,4,5-P3-mediated Ca2+ release but did inhibit re-accumulation of the released Ca2+ back into intracellular stores. This effect was not mimicked by Ins 1,3,4-P3. In hepatocytes, the re-uptake phase of the response results from Ins 1,4,5-P3 hydrolysis. Measurements using labeled substrates indicate that Ins 1,3,4,5-P4 inhibits the hydrolysis of Ins 1,4,5-P3 and vice versa. Since the removal of the 5-phosphate on Ins 1,4,5-P3 and Ins 1,3,4,5-P4 is a common step in the disposal of both compounds, it is suggested that one of the biological effects of Ins 1,3,4,5-P4 may be to slow hydrolysis of Ins 1,4,5-P3 and thereby prolong the duration of a Ca2+ transient.

Adherence of human neutrophils changes Ca2+ signaling during activation with opsonized particles.

Changes in the cytosolic free Ca2+ concentration ([Ca2+]i) upon activation of human neutrophils by opsonized particles (serum-treated zymosan; STZ) were evaluated by three different methods: (i) measurement of total fluorescence changes in indo-1 loaded neutrophils activated in suspension; (ii) measurement of fluorescence changes in individual indo-1 loaded neutrophils in a flow cytometer and (iii) measurement of fluorescence changes in individual fura-2 loaded neutrophils adherent to serum-coated coverslips. Our study shows that the opsonized particle-induced change in [Ca2+]i in neutrophils is altered during adherence of the cells to a serum-coated surface. These observations might be of importance for neutrophil function in vivo, since adherence is a prerequisite for diapedesis and chemotaxis.

Differential coupling of alpha1-adrenoreceptor subtypes to phospholipase C and mitogen activated protein kinase in neonatal rat cardiac myocytes.

Activation of cardiac alpha1-adrenoreceptors has a number of physiological effects. Ascribing these effects to a specific alpha1-adrenoreceptor subtype first requires the elucidation of the subtypes that are present in the tissue of interest. In the present study, mRNA transcripts for the alpha1A, alpha1B and alpha1D-adrenoreceptor subtypes were detected in cultured neonatal rat cardiac myocytes, using reverse transcriptase-polymerase chain reaction analysis. However, binding sites for only the alpha1A and alpha1B-adrenoreceptor subtypes were detected in cultured neonatal rat cardiac myocytes, using competition binding analysis with a variety of alpha1 selective receptor antagonists. Phenylephrine-stimulated phosphatidylinositol hydrolysis was inhibited by alpha1 selective receptor antagonists with affinities consistent with the alpha1A-adrenoreceptor subtype, whereas phenylephrine-induced activation of the mitogen activated protein kinase cascade was inhibited by these same antagonists with affinities more closely resembling the alpha1B-adrenoreceptor subtype. In the case of both signaling pathways, the alpha1D selective receptor antagonist, BMY 7378, exhibited affinities suggestive of the relative absence of a alpha1D-adrenoreceptor subtype. Thus, despite the presence of mRNA transcripts for all three alpha1-adrenoreceptor subtypes, only the alpha1A and alpha1B-adrenoreceptor subtypes were expressed and functionally coupled at detectable levels in neonatal rat cardiac myocytes. Of particular interest, phenylephrine-induced activation of the mitogen activated protein kinase cascade appears to be mediated by a subtype resembling most closely the pharmacological profile of the alpha1B-adrenoreceptor subtype.

Adherence-health status relationships in childhood diabetes.

Used 24-hr recall interviews to assess adherence in a sample of seventy-eight 6- to 19-year-olds with insulin-dependent diabetes mellitus over a 3-month period. Thirteen adherence measures were quantified and grouped into six adherence factors (Injection, Exercise, Diet Type, Testing/Eating Frequency, Calories Consumed, and Concentrated Sweets). Prevailing glucose levels over a 2- to 3-month interval were indexed by glycosylated hemoglobin A1c (HA1c) and glycosylated serum protein (GSP) assays. Fasting triglycerides (TRIG) and total cholesterol (CHOL) assays were used to estimate lipid metabolism. Adolescents were generally less adherent than their young counterparts. Using hierarchical multiple-regression techniques, HA1c and GSP were not reliably predicted by most of the adherence factors; only Calories Consumed showed any predictive power. No significant regression equations emerged for CHOL. In contrast, TRIG was significantly associated with five of the six adherence factors; in all cases, adherence interacted with the patients' metabolic status (as defined by HA1c) at study entry, suggesting that adherence had different effects for youngsters in good versus poor diabetes control.

The inositol phosphate pathway as a mediator in the proliferative response of rat calvarial bone cells to cyclical biaxial mechanical strain.

Isolated newborn rat calvarial bone cells grown in monolayer on polyurethane membranes in specially constructed culture chambers and subjected to a cyclical biaxial mechanical strain of 0.17% at a frequency of 1 Hz for 30 min demonstrated a 16% increase in DNA synthesis during the subsequent 24 h. The metabolites of the inositol phosphate pathway, shown to be an important second messenger in many cell types, were shown to be elevated using high-performance liquid chromatography to separate and quantitate the various inositol polyphosphates. Inositol 1,4,5-trisphosphate, inositol 1,4-bisphosphate, and inositol 1,3,4,5-tetrakisphosphate reached peak accumulations after 20 s of mechanical strain. Inositol 1,3,4-trisphosphate reached a peak accumulation after 2 min, and inositol 1,2,3,4,5,6 phosphate reached a peak accumulation after 60 min of mechanical strain. Neomycin, an inhibitor of phospholipase C, a membrane-bound enzyme that hydrolyzes phosphatidyl inositol 4,5-bisphosphate to start the inositol phosphate cascade, completely inhibited accumulation of the above inositol phosphates during mechanical straining of the bone cells. Neomycin also completely abolished the increase in DNA synthesis that was seen after a mechanical strain of 0.17%. It is concluded from this study that the inositol phosphate pathway is activated by mechanical strain in bone cells and that this pathway is an important and primary mediator in the transduction of mechanical strain into cellular proliferation in these cells.

Intra-arterially administered papaverine for the treatment of symptomatic cerebral vasospasm.

OBJECTIVE: We examined the therapeutic benefits of intra-arterially administered papaverine for treatment of symptomatic cerebral vasospasm after subarachnoid hemorrhage (SAH). Recent advances in microcatheter technology have facilitated endovascular approaches to vessels experiencing vasospasm after SAH. However, despite numerous encouraging anecdotal reports, no rigorous examination of the efficacy of these procedures has been published. Intra-arterial infusion of papaverine has become part of the standard management of vasospasm at some centers. METHODS: We examined a series of 31 patients undergoing papaverine infusion for the treatment of symptomatic vasospasm after SAH. The patients were a subgroup of the series enrolled in the North American Trial of Tirilizad for Aneurysmal Subarachnoid Hemorrhage. These individuals were matched with patients from the same trial who exhibited similar clinical characteristics (including the degree of vasospasm and the modified Glasgow Coma Scale scores measured at the time of admission and on the day of papaverine infusion) but received medical management alone for vasospasm. RESULTS: Logistic regression analysis comparing these two groups showed no statistical difference in the 3-month Glasgow Outcome Scale scores between patients receiving papaverine and control subjects (58% favorable outcomes for control subjects versus 45% for patients receiving papaverine). CONCLUSION: Although isolated series documenting clinical successes have prompted the increased use of papaverine as a treatment for vasospasm after SAH, this series suggests that, as it is currently being used, the drug does not provide added benefits, compared with medical treatment of vasospasm alone. This result does not preclude the possibility that alterations in the timing of or indications for drug treatment might produce beneficial effects.

Phase II trial of tirilazad in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study.

Tirilazad mesylate, a 21-aminosteroid free-radical scavenger, has been shown to ameliorate cerebral vasospasm and reduce infarct size in animal models of subarachnoid hemorrhage (SAH) and focal cerebral ischemia. In preparation for performing large-scale clinical trials in humans with aneurysmal SAH, the safety of varying doses of tirilazad was tested in a randomized, double-blind, vehicle-controlled, sequential dose-escalation study at 12 Canadian neurosurgical centers. Two hundred forty-five patients with an aneurysmal SAH documented by angiography were enrolled in the study sequentially within 72 hours of hemorrhage. The patients were assigned to one of three dosage tiers: receiving 0.6 mg/kg, 2 mg/kg, or 6 mg/kg tirilazad or vehicle per day intravenously in divided doses through Day 10 following the SAH. All patients also received oral nimodipine. No serious side effects of tirilazad treatment were identified at any of the three doses, despite close monitoring of hepatic and cardiac toxicity. A trend toward improvement in overall 3-month patient outcome was seen in the 2 mg/kg per day tirilazad-treated group compared to the outcomes in the vehicle-treated groups. We conclude that tirilazad mesylate is safe in SAH patients at doses up to 6 mg/kg per day for up to 10 days and is a promising drug for the treatment of patients with aneurysmal SAH.

Efficacy of transluminal angioplasty for the management of symptomatic cerebral vasospasm following aneurysmal subarachnoid hemorrhage.

OBJECT: Transluminal angioplasty has become a widely used adjunct therapy to medical management of symptomatic cerebral vasospasm following subarachnoid hemorrhage (SAH). Despite anecdotal reports of universal, angiographically confirmed reversal of vasospasm and high rates of clinical improvement, no rigorous examination of the efficacy of this procedure has been conducted. In this study the authors assess the efficacy of the aforementioned procedure. METHODS: Thirty-eight patients enrolled as part of the North American trial of tirilazad in aneurysmal SAH underwent transluminal angioplasty for symptomatic cerebral vasospasm. Fifty-three percent of these patients showed good recovery or moderate disability based on their 3-month Glasgow Outcome Scale score. Among the 38 patients who underwent angioplasty, the severity and type of vasospasm, use of papaverine in addition to balloon angioplasty, timing of treatment, and dose of study drug did not have an effect on the outcome. The results of their neurological examinations improved in only four of the 38 patients immediately after the procedure. A conditional logistic regression analysis was performed in which these patients were compared with individuals matched for age, sex, dose of study drug, admission neurological grade, and modified Glasgow Coma Scale score at the time of angioplasty. No effect on favorable outcomes was found for this procedure. CONCLUSIONS: Transluminal cerebral angioplasty is very effective in reversing angiographically confirmed vasospasm, and anecdotal reports of its clinical utility are numerous. However, in this report the authors conclude that its superiority to medical management for symptomatic cerebral vasospasm is questionable.

Surgical approaches for the correction of unstable thoracolumbar burst fractures: a retrospective analysis of treatment outcomes.

The authors retrospectively studied 49 nonparaplegic patients who sustained acute unstable thoracolumbar burst fractures. All patients underwent surgical treatment and were followed for an average of 27 months. All but one patient achieved solid radiographic fusion. Three treatment groups were studied: the first group of 16 patients underwent anterior decompression and fusion with instrumentation; the second group of 27 patients underwent posterior decompression and fusion; and the third group of six patients had combined anterior-posterior surgery. Prior to surgical intervention, these groups were compared and found to be similar in age, gender, level of injury, percentage of canal compromise, neurological function, and kyphosis. Patients treated with posterior surgery had a statistically significant diminution in operative time and blood loss and number of units transfused. There were no significant intergroup differences when considering postoperative kyphotic correction, neurological function, pain assessment, or the ability to return to work. Posterior surgery was found to be as effective as anterior or anterior-posterior surgery when treating unstable thoracolumbar burst fractures. Posterior surgery, however, takes the least time, causes the least blood loss, and is the least expensive of the three procedures.

Metabolic rates in normal and infarcted myocardium.

The effects of myocardial infarction in rat hearts on the utilization of fatty acids and glucose by the surviving, non-infarcted tissue were studied. Hearts were removed from the animals one-week post-infarcted and perfused in the isolated working heart preparation. Oxygen consumption and oxidation of palmitate and glucose were determined at two levels of cardiac work. Rates of substrate oxidation were estimated by 14CO2 production from [14C]-labeled substrates. This approach to measuring metabolic rates may seriously under-estimate the true oxidative rate particularly when measuring oxidation of long-chain fatty acids. Because of the large endogenous stores of fatty acids in tissue lipids, the [14C]-specific activity of the intracellular metabolites involved in the free fatty acids oxidation pathway do not equilibrate with the specific activity of the perfusate fatty acids oxidation pathway do not equilibrate with the specific activity of the perfusate fatty acid even when 14CO2 production has reached an apparent steady state. When comparing an experimental condition to the normal heart, a lower rate of 14CO2 production may not necessarily indicate a lower rate of oxidation of free fatty acids, but a difference in the rate of turnover of endogenous sources of unlabeled fatty acid such that the specific activity of intracellular metabolites equilibrate with extracellular labeled substrate to a lesser extent than in the normal heart. At physiological concentrations of fatty acids, a shift from fatty acid to carbohydrate oxidation occurred in the hypertrophied, surviving tissue following myocardial infarction in the rat.(ABSTRACT TRUNCATED AT 250 WORDS)

An anatomical study of mental neurovascular bundle-implant relationships.

When five to six implants are used in a fixed reconstruction, it is desirable to place the most distal implant as close to the mental nerve as possible. This allows the cantilever of the fixed prosthesis to be extended posteriorly as much as is biomechanically feasible. Forty-seven mental nerve regions were dissected on cadavers to determine the exact relationship between the mental foramen, the inferior alveolar nerve, and its two terminal branches--the incisive and mental nerves. The most anterior position in which the mental nerve was encountered was 1 mm forward or mesial to the most anterior aspect of the mental foramen. Based upon this finding, it is likely that damage to the mental nerve can be avoided if the distal surface of the most posterior implant is 1 mm anterior to the anterior border of the mental foramen.

Endovascular treatment for symptomatic cerebral vasospasm after subarachnoid hemorrhage: transluminal balloon angioplasty compared with intraarterial papaverine.

The authors retrospectively evaluated the short-term neurological improvement of 69 patients undergoing endovascular treatment for symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). The patient group observed here is a subset of patients enrolled in the multicenter North American Trial of Tirilazad in SAH. Thirty-one patients were treated with intraarterial administration of papaverine (IAP). Fourteen patients were only treated with transluminal balloon angioplasty (TBA), and 24 patients received a combination of angioplasty and papaverine. The purpose of this study was to compare the effects of IAP and TBA on short-term clinical improvement of patients. Daily clinical staging with the modified Glasgow Coma Scale and every-other-day transcranial Doppler (TCD) measurements allowed for a close investigation of the clinical course. Furthermore, this study was designed to investigate the effects of treatment timing on short-term outcome. Although TCD studies demonstrated a decrease in flow velocities in the middle cerebral artery in both treatment groups, indicating a vasodilating effect of both treatment modalities (dv = -18.4 cm/second for papaverine, dv = -26.04 cm/second for angioplasty; p = 0.5509), there was no significant difference in clinical improvement at Days 1 and 4 postprocedure (p = 0.1996). Neither of the two treatment forms showed an effect of therapy timing on neurological outcome. Neither IAP nor TBA was correlated with a high percentage of short-term neurological improvement. The authors discuss reasons why those procedures may result in limited clinical change.