Temporal macrodynamics and microdynamics of the postoperative impedance at the tissue-electrode interface in deep brain stimulation patients.

OBJECTIVE: To study the temporal dynamics of tissue impedance after deep brain stimulation (DBS). BACKGROUND: DBS therapy commonly employs a constant voltage approach, and current delivery to the tissue is a function of electrode-tissue impedance. It is presumed that impedance fluctuates early postimplantation, with implications for variations in current delivery and therapeutic efficacy. We hypothesised that the largest variation will be recorded early after surgery, followed by stabilisation. METHODS: Review of impedance checks of implanted DBS systems at standard parameters during the first five months postimplantation. All measurement time points were binned into 1-week periods, and we used repeated measures analysis of variance with Tukey pairwise multiple comparisons correction. The analysis was repeated after normalising impedance values for each subject to that patient's baseline value. RESULTS: There was an initial (non-significant) drop in impedance at week 1, followed by significant increase at week 3 (p=0.0002). There were no further significant differences in impedance values at subsequent time points. Analysis of normalised data showed a significant difference between the initial measurement in postoperative week 1 (normalised value 1) and week 3 (normalised value 1.73, p<0.0001), with no further difference among the subsequent weekly points during the 5-month follow-up. No significant hourly variations were found at any time points. CONCLUSIONS: We found major changes in impedance within the first month postimplantation, with no further variation. This is an important confirmation in patients of this temporal dynamics of the impedance of implanted DBS hardware, with potential therapeutic implications.

Fast, optically controlled Kerr phase shifter for digital signal processing.

We demonstrate an optically controlled Kerr phase shifter using a room-temperature 85Rb vapor operating in a Raman gain scheme. Phase shifts from zero to π relative to an unshifted reference wave are observed, and gated operations are demonstrated. We further demonstrate the versatile digital manipulation of encoded signal light with an encoded phase-control light field using an unbalanced Mach-Zehnder interferometer. Generalizations of this scheme should be capable of full manipulation of a digitized signal field at high speed, opening the door to future applications.

Heralded, pure-state single-photon source based on a Potassium Titanyl Phosphate waveguide.

We analyze the generation of single spatial mode, spectrally uncorrelated photon pairs via type II spontaneous parametric down-conversion in a Potassium Titanyl Phosphate (KTP) waveguide using real experimental parameters. We show that this source can be used as an efficient, heralded, pure-state single-photon source.

Proposed grading system to predict the extent of resection and outcomes for cranial base meningiomas.

OBJECTIVE: This investigation was performed to construct a grading system for cranial base meningiomas that augments the current system of topographic labeling. This new system classifies cranial base meningiomas based on predicted surgical resection and patient outcomes. METHODS: Two hundred thirty-two consecutive patients with cranial base meningiomas were surgically treated by the two senior authors between April 1993 and August 1997. Using standard statistical tests, a large number of preoperative, intraoperative, and follow-up findings were analyzed for correlation with the extent of resection. These included the presence of previous radiotherapy, Cranial Nerve III, V, and VI palsies, multiple fossa involvement, and vessel encasement. RESULTS: Analysis revealed that each variable tested was independently and inversely correlated with total tumor resection (P < 0.002). We were able to construct a grading system based on these variables; when more variables are present, the grade is higher. With the grading system, lower-grade tumors were correlated with increased probabilities of total resection (r2 = 0.9947) and better patient outcomes, as measured by Karnofsky performance scale scores (r = 0.9291). We also found that, as a group, patients who underwent subtotal resection exhibited worse Karnofsky performance scale scores and had longer hospital stays. CONCLUSION: The current system of classifying cranial base meningiomas provides no information regarding the tumor except location and no information concerning patient prognosis. We present a more useful system to categorize these tumors. Our scheme must be tested at other centers to corroborate our findings. This new grading system should serve to guide surgical treatment, inform patients, and improve communication among surgeons.

Calibration of High-Resolution X-Ray Tomography With Atomic Force Microscopy.

For two-dimensional x-ray imaging of thin films, the technique of scanning transmission x-ray microscopy (STXM) has achieved images with feature sizes as small as 40 nm in recent years. However, calibration of three-dimensional tomographic images that are produced with STXM data at this scale has not yet been described in the scientific literature, and the calibration procedure has novel problems that have not been encountered by x-ray tomography carried out at a larger scale. In x-ray microtomography, for example, one always has the option of using optical imaging on a section of the object to verify the x-ray projection measurements; with STXM, on the other hand, the sample features are too small to be resolved by light at optical wavelengths. This fact implies that one must rely on procedures with higher resolution, such as atomic force microscopy (AFM), for the calibration. Such procedures, however, generally depend on a highly destructive sectioning of the sample, and are difficult to interpret because they give surface information rather than depth information. In this article, a procedure for calibration is described that overcomes these limitations and achieves a calibration of an STXM tomography image with an AFM image and a scanning electron microscopy image of the same object. A Ge star-shaped pattern was imaged at a synchrotron with a scanning transmission x-ray microscope. Nineteen high-resolution projection images of 200 × 200 pixels were tomographically reconstructed into a three-dimensional image. Features in two-dimensional images as small as 40 nm and features as small as 80 nm in the three-dimensional reconstruction were resolved. Transverse length scales based on atomic force microscopy, scanning electron microscopy, x-ray transmission and tomographic reconstruction agreed to within 10 nm. Toward the center of the sample, the pattern thickness calculated from projection images was (51 ± 15) nm vs (80 ± 52) nm for tomographic reconstruction, where the uncertainties are evaluated at the level of two standard deviations.

Acute effects of therapeutic ultrasound delivered at varying parameters on the blood flow velocity in a muscular distribution artery.

Therapeutic modalities that alter hemodynamic parameters may have a dramatic impact on the viability of living tissues. The purpose of the current study was to investigate the response of blood flow velocity to various treatment parameters of therapeutic ultrasound. Twenty healthy volunteers attended six randomly selected, 15-minute treatment sessions of the following parameters: Tx-1 = 1.0 MHz at 1.5 W/cm2, Tx-2 = 1.0 MHz at 1.0 W/cm2; Tx-3 = 3.0 MHz at 1.2 W/cm2; Tx-4 = 3.0 MHz at 1.0 W/cm2, Tx-5 = sham; and Tx-6 = control. Ultrasound was applied to a circular area over the triceps surae muscle mass. Blood flow velocity in the popliteal artery was assessed after 5, 10, and 15 minutes of ultrasound and at two posttreatment intervals via a dual frequency, bidirectional ultrasound Doppler. A two-factor analysis of variance (p < or = 0.05) with repeated measures for treatment and time was performed on the data. Groups Tx-1 and Tx-2 showed significant increases in blood flow velocity when compared with the control and all other groups. The sham group showed significant increases in blood flow velocity when compared with the control group. Group Tx-3 and Tx-4 showed no significant change when compared with the sham condition. The results of the current study indicate that 1.0 MHz ultrasound delivered at 1.0 and 1.5 W/cm2 to the triceps surae musculature as described in the present study can increase the blood flow velocity in the popliteal artery.

The effect of diabetes on alpha2-adrenergic receptor activity in the reproductive centers of the female rat brain.

OBJECTIVE: We hypothesized that known diabetes-induced deficits in female rat reproduction may result in part from decreased central alpha(2)-noradrenergic receptor density or affinity. STUDY DESIGN: Female rats were oophorectomized and divided into 2 groups; one group received streptozocin during the operation to induce diabetes, and the other served as a nondiabetic control group. Random blood glucose levels were measured. Half the rats in each group were killed on postoperative day 10, and half were killed on postoperative day 14. Direct radioligand binding assays were performed on tissue prepared from the hypothalamus, preoptic area, and cortex of each rat. Analysis of variance was used to evaluate intergroup differences in receptor concentration or equilibrium constant. RESULTS: We detected no significant difference in the mean receptor concentration or equilibrium constant between the groups with and without diabetes in the hypothalamus, the preoptic area, and the cortex on postoperative day 10 or 14. CONCLUSION: Diabetes-induced impairments in female rat reproduction do not involve alterations in alpha(2)-receptor density or affinity in the hypothalamus, preoptic area, or cortex.

Nonimmune hydrops fetalis due to congenital syphilis associated with negative intrapartum maternal serology screening.

We present an unusual case, in which a woman presenting with markedly decreased fetal movements at 29 weeks gestation following a recent increase in fundal height was noted sonographically to have fetal hydrops consisting of scalp edema, marked hepatomegaly, ascites, and polyhydramnios. No lethal structural congenital anomaly was noted. Admission laboratory examinations revealed a negative antibody screen and a negative RPR. Emergent cesarean section was performed due to prolonged fetal bradycardia during biophysical profile testing. The acidotic hydropic neonate weighing 1825 g was resuscitated yet succumbed at 3 hr of life following intravenous administration of antibiotics. Neonatal blood was RPR positive at 1:16. Postmortem pathology examination demonstrated severe multiorgan system failure secondary to overwhelming congenital syphilis. Extensive extramedullary hematopoiesis was noted and histopathology with Dieterle stains revealed numerous hepatic spirochetes. Postpartum reexamination of the maternal blood with serial dilutions revealed a positive RPR at 1:1024. This case emphasizes that initial negative screening for syphilis may be seen despite overwhelming infection, a condition that has been termed the "prozone effect."

cGMP formation in rat atrial slices is ligand and endothelin receptor subtype specific.

Involvement of a cGMP pathway in signal transduction stimulated by endothelins(ETs) and sarafotoxins (SRTXs) was examined in rat atrial slices. These peptides activated different receptor-binding sites (ET-1 and SRTX-b reacted with picomolar binding sites of the ET(A) receptor, and ET-3 and SRTX-c reacted with the nanomolar binding sites of the ET(B) receptor) to produce cGMP. ET-1 and SRTX-b stimulated an increase in cGMP levels via a Ca2+-dependent NO pathway involving a pertussis toxin-insensitive G protein, whereas ET-3 and SRTX-c elevated cGMP levels via a Ca2+-independent CO pathway involving a pertussis toxin-sensitive G protein. These results can best be explained in terms of formation of different ligand-receptor-G-protein complexes. The ligands had no effect on ventricular slices, indicating that these signal transduction mechanisms are unique to the atria.

Functional coupling of G proteins to endothelin receptors is ligand and receptor subtype specific.

1. The aims of the present study were (a) to determine the identity of the G proteins with which the endothelin receptor interacts and whether this interaction is subtype specific and (b) to determine whether agonist exposure can result in specific coupling between the endothelin receptor and G proteins. 2. Coupling between endothelin A (ET(A)) or endothelin B (ET(B)) receptors and G proteins was assessed in two fibroblast cell lines, each expressing one receptor subtype. Four ligands, ET-1, ET-3, SRTXb, and SRTXc, were used for receptor stimulation. The G protein alpha-subunit coupled to the receptor was identified by immunoprecipitation with an antibody against the endothelin receptor and immunoblotting with specific antibodies against different G protein alpha-subunits. 3. Unstimulated ET(A) and ET(B) receptors (ET(A)R and ET(B)R, respectively) were barely coupled to Go(alpha). The unstimulated ET(A)R coimmunoprecipitated with Gi3alpha, whereas the unstimulated ETBR was much less strongly coupled to Gi3alpha. The coupling of ETBR to Gi1Gi2 alpha-subunits was much stronger than the coupling of ET(A)R to these alpha-subunits. Stimulation with the different ET agonists also resulted in differential coupling of G proteins to the receptor subtypes. All four ligands caused a strong increase in coupling of the ET(B)R to Gi3alpha, whereas coupling of the ET(A)R to this subunit was not affected by ET-1 and was even decreased by SRTXc. On the other hand, all four ligands caused a much greater increase in the coupling of ET(A)R to G(q)alpha/G11alpha than in the coupling of ET(B)R to these alpha-subunits. Ligand-induced coupling between the receptors and the Gi1 and Gi2 alpha-subunits is similar for the two receptor subtypes. The same was true for ligand-induced coupling of the receptors to Go(alpha), except that ET-3 increased the coupling of this alpha-subunit to ET(B)R and decreased the coupling to ET(A)R. Taken together, the results of this study show that coupling between ET receptors and G proteins is ligand and receptor subtype specific. 4. It remains to be established whether this diversity of receptor-G protein coupling is of relevance for the various endothelin signaling pathways and/or pathological states.

Functional role for glycosylated subtypes of rat endothelin receptors.

Glycosylation of endothelin (ET) receptors was found to occur in rat cerebellar and atrial membranes. Specifically, we investigated whether the ETA and ETB receptor subtypes differed in their sensitivity to deglycosylation treatment and whether the two affinity states (nanomolar and picomolar) observed in each receptor subtype reflect differences in glycosylation states. Pretreatment of cerebellar or atrial membranes with endoglycosidase H (endo H) caused a marked decrease in the number of maximal binding sites that bind ligand with nanomolar affinity, whereas ligand affinity remained the same. The picomolar-affinity binding sites were not affected by endo H. The use of specific antagonists indicated that the receptor subtype most likely to be influenced by glycosylation is ETA. We suggest that in both cerebellar and atrial membranes, the carbohydrate chains of the ETA receptor contribute to the binding of ligand to the nanomolar-affinity binding sites, but not to the picomolar-affinity binding sites.

Blood preservation XXVII. Fructose and mannose maintain ATP and 2,3-DPG.

Mannose and fructose as well as glucose have been shown to be effective for maintaining ATP and thus viability of stored red blood cells. Normal 2,3-DPG levels are desirable in stored red blood cells to provide the needed oxygen transport upon transfusion. ATP levels in sotred concentrated red blood cells in the new preservative, CPD-adenine (citrate-phosphate-dextrose-adenine) become critically low in the 5th week. In this study two hexoses and two pentoses are compared with dextrose in their ability to maintain ATP and 2,3-DPG. ATP levels were best maintained by fructose, then dextrose and mannose. ATP levels had fallen to critically low levels by four weeks with ribose and xylose. Red blood cell 2,3-DPG concentrations were also maintained by hexoses, with mannose being best, dextrose and fructose being similar. When ribose was used in addition to dextrose in CPD-adenine, ATP maintenance was improved and under the same conditions xylose improved 2,3-DPG maintenance. Fructose and mannose may be as useful as dextrose in citrate-phosphate preservatives for maintaining ATP and 2,3-DPG levels. Also, ribose and xylose may help the maintenance of ATP and 2,3-DPG, respectively, in CPD-adenine.

Cyclic GMP formation in rat cerebellar slices is stimulated by endothelins via nitric oxide formation and by sarafotoxins via formation of carbon monoxide.

Involvement of a cyclic GMP pathway in signal transduction stimulated by endothelins (ETs) and sarafotoxins (SRTXs) was explored using rat cerebellar slices. These peptides activated the same receptor binding sites (ET-1 and SRTX-b at the picomolar sites; ET-3 and SRTX-c at the nanomolar sites) to produce cyclic GMP, but their signaling pathways differed. The endothelins (ET-1 and ET-3) were found to signal via nitric oxide formation and to involve pertussis toxin-sensitive G-protein(s). The SRTXs (b and c), while also stimulating cyclic GMP production, did so via a pathway which is not L-arginine-dependent, i.e., carbon monoxide formation, and did not involve pertussis-toxin-sensitive G-protein(s). This is the first demonstration that the signaling pathways of endothelins and sarafotoxins may differ, even though they share the same binding sites.

Activation of protein kinase C beta gene expression by gonadotropin-releasing hormone in alpha T3-1 cell line. Role of Ca2+ and autoregulation by protein kinase C.

The gonadotroph-derived alpha T3-1 cell line was used to investigate the effect of gonadotropin-releasing hormone (GnRH) upon conventional protein kinase C sub-types (cPKCs) gene expression. Addition of the stable analog [D-Trp6]GnRH (GnRH-A, 0.1 nM) resulted in a rapid increase (30 min) of the steady state levels of PKC beta, but not PKC alpha, mRNA levels, while PKC gamma is not expressed in the cells. The rapid stimulatory effect of GnRH-A was blocked by pretreatment with actinomycin D or with the GnRH antagonist (D-pGlu1, pC1Phe2,D-Trp3,6)GnRH and was not mimicked by thyrotropin-releasing hormone. Addition of the PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) resulted also in a rapid (30 min) and selective increase in PKC beta, but not PKC alpha, mRNA levels. In contrast, the calcium ionophore, ionomycin, increased rapidly (30 min) both PKC alpha and PKC beta mRNA levels, and its stimulatory effect on PKC beta was not additive with that of TPA. The rapid stimulatory effect of GnRH-A was blocked by the PKC inhibitor bisindolylmaleimide (GF 109203X) or by down-regulation of endogenous PKC. Similarly, the rapid effect of GnRH-A was abolished by the intracellular Ca2+ chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) or by removal of extracellular Ca2+. Stimulation of PKC beta mRNA levels by ionomycin was only reduced by GF 109203X and was not affected by down-regulation of PKC. In contrast the effect of TPA on PKC beta mRNA levels was reduced by BAPTA and abolished by removal of Ca2+. We conclude that Ca2+ and PKC act sequentially during GnRH-A-induced PKC beta gene expression and that PKC beta gene expression induced by GnRH-A is autoregulated by PKC.

Ligand-specific stimulation/inhibition of cAMP formation by a novel endothelin receptor subtype.

The possible involvement of a cAMP pathway in endothelin (ET) signal transduction was explored using rat atrial slices. We show that ET-1 induces both stimulation and inhibition of cAMP formation, depending on its concentration. Unexpectedly, the effects of ET-3 and of sarafotoxins b and c (SRTX-b and SRTX-c) on this pathway differ from that of ET-1. Moreover, we show that the ET-1-induced formation of cAMP results from catecholamine release in a process mediated by a Ca2+ channel coupled to a pertussis toxin sensitive G-protein. It is concluded that this pathway is mediated by a new ETA receptor subtype (probably presynaptic), for which ET-1 is an agonist and ET-3, SRTX-b, and SRTX-c are antagonists.

Arachidonic acid and lipoxygenase products stimulate protein kinase C beta mRNA levels in pituitary alpha T3-1 cell line: role in gonadotropin-releasing hormone action.

The cross-talk of arachidonic acid (AA) and its lipoxygenase products with protein kinase C beta (PKC beta) mRNA levels during the action of gonadotropin-releasing hormone (GnRH) was investigated in the pituitary alpha T3-1 cell line. The addition of AA or its 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid (5-HETE) or leukotriene C4 (LTC4) for 30 or 60 min stimulated PCK beta, but not PKC alpha mRNA levels (3-5-fold); PCK gamma is not expressed by the cells. Other HETEs or leukotrienes tested showed no significant effect. The range of effective concentration for LTC4 and 5-HETE (around 10(-10) M) is the range found in GnRH-stimulated pituitary cells. Although PKC beta mRNA levels were preferentially elevated by LTC4 and 5-HETE at early time points, PKC alpha mRNA levels were elevated at 6-12 h of incubation when PKC beta mRNA levels returned to basal levels. The addition of the phospholipase A2 inhibitor 4-bromophenacyl bromide or the selective 5-lipoxygenase inhibitor L-656,224 abolished [D-Trp6]GnRH (GnRH-A) elevation of PKC beta mRNA levels, whereas PKC alpha mRNA levels were not increased by this neurohormone. The cyclo-oxygenase inhibitor indomethacin elevated basal PKC beta mRNA levels and potentiated the GnRH-A response. Cross-talk exists between AA and some of its lipoxygenase products and PKC beta gene expression during cell signalling. AA, 5-HETE and LTC4 participate in the rapid stimulation of PKC beta mRNA levels by GnRH.

Management of Zone III Missile Injuries Involving the Carotid Artery and Cranial Nerves.

Carotid and cranial nerve injuries from zone III (high cervical/cranial base) missile injuries are rare and difficult to treat. We have treated five patients with such injuries. We present our management scheme, and compare it to the management of the same injuries in other reports. Five consecutive zone III missile injuries presented to our institution. Trauma assessment by the trauma team, followed by detailed neurological assessment and radiographs (angiogram and computed tomography) were obtained on admission. All patients presented with dysphagia and carotid artery injury with good collateral flow, documented by angiogram. Two patients had facial nerve injury, one had trigeminal nerve injury, one patient presented with tongue weakness, and one patient suffered conductive hearing loss. No patient had evidence of stroke clinically or radiographically. Carotid artery injury was managed with bypass (3 of 5) or ligation (2 of 5). Cranial nerve injuries were documented and treated aggressively with surgery if needed. All patients were discharged to home. Patients presenting with zone III missile injuries should receive an expeditious neurological exam and four-vessel angiogram after initial trauma survey and resuscitation. Bypass of the injured portion of carotid artery is a valid treatment in the hemodynamically stable patient. The unstable patient should undergo ligation to stop hemorrhage and protect against immediate risk for stroke, with the option to bypass later. Cranial nerve injuries should be pursued and aggressively treated to minimize morbidity and prevent mortality.

Mechanism of action of gonadotropin-releasing hormone upon gonadotropin alpha-subunit mRNA levels in the alpha T3-1 cell line: role of Ca2+ and protein kinase C.

Addition of [D-Trp6]gonadotropin-releasing hormone (GnRHa) to alpha T3-1 cells induced a very rapid response upon gonadotropin alpha-subunit mRNA which was detected after 30-60 min and was abolished by pretreatment with actinomycin D. A similar response was obtained with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA), or the Ca2+ ionophore, ionomycin. GnRHa (10 nM) also stimulated a secondary rise in alpha-subunit mRNA levels between 12 and 24 h of incubation. No additivity was obtained (at 60 min) upon the combined addition of GnRHa and PMA, GnRHa and ionomycin, or PMA and ionomycin. The effect of GnRHa upon alpha-subunit mRNA was blocked by the PKC inhibitors staurosporine or GF 109203X. Down-regulation of endogenous PKC activity resulted in inhibition of the stimulatory effect of gonadotropin-releasing hormone (GnRH), PMA and ionomycin. Removal of extra-cellular Ca2+ abolished the effect of GnRHa and PMA upon alpha-subunit mRNA levels. Interestingly PMA and ionomycin had no effect on alpha-subunit mRNA levels at 24 h of incubation; however, the combined addition of the drugs mimicked the late phase of GnRHa (10 nM) action. The data provide evidence that PKC and Ca2+ are involved in mediating the early and the late responses of GnRHa upon alpha-subunit mRNA elevation and that differential cross-talk exists between the messengers.