Sex-specific effects of subthalamic nucleus stimulation on pain in Parkinson's disease.

OBJECTIVE: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is known to reduce motor symptoms of Parkinson's disease (PD). The effects of DBS on various nonmotor symptoms often differ from patient to patient. The factors that determine whether or not a patient will respond to treatment have not been elucidated. Here, the authors evaluated sex differences in pain relief after DBS for PD. METHODS: The authors prospectively evaluated 20 patients preoperatively and postoperatively after bilateral STN DBS with the validated numeric rating scale (NRS), Revised Oswestry Disability Index for low-back pain (RODI), and King's Parkinson's Disease Pain Scale (KPDPS) and assessed the impact of sex as a biological variable. RESULTS: The cohort consisted of 6 female and 14 male patients with a mean duration of 11.8 ± 2.0 months since DBS surgery. Females were significantly older (p = 0.02). Covariate analysis, however, showed no effect of age, stimulation settings, or other confounding variables. KPDPS total scores statistically significantly improved only among males (p < 0.001). Males improved more than females in musculoskeletal and chronic subsets of the KPDPS (p = 0.03 and p = 0.01, respectively). RODI scores significantly improved in males but not in females (p = 0.03 and p = 0.30, respectively). Regarding the NRS score, the improvements seen in both sexes in NRS were not significant. CONCLUSIONS: Although it is well recognized that pain complaints in PD are different between men and women, this study is unique in that it examines the sex-specific DBS effects on this symptom. Considering sex as a biological variable may have important implications for DBS pain outcome studies moving forward.

Effect of Directional Deep Brain Stimulation on Sensory Thresholds in Parkinson's Disease.

OBJECTIVE: Previous studies showed that deep brain stimulation (DBS) relieves pain symptoms in Parkinson disease (PD) patients when programmed for motor-symptom relief. One factor involved in pain processing is sensory perception of stimuli. With the advent of directional leads, we explore whether directional DBS affects quantitative sensory testing (QST) metrics acutely. METHODS: PD patients with subthalamic (STN) DBS and directional leads were tested in 5 settings (DBS-OFF, DBS-ON with omnidirectional stimulation, and DBS-ON) for each of three directional segments of contact used for clinical programming. The Unified Parkinson's Disease Rating Scale (UPDRS-III) assessed patient's motor skills at time of study visit at clinical contact and at contact which produced optimal sensory threshold (defined by the greatest tolerance to mechanical stimuli). Correlation analyses were performed between stimulation parameters [amplitude, frequency, pulse width (PW), total electrical energy delivered (TEED)] and outcome metrics. RESULTS: Sensory thresholds were obtained in nine patients. Directional stimulation did not significantly alter patient perceptions of sensory stimulus [cold pain (p = 0.69), warm pain (p = 0.99), Von frey fibers (p = 0.09), pin-prick (p = 0.88), vibration (p = 0.40), pressure (p = 0.98)]. With correlation analysis, increasing PW at the posterior contact increased pin prick and vibration sensitivity (p < 0.001). Additionally, an increase in TEED caused a decrease in sensitivity to warm detection when using the anterior (p = 0.04), lateral (p = 0.02), and medial contacts (p = 0.03), and also caused a decrease in sensitivity to cold detection when using the medial contact (p = 0.03). UPDRS-III remained stable during testing. CONCLUSION: Motor benefit can be acutely maintained at directional contacts, whereas directional stimulation can modulate thermal and mechanical sensitivity. Further investigation will determine whether these changes are maintained chronically or can be improved with optimized programming.

Lateral medullary stroke in patient with granulomatous polyangiitis.

Granulomatous polyangiitis (GPA), also known as Wegener granulomatosis, is a systemic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that infrequently affects the central nervous system. We report a 41-year-old man with lateral medullary infarction who developed rapidly progressive renal failure. He was diagnosed with GPA based on positive serum c-ANCA and antiproteinase 3 antibodies and demonstration of pauci-immune crescentic glomerulonephritis on kidney biopsy. He was treated with Coumadin, pulse steroids, cyclophosphamide, and plasmapheresis. He had resolution of his neurologic deficits and improvement in renal function. This case report highlights the importance to consider GPA vasculitis in the differential diagnosis of stroke in patients with development of acute kidney injury.

Photoperiodic response of the hypothalamo-pituitary-gonad axis in male and female canaries, Serinus canaria.

Although the gonadal photoperiodic response and its influence upon the song control system in canaries have been extensively studied, photoperiodic regulation of the GnRH system has not been investigated. To examine the relationship between photoperiod and the reproductive neuroendocrine system in male and female canaries, three groups of canaries were exposed to chronic short days (8L:16D; Phsens), acute long days (18L:6D; Phstim) and chronic long days (also 18L:6D; Phrefr) to induce the reproductive states of photosensitivity, photostimulation, and photorefractoriness, respectively. Brain sections were processed for GnRH immunocytochemistry. The canaries in this study did not demonstrate consistent or uniform responses to different photoperiodic treatments. In males, gonad size varied with photoperiod; Phstim males had larger gonads than either the Phsens or Phrefr males. In contrast, there was no difference between groups in female gonad size as a result of photoperiodic treatment. Brain GnRH cell number, cell size, and fiber density were similar in all groups. The results suggest that canaries are not as obligatory photoperiodic as previously thought (or at least not all varieties of domestic canaries are). This could be a result of many years of domestication, the natural history of the species, phylogenetic constraint, or a combination of these factors.

Initial investigations of 99mTc-labeled morpholinos for radiopharmaceutical applications.

This laboratory is evaluating phosphorothioate deoxyribonucleic acids (DNAs) and peptide nucleic acids (PNAs) for a variety of nuclear medicine applications. Morpholinos (MORFs) are a new class of oligomers with a nuclease-resistant, nonionic and water-soluble phosphorodiamidate backbone. We now report on the in vitro and in vivo properties of MORFs labeled with technetium-99m. Both 15-mer and 18-mer MORFs were obtained, each with a primary amine attached to the 3' equivalent end via a three-carbon beta-alanine linker. The amine was used to conjugate with NHS-MAG3 for 99mTc radiolabeling. By surface plasmon resonance at room temperature, the association rate constant for hybridization of the 18-mer MORF to its complementary oligomer (cMORF) was equivalent to that of DNAs and PNAs of comparable length. Hybridization of 99mTc-MORF in vitro to free cMORF, to a cMORF polymer and to cMORF beads was nearly quantitative under a variety of conditions. Kinetic studies in vitro at room temperature showed rapid (2-5 min) and nearly quantitative (90%) binding to cMORF beads. Using size-exclusion high-performance liquid chromatography, the stability of the 99mTc-MORF was found to be greater than 85% over 24 h in 37 degrees C serum with minimal protein binding. In normal mice, the 99mTc-MORF showed rapid pharmacokinetics, with only 21% and 8% remaining in the whole body at 3 and 24 h post administration, respectively. In vivo targeting with 99mTc-MORF of cMORF beads in one thigh of normal mice compared to control beads in the other thigh showed target/control thigh ratios of 2-10 between 3 and 24 h. These results demonstrate that MORF oligomers are capable of in vivo hybridization. Their properties of hybridization affinity and kinetics and their in vivo stability and pharmacokinetics make them suitable subjects for in vivo studies.

Synthesis and evaluation of the (99m)tc-complexes of L-cysteine acetyldiglycine (a hybrid of MAG3 and L,L-EC) and of L-beta-homocysteine acetyldiglycine.

L-Cysteine acetyldiglycine (L-CAG2), a hybrid compound of L,L-EC and MAG3, and its L-beta-homocysteine analogue L-HAG2 were synthesized. After labeling with (99m)Tc, (99m)Tc-L-CAG2 and (99m)Tc-L-HAG2 gave two peaks on high performance liquid chromatography. Urinary excretion of both isomers of (99m)Tc-L-CAG2 and (99m)Tc-L-HAG2 was slower than for the "parent" complexes (99m)Tc-MAG3 or (99m)Tc-L,L-EC. Isomer B of (99m)Tc-L-CAG2 showed pronounced kidney retention in mice (57% of ID in kidneys at 30 min postinjection), but further evaluation in baboon did not reproduce this phenomenon.

Accessing the Orbital Roof via an Eyelid Incision: The Transpalpebral Approach.

THIS ARTICLE OUTLINES A NEW SURGICAL TECHNIQUE FOR ACCESSING THE ORBITAL ROOF: the transpalpebral approach. It involves making an incision on the double fold of the upper eyelid, then dissecting the orbital septum and the orbicular muscle of the eye. This exposes the orbital roof and enables the surgeon to approach without a coronal incision of the scalp; the direct eyelid incision provides adequate workspace. We use this approach in three orbital roof fractures and one orbital hemangioma. This orbital approach offers a simpler surgical technique, a less invasive one, and still provides excellent exposure of the superior orbital cavity.

Influence of a 99mTcN core on the biological and physicochemical behavior of 99mTc complexes of L,L-EC and L,L-ECD.

99mTc-nitrido complexes of L,L-ethylene dicysteine (99mTcN-L,L-EC) and 99mTcN-L,L-ethylene dicysteine diethylester (99mTcN-L,L-ECD) were prepared and their characteristics compared to those of the respective 99mTc-oxo complexes. 99mTcN-L,L-EC and 99mTcO-L,L-EC migrate to similar extents during electrophoresis at pH 12, but, at pH6, 99mTcN-L,L-EC migrates further than 99mTcO-L,L-EC. Renal excretion of 99mTcN-L,L-EC is inferior to that of 99mTcO-L,L-EC, indicating that the TcN-glycine sequence has lower affinity for the renal tubular system. Both 99mTcO-L,L-ECD and 99mTcN-L,L-ECD are neutral, but 99mTcN-L,L-ECD is hydrophilic and shows minimal brain uptake in both mice and the baboon.

Comparison of reversed phase and reversed phase ion pair high performance liquid chromatography for analysis of TcO and TcN complexes of L,L-ethylene dicysteine di-ethylester and its acid analogues.

99mTc(V)-oxo complexes of L,L-ethylene dicysteine (L,L-EC) and its di-ester derivative L,L-ethyl cysteinate dimer (L,L-ECD) are useful tracer agents for evaluation of renal function and cerebral blood flow respectively. Labelling of these molecules with a 99mTc(V)-nitrido core instead of the 99mTc(V)-oxo core alters their biological and physiochemical behavior. In the reversed phase high performance liquid chromatography (HPLC) method presently used to analyse 99mTc(V)-oxo preparations of L,L-EC and L,L-ECD, the 99mTc(V)-nitrido-L,L-EC complex and the possible impurities of a 99mTc(V)-nitrido-L,L-ECD preparation were found to elute with the void volume. In this study, a reversed phase ion pair HPLC method has been developed that is useful for the analysis of both 99mTc(V)-oxo and 99mTc(V)-nitrido preparations of L,L-EC and L,L-ECD. Tetrabutylammonium hydroxide is used as a cationic ion pairing agent.

Stabilisation of high-activity 99mTc-d,l-HMPAO preparations with cobalt chloride and their biological behaviour.

It has been reported that the stability of a 1.11-GBq (30 mCi) technetium-99m d,l-hexamethyl-propylene amine oxime (HMPAO) preparation can be improved to up to 5 h by the addition of 200 micrograms CoCl2.6H2O within 2 min after reconstitution. However, it is not clear whether this method is also efficient for high-activity preparations (5.55 GBq) and whether this modified 99mTc-d,l-HMPAO has the same biological properties and can safely be used. We have now studied CoCl2-stabilised 99mTc-d,l-HMPAO preparations containing different amounts of "in-house" HMPAO ligand and SnCl2 and reconstituted with activities from 1.11 GBq to 5.55 GBq 99mTc. The characteristics of the generator eluates were also divergent, ranging from fresh eluates from a generator eluted less than 2 h previously to 4-h-old eluates from a generator not eluted during the preceding 72 h. Preparations containing up to 5.55 GBq 99mTc and as low as 2 micrograms SnCl2.2H2O can be efficiently stabilised for at least 6 h by the addition of CoCl2 shortly after reconstitution. Interestingly, it was found that the stabilisation method is not efficient if the cobalt ions are added prior to reconstitution of the preparation. This implies that the cobalt chloride cannot be incorporated in the labelling kit. Also, preparations with amounts of the ligand lower or higher than 0.5 mg formed the 99mTc-d,l-HMPAO complex with low radiochemical yield or showed rapid degradation. Therefore, combination of a subdivision and storage of Ceretec kits in fractions (as reported in the literature) is contra-indicated with this CoCl2 stabilisation method. CoCl2-stabilised Ceretec kits reconstituted with 5550 MBq 99mTcO4- and used 4-5 h after preparation retain the diagnostic usefulness of the fresh 1110-MBq preparation with regard to leucocyte labelling and brain imaging. Although baboon brain uptake of the stabilised preparation was 6%-9% lower, this small difference could not be distinguished in the tomographic images. The data obtained with both inhouse prepared d,l-HMPAO and Ceretec kits suggest that the eluate restrictions recommended by the Ceretec manufacturer can be neglected if the preparation is stabilised with Co2+ ions. Studies with 57Co-spiked CoCl2 added to d,l-HMPAO preparations demonstrated that the Co2+ ions clearly interact with the d,l-HMPAO ligand, probably to form one or more complexes. From biodistribution studies in mice it became evident that the toxicological profile of the Co2+ ions in the presence of d,l-HMPAO should be more favourable than that of cobaltous ions. For these reasons, it seems justifiable that CoCl2-stabilised 99mTc-d,l-HMPAO preparations should undergo rigorous studies to elucidate their clinical usefulness and pharmacological safety.

Optimum albumin concentration of supplementation fluid for double filtration plasmapheresis.

Until recently, the albumin concentration of supplementation fluid for double filtration plasmapheresis (DFPP) has been empirically determined. Inadequate albumin infusion often leads to hypoproteinemic symptoms such as edema. In the current study, an aimed condensation coefficient (CCaimed) was introduced in an attempt to estimate the appropriate plasma albumin level for each patient. This coefficient is theoretically derived from a one-compartment model for the patient's plasma albumin: CCaimed = CS/CD = 1 - (1 - CR)/[1 - exp(- CC.VR)] where CD and CS are albumin concentrations in discarded plasma and supplementation fluid. CR is the change ratio of albumin concentration in the patient's plasma during a DFPP treatment, and VR(= VS/VP) is the ratio of supplementation fluid volume (VS) to the patient's total plasma volume (VP). And CC denotes the albumin condensation coefficient in a DFPP line, which depends on the filtration fraction of the plasma fractionator (FFPF) and the sieving coefficients of both the plasma separator (SCPS) and the plasma fractionator (SCPF): CC = CD/CP = SCPS.(1 - FFPF.SCPF)/(1 - FFPF) where CP is the albumin concentration of the patient's plasma. From the above relations, CS can be determined as follows: CS = CC.CCaimed.CP Because many kinds of proteins are removed during a single DFPP treatment, a slightly higher albumin concentration in the supplementation fluid is needed to maintain an appropriate plasma level. Therefore, the CR value should be more than unity. For a patient with hematocrit (HCT) of 30%, body weight (BW) of 50 kg, and CP of 3.0 g/dl, who is receiving a DFPP treatment using AP-05H (SCPS of 0.970) and Evaflux 2A (SCPF of 0.526) under FFPF of 0.8 with VS of 500 ml, VP = BW(1- HCT/100)/13 = 50 x (1 - 30/100)/13 = 2.69 L, VR = 500/(2.69 x 1,000) = 0.186, CC = 2.81, and CCaimed = 1.25 assuming 1.1 for CR. Therefore, CS = 2.81 x 1.25 x 3.0 = 10.5 g/dl using the above equations.

Development of continuous recirculating peritoneal dialysis using a double lumen catheter.

Continuous recirculating peritoneal dialysis (CRPD) was newly introduced to improve solute removal efficiency in conventional dialysis therapies such as hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In CRPD, a part of the dialysate in the peritoneal cavity was drained through a double-lumen catheter and purified by an extracorporeal dialyzer. Urea removal characteristics in CRPD were examined in a canine study. In this study, a recirculation-dialysis experiment using a dog weighing 9.0 kg was carried out under 100 and 200 ml/min of flow for recirculating and delivered dialysates, respectively. An FB-50H (Nipro Medical Industries, Ltd., Osaka, Japan) composed of cellulose diacetate membrane with 0.5 m2 of surface area and Dianeal-1.5 (Baxter Limited Laboratories, Tokyo, Japan) containing urea were used as the extracorporeal dialyzer and dialysate. Urea peritoneal and dialyzer dialysances (DBP and DBD) were 3.05 and 33.3 ml/min by computer simulation using a compartment model for CRPD. This DBP value can be estimated as 20.3 ml/min for a 60 kg human. From this result, time-averaged value for BUN over an 8 hr/day CRPD, combined with three exchanges/day as CAPD is estimated to be 34.3 mg/dl, which is much lower than 45.2 mg/dl for a 12 hr/week HD, or 53.0 mg/dl for conventional CAPD.

Non-heparin hemodialysis with oral administration of newly developed antiplatelet agent.

Non-heparin hemodialysis (HD) was successfully done in anuric dogs with the oral administration of a newly developed antiplatelet agent, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, (E5510, Eisai Pharmaceutical Co., Japan). In the current study, the antithrombotic effect of E5510 during HD was investigated. Eleven mongrel dogs with bilateral ureteral ligation were given 0.1 mg/kg of E5510 orally 1 hr before undergoing 4 hr HD using hollow fiber dialyzers, (PMMA 5, regenerated cellulose 6) without heparin and under general anesthesia. Blood samples were taken before the administration of E5510 and before and 1, 2, 3, and 4 hr after starting HD; blood counts, hematocrits, blood chemistries, and plasma thromboxane levels (TxB2) were examined. Platelet aggregation, activated clotting times (ACT), and activated partial thrombin times (APTT) were also measured, and sequential plasma E5510 concentrations were determined. In 10 of 11 anuric dogs, non-heparin HD was successfully done with minimal clotting in the dialyzer and drip chambers. The maximum aggregation rate was depressed to less than 20% of the initial value throughout HD. Plasma TxB2 concentration was depressed, and ACT and APTT were mildly, but not significantly prolonged. Neither hemorrhagic complications nor other side effects of E5510 were observed.

Difference in beta 2-microglobulin removal between cellulosic and synthetic polymer membrane dialyzers.

Several kinds of dialyzers, with highly permeable membranes (HPM), have been designed to specifically remove beta 2-microglobulin (BMG). To clarify their solute transport characteristics, nine types of HPM dialyzers were evaluated during in vivo and in vitro studies using human plasma and aqueous solutions. No BMG membrane adsorption and/or plugging was seen with cellulosic membrane dialyzers during in vitro experiments using human plasma. On the other hand, all synthetic polymer membrane dialyzers had adsorptive properties, and in a dialyzer with a polymethylmethacrylate membrane, a large amount of BMG was removed by adsorption alone. Dialyzers with cellulose triacetate and polyacrylonitril membranes showed higher values of BMG diffusive dialysance (greater than 20 ml/min) and sieving coefficient (greater than 0.9). From in vitro experiments using an aqueous solution containing several solutes with relatively small or middle molecular weights, all HPM dialyzers had a higher overall mass transfer coefficient than any conventional membrane dialyzer.

Microscopic observation of leukocyte kinesis in the vascular bed during hemodialysis using the rabbit ear chamber technique.

Leukocyte kinesis in the capillary vascular bed during hemodialysis (HD) was investigated to elucidate the mechanism of transient leukopenia. Leukocyte movement was observed microscopically during HD using the rabbit ear chamber (REC) technique, which permits visualization of the movement of blood corpuscles in capillaries. Blood was drawn from the femoral artery and returned into the auricular and/or carotid artery so that the blood passing through the hollow fiber artificial kidney (HFAK) flowed into capillaries in the REC. Leukocyte counts of blood samples taken from the afferent and efferent limbs of the HD circuit, the right jugular vein and the right atrium were determined consecutively during HD. The difference in the leukocyte count was observed between the afferent and efferent limbs for the first 15 minutes and thereafter between the efferent limb and the jugular vein. The "transpulmonary" difference in the leukocyte count was not noticed throughout HD. Between 15 and 90 minutes after the start of HD, scarcely any circulating leukocytes were found in capillaries in the REC and some leukocytes were attached to the endothelial surface. Thereafter circulating leukocytes were seen again and detachment of leukocytes from the endothelial surface was observed. No leukocyte aggregation or embolization of aggregating leukocytes was noticed. This evidence suggests that leukopenia may be attributed to the transient shift of leukocytes to the marginal pool of the vessel lumen and this process may not be specific for the pulmonary vasculature, but may occur in the first capillary bed into which the blood passing through the HFAK flows.(ABSTRACT TRUNCATED AT 250 WORDS)