Improved Side-Effect Stimulation Thresholds and Postoperative Transient Confusion With Asleep, Image-Guided Deep Brain Stimulation.

BACKGROUND AND OBJECTIVES: Asleep, image-guided deep brain stimulation (DBS) is a modern alternative to awake, microelectrode recording (MER) guidance. Studies demonstrate comparable efficacy and complications between techniques, although some report lower stimulation thresholds for side effects with image guidance. In addition, few studies directly compare the risk of postoperative transient confusion (pTC) across techniques. The purpose of this study was to compare clinical efficacy, stimulation thresholds for side effects, and rates of pTC with MER-guided DBS vs intraoperative 3D-fluoroscopy (i3D-F) guidance in Parkinson's disease and essential tremor. METHODS: Consecutive patients from 2006 to 2021 were identified from the departmental database and grouped as having either MER-guided DBS or i3D-F-guided DBS insertion. Directional leads were used once commercially available. Changes in Unified Parkinson's Disease Rating Scale (UPDRS)-III scores, levodopa equivalent daily dose, Fahn-Tolosa-Marin scores, and stimulation thresholds were assessed, as were rates of complications including pTC. RESULTS: MER guidance was used to implant 487 electrodes (18 globus pallidus interna, GPi; 171 subthalamic nucleus; 76 ventrointermediate thalamus, VIM) in 265 patients. i3D-F guidance was used in 167 electrodes (19 GPi; 25 subthalamic nucleus; 41 VIM) in 85 patients. There were no significant differences in Unified Parkinson's Disease Rating III Scale, levodopa equivalent daily dose, or Fahn-Tolosa-Marin between groups. Stimulation thresholds for side effects were higher with i3D-F guidance in the subthalamic nucleus (MER, 2.80 mA ± 0.98; i3D-F, 3.46 mA ± 0.92; P = .002) and VIM (MER, 2.81 mA ± 1.00; i3D-F, 3.19 mA ± 1.03; P = .0018). Less pTC with i3D-F guidance (MER, 7.5%; i3D-F, 1.2%; P = .034) was also found. CONCLUSION: Although clinical efficacy between MER-guided and i3D-F-guided DBS was comparable, thresholds for stimulation side effects were higher with i3D-F guidance and the rate of pTC was lower. This suggests that image-guided DBS may affect long-term side effects and pose a decreased risk of pTC.

Frequency of Parkinson disease following COVID-19 infection: A two-year retrospective cohort study.

INTRODUCTION: COVID-19 infection is known to cause various neurological symptoms, and potentially increases the risk of developing subsequent neurodegenerative conditions including parkinsonism. To our knowledge, no study to date has used a large data set in the United States to ascertain the risk of developing incident Parkinson disease in patients with history of COVID-19 infection compared to the risk amongst those without prior COVID-19 infection. METHODS: We utilized data from TriNetX electronic health records network which includes 73 healthcare organizations and over 107 million patients. We compared adult patients with and without COVID-19 infection, with health records from January 1, 2020 through July 26, 2022, to determine the relative risk of developing Parkinson disease stratified by 3-month intervals. We used propensity score matching to control for patients' age, sex, and smoking history. RESULTS: We collected data on 27,614,510 patients meeting our study criteria: 2,036,930 patients with a positive COVID-19 infection (COVID-19) and 25,577,580 without a positive COVID-19 infection (non-COVID-19). After propensity score matching, age, sex, and smoking history differences became non-significant, with 2,036,930 patients in each cohort. After propensity score matching, we found significantly increased odds of new onset Parkinson disease in the COVID-19 cohort at three, six, nine, and twelve months from the index event, with peak odds ratio at six months. After twelve months there is no significant difference between the COVID-19 group and non-COVID-19 group. CONCLUSIONS: There may be a transiently increased risk of developing Parkinson disease in the first year following COVID-19 infection.

DNM1L variant presenting as adolescent-onset sensory neuronopathy, spasticity, dystonia, and ataxia.

DMN1L encodes for dynamin-like protein 1 (DLP1) which plays a key role in perixosomal and mitochondrial fission. Individuals with heterozygous variants in DNM1L present with a wide range of neurologic symptoms, including encephalopathy, epilepsy, and motor deficits. Here we report on a woman presenting with adolescence onset of sensory neuronopathy, spasticity, dystonia, and ataxia. Trio genome sequencing identified a heterozygous variant in DNM1L (NM_012062.3 c.121G>A/p.Val41Met) which was thought to be pathogenic. This case describes the latest known symptomatic onset of DMN1L-related disease described in literature. We highlight our approach to a challenging diagnostic workup and interpretation of a specific variant that has not been previously reported. Furthermore, the case highlights the diagnostic importance of utilizing genomic sequencing and research studies for patients with rare disease.

Dystonia Due to GM3 Synthase Deficiency.

BACKGROUND: Gangliosides are expressed in neuronal membranes, and play roles in neuronal differentiation and cell regulation during brain development. The ST3GAL5 gene encodes the enzyme GM3 synthase, and its deficiency causes a rare condition described to cause refractory epilepsy, profound intellectual disability, quadriplegia, choreoathetosis, and pigmentary skin changes. GM3 synthase deficiency is rarely reported to cause dystonia. We report five cases of GM3 synthase deficiency involving a dystonic phenotype. CASES: The five reported individuals were born of unaffected consanguineous parents from Old Order Amish families. They all developed refractory epilepsy and developmental regression within the first few months of life. They exhibit variable degrees of extrapyramidal movements, including orofacial, cervical, and limb dystonia, as well as choreoathetosis. CONCLUSIONS: We report five individuals with GM3 synthase deficiency who developed dystonic features. Dystonia has previously been reported in only one case of GM3 synthase deficiency.

Paracervical Block or Uterosacral Ligament Infiltration for Benign Minimally Invasive Hysterectomy: A Systematic Review and Meta-analysis.

OBJECTIVE: The aim of this study was to estimate the efficacy of preemptive paracervical block or uterosacral ligament infiltration in reducing postoperative pain and opioid consumption after benign minimally invasive hysterectomy. DATA SOURCES: We searched MEDLINE, Cochrane Library, Embase, ClinicalTrials.gov, and Google Scholar from inception until February 2020. METHODS OF STUDY SELECTION: We identified randomized placebo-controlled trials assessing the primary outcome of pain and opioid consumption after paracervical block or uterosacral infiltration in benign laparoscopic, vaginal, or robotic hysterectomy. Two investigators evaluated studies for risk of bias and quality of evidence. TABULATION, INTEGRATION, AND RESULTS: We reviewed 219 abstracts; 6 studies met the inclusion criteria: 3 using paracervical block (2 vaginal and 1 laparoscopic) and 3 using uterosacral ligament infiltration (all vaginal). Two studies were included in the meta-analysis (both vaginal hysterectomy). Because of lack of numerical data, or comparison, the other 4 studies are reported in narrative form. Three controlled trials reported a moderate benefit from paracervical block up to 8 hours after vaginal and 4 hours after laparoscopic surgery. Meta-analysis could not be performed because of the lack of numerical data for pooling results or the lack of a laparoscopic hysterectomy comparison group. Three trials reported that uterosacral infiltration decreases pain up to 6 hours after vaginal hysterectomy, and meta-analysis pooling the results of 2 of these studies demonstrated improvement in pain up to 4 hours on a 0- to 100-mm visual analog scale for pain (-19.97 mm; 95% confidence interval, -29.02 to -10.91; P < 0.000). Five trials reported a moderate reduction in cumulative opioid use within 24 hours after vaginal surgery for both paracervical block and uterosacral infiltration. Meta-analysis was not performed for paracervical block because only 1 trial provided suitable data for pooling. Meta-analysis pooling the results of 2 trials of uterosacral infiltration demonstrated opioid consumption of 20.73 morphine milligram equivalents less compared with controls (95% confidence interval, -23.54 to -17.91; P < 0.000). CONCLUSIONS: There were a total of 6 randomized placebo-controlled studies evaluated in this study. Although a meta-analysis was unable to be performed for all studies because of lack of comparison groups or numerical data, there is evidence that preemptive uterosacral ligament infiltration may reduce postoperative pain and opioid consumption after vaginal hysterectomy. Our study does not allow us to make any substantive conclusions on the use of paracervical block in vaginal hysterectomy or the use of either type of injection in laparoscopic or robotic hysterectomy.

Systematic review of the pharmacoeconomics of Parkinson disease medications.

Introduction: Parkinson's disease (PD) causes progressive motor symptoms including tremor, rigidity, and bradykinesia, along with non-motor symptoms such as dementia, orthostatic hypotension, and depression. Over time, PD can lead to falls, disability, institutionalization, and caregiver burden. Its treatment is symptomatic and can be associated with high costs. Areas covered: The authors performed a literature search of PubMed, Web of Science, and Cochrane Library Current for English language PD pharmacoeconomic evaluations starting from 1 January 2000. The authors found 26 papers covering treatment of motor symptoms (n = 24), dementia (n = 1), and orthostatic hypotension (n = 1). The scope of literature was limited in that there were few articles overall. Expert opinion: Overall, the authors found a scarcity of primary PD pharmacoeconomic literature in the 21st Century. Given the myriad of PD motor and non-motor treatments, only 24 papers evaluating motor treatments and two papers evaluating non-motor treatments met our search criteria. More studies are clearly needed to better define the pharmacoeconomics of PD therapeutics.

Trivalent arsenicals induce lipid peroxidation, protein carbonylation, and oxidative DNA damage in human urothelial cells.

Drinking arsenic-contaminated water is associated with an increased risk of bladder cancer. Arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonous acid (MMA(III)), monomethylarsonic acid (MMA(V)), dimethylarsinous acid (DMA(III)), and dimethylarsinic acid (DMA(V)) have all been detected in the urine of people who drink arsenic-contaminated water. The aim of this research was to investigate which of these arsenicals are more hazardous to human urothelial cells. The results indicate that iAs(III), MMA(III), and DMA(III) were more potent in inducing cytotoxicity, lipid peroxidation, protein carbonylation, oxidative DNA damage, nitric oxide, superoxide, hydrogen peroxide, and cellular free iron than MMA(V), DMA(V), and iAs(V) in human urothelial carcinoma and transformed cells. However, the results did not show convincingly that the trivalent arsenicals were more potent than pentavalent arsenicals in decreasing the intracellular contents of total thiol, protein thiol, and reduced glutathione. Induction of oxidative DNA damage was observed with 0.2 microM of iAs(III), MMA(III), or DMA(III) as early as 1h. Because of its high oxidative damage, higher proportion in urine, and lower cytotoxicity, DMA(III) may be the most hazardous arsenical to human urothelial cells.

8-Oxoguanine DNA glycosylase and MutY homolog are involved in the incision of arsenite-induced DNA adducts.

Since arsenite is known to induce oxidative DNA damage in human cells, we asked if it induces other types of DNA damage and how the DNA damage is repaired. Treatment of human promyelocytic leukemia NB4 cells with 0.5muM As(2)O(3) for 30 min induced no DNA breaks, as analyzed by a standard comet assay. However, breaks were detected if these cells were then digested with endonuclease III (EnIII), formamidopyrimidine-DNA glycosylase (Fpg), or a nuclear extract (NE) of NB4 cells. Using either H(2)O(2)-Fe-treated nuclei or As(2)O(3)-treated cells, digestion with either NE or EnIII + Fpg generated the same amount of breaks, and subsequent treatment with EnIII + Fpg resulted in no increase in breaks in NE-digested cells and vice versa. The human cell lines, defective in nucleotide excision protein, such as xeroderma pigmentosum (XP) A, XPD, and XPG, excised Ultraviolet C-induced adducts less rapidly than normal fibroblasts, but excised As(2)O(3) adducts at the same rate as the normal cells. Immunodepletion of the NE with antibody against 8-oxoguanine DNA glycosylase (OGG1) or MutY homolog (MYH) decreased the incision of As(2)O(3)-induced adducts, while antibodies against XPA, XPB, XPD, XPF, or XPG, did not. These results suggest that As(2)O(3) induces the formation of only oxidative DNA adducts and that OGG1 and MYH are involved in this incision process.

OGG1 and MYH are involved in the incision of trivalent arsenical-induced DNA adducts.

Since trivalent arsenicals are known to induce oxidative DNA damage in human cells, we asked if they induce other types of DNA damage and how these DNA damages are repaired. Treatment of human promyelocytic leukemia NB4 cells with 0.5 microM As2O3 for 30 min induced no DNA breaks, as analyzed by a standard comet assay. However, breaks were detected if these cells were then digested with endonuclease III (EnIII), formamidopyrimidine-DNA glycosylase (Fpg), or a nuclear extract (NE) of NB4 cells. Using either H2O2-Fe treated nuclei or As2O3-treated cells, digestion with either NE or EnIII+Fpg generated the same amount of breaks, and subsequent treatment with EnIII+Fpg resulted in no increase in breaks in NE-digested cells and vice versa. The human cell lines, defective in nucleotide excision protein, such as XPA, XPD, and XPG, excised UVC-induced adducts less rapidly than normal fibroblasts, but excised As2O3-adducts at the same rate as the normal cells. Immunodepletion of the NE with antibody against OGG1 or MYH decreased the incision of DNA adducts induced by As2O3, NaAsO2, monomethylarsonic acid, and dimethylarsinic acid, while antibodies against XPA, XPB, XPD, XPF, or XPG, did not. These results suggest that these trivalent arsenicals induce the formation of only oxidative DNA adducts and that OGG1 and MYH are involved in these incision processes.

Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells.

Ultrafine titanium dioxide (TiO(2)) particles have been shown to exhibit strong cytotoxicity when exposed to UVA radiation, but are regarded as a biocompatible material in the absence of photoactivation. In contrast to this concept, the present results indicate that anatase-sized (10 and 20 nm) TiO(2) particles in the absence of photoactivation induced oxidative DNA damage, lipid peroxidation, and micronuclei formation, and increased hydrogen peroxide and nitric oxide production in BEAS-2B cells, a human bronchial epithelial cell line. However, the treatment with anatase-sized (200 and >200 nm) particles did not induce oxidative stress in the absence of light irradiation; it seems that the smaller the particle, the easier it is for the particle to induce oxidative damage. The photocatalytic activity of the anatase form of TiO(2) was reported to be higher than that of the rutile form. In contrast to this notion, the present results indicate that rutile-sized 200 nm particles induced hydrogen peroxide and oxidative DNA damage in the absence of light but the anatase-sized 200nm particles did not. In total darkness, a slightly higher level of oxidative DNA damage was also detected with treatment using an anatase-rutile mixture than with treatment using either the anatase or rutile forms alone. These results suggest that intratracheal instillation of ultrafine TiO(2) particles may cause an inflammatory response.

Comet assay with nuclear extract incubation.

Alkaline comet assay is a simple sensitive method for detecting DNA strand breaks. However, at the time of cell lysis, only a fraction of the entire DNA damage appears as DNA strand breaks, while some DNA strand breaks may have been rejoined and some DNA lesions may still remain unexcised. We showed that nuclear extract (NE) prepared from human cells could excise the DNA adducts induced by UVC, X-ray, and methyl methanesulfonate (MMS). Thus, the comet assay with NE incubation allows a closer estimation of total DNA damage. Among the human urothelial carcinoma cell lines we tested, the NE of NTUB1 cells showed higher activity in excising the DNA adducts induced by UVC, but with a lower activity in excising the DNA adducts induced by MMS than the NE of BFTC905 cells. Moreover, under the same dose of X-ray irradiation, a larger difference in total DNA damage between two cell lines was revealed in comet assay incubated with NE than without NE. Therefore, the comet assay with NE incubation may be useful in the research of cancer risk, drug resistance, and DNA repair proteins.

Reactive oxygen species are involved in arsenic trioxide inhibition of pyruvate dehydrogenase activity.

Arsenite was shown to inhibit pyruvate dehydrogenase (PDH) activity through binding to vicinal dithiols in pure enzyme and tissue extract. However, no data are available on how arsenite inhibits PDH activity in human cells. The IC(50) values for arsenic trioxide (As(2)O(3)) to inhibit the PDH activity in porcine heart pure enzyme preparation and in human leukemia cell line HL60 cells were estimated to be 182 and 2 microM, respectively. Thus, As(2)O(3) inactivation of PDH activity was about 90 times more potent in HL60 cells than in purified enzyme preparation. The IC(50) values for As(2)O(3) and phenylarsine oxide to reduce the vicinal thiol content in HL60 cells were estimated to be 81.7 and 1.9 microM, respectively. Thus, As(2)O(3) is a potent PDH inhibitor but a weak vicinal thiol reacting agent in HL60 cells. Antioxidants but not dithiol compounds suppressed As(2)O(3) inhibition of PDH activity in HL60 cells. Conversely, dithiol compounds but not antioxidants suppressed the inhibition of PDH activity by phenylarsine oxide. As(2)O(3) increased H(2)O(2) level in HL60 cells, but this was not observed for phenylarsine oxide. Mitochondrial respiration inhibitors suppressed the As(2)O(3)-induced H(2)O(2) production and As(2)O(3) inhibition of PDH activity. Moreover, metal chelators ameliorated whereas Fenton metals aggravated As(2)O(3) inhibition of PDH activity. Treatment with H(2)O(2) plus Fenton metals also decreased the PDH activity in HL60 cells. Therefore, it seems that As(2)O(3) elevates H(2)O(2) production in mitochondria and this may produce hydroxyl through the Fenton reaction and result in oxidative damage to the protein of PDH. The present results suggest that arsenite may cause protein oxidation to inactivate an enzyme and this can occur at a much lower concentration than arsenite binding directly to the critical thiols.

Oxidative DNA adducts and DNA-protein cross-links are the major DNA lesions induced by arsenite.

Arsenic is recognized to be a nonmutagenic carcinogen because it induces DNA damage only at very high concentrations. However, many more DNA strand breaks could be detected by digesting the DNA of arsenite-treated cells with endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K. By doing so, arsenite could be shown to induce DNA damage in human cells within a pathologically meaningful concentration range. Oxidized guanine products were detected in all arsenite-treated human cells examined. DNA-protein cross-links were also detected in arsenite-treated NB4 and HL60 cells. In human umbilical vein endothelial cells, the induction of oxidized guanine products by arsenite was sensitive to inhibitors of nitric oxide (NO) synthase but not to oxidant modulators, whereas the opposite result was obtained in vascular smooth muscle cells. On the other hand, the arsenite-induced oxidized guanine products and DNA-protein cross-links in NB4 and HL60 cells were sensitive to modulators of calcium, NO synthase, oxidant, and myeloperoxidase. Therefore, although oxidized guanine products were detected in all the human cells treated with arsenite, the pathways could be different in different cell types. Because the sensitivity and the mechanism of arsenic intoxication are cell specific, it is important that target tissues and target cells are used for investigations. It is also important that pathologically or pharmacologically meaningful concentrations of arsenic are used. This is because in most cases we are dealing with the chronic effect rather than acute toxicity.

Endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K additively enhance arsenic-induced DNA strand breaks in human cells.

We report here that sequential digestion with endonuclease III, formamidopyrimidine-DNA glycosylase, and proteinase K in Tris buffer markedly increased the sensitivity for detecting DNA damage in arsenic-treated cells. These three enzymes increased DNA strand breaks in an additive manner. By using this sequential-enzyme-digestion comet assay, we demonstrated that trivalent inorganic arsenic induced more DNA damage than monomethylarsonous acid, monomethylarsonic acid, and dimethylarsinic acid in human blood cell lines. However, trivalent inorganic arsenic was far less potent than monomethylarsonous acid in inhibiting pyruvate dehydrogenase activity. Therefore, different mechanisms are involved in inhibiting pyruvate dehydrogenase activity and inducing DNA damage. Our results also indicate while trivalent inorganic arsenic induced more endonuclease III-digestible adducts, monomethylarsonous acid and monomethylarsonic acid induced more proteinase K-digestible adducts. These results suggest there is a difference in the mechanism for inducing DNA damage between inorganic and organic methylated arsenic compounds.