Lateralized readiness potentials can identify hemisphere of recovery in stroke patients.

BACKGROUND: Event related cortical potentials related to motor action are referred to as movement related cortical potentials. The late component of which is the readiness potential (RP) and its polarity is more negative in the hemisphere responsible for planning of motor action. This lateralized nature of RP during unilateral hand movement is studied as lateralized readiness potential (LRP) by calculating the contralateral-minus-ipsilateral difference wave for each hand. OBJECTIVE: The aim was to identify the hemisphere contributing to motor recovery in acute and chronic stroke patients through recording LRPs. METHODS: Twenty-nine cases with cerebrovascular stroke (15 acute and 14 chronic) were included in the study. EEG was recorded in response to self-cued button presses by the paretic side to obtain the averaged LRP amplitude. The hemisphere with greater negativity was considered the side of recovery. Functional recovery was assessed by Fugl Meyer test. RESULTS: In acute cases, recovery was more related to LRP activity in the contralesional hemisphere (73%), whereas lateralization was equal in chronic cases; 50% in either group. LRP amplitude was higher in the contralesional hemisphere (p = 0.02). Functional recovery assessed by the Fugl Meyer test (FM) was similar whether recovery was ipsi- or contralesional. CONCLUSIONS: Early after stroke, motor recovery is more likely to involve compensatory activity in the contralesional hemisphere, while in the chronic phase, the ipsilesional hemisphere may recover its function and become more active. Further research is needed to verify if the technique mentioned in our study could be used to guide customized NIBS protocols tailoring the optimal site and parameters for each patient.

Serum CGRP Changes following Ultrasound-Guided Bilateral Greater-Occipital-Nerve Block.

Background: Calcitonin-gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal nerve cells, and treatments targeting CGRP are effective in migraines. For headaches that do not respond to pharmacological treatment, minimally invasive techniques such as greater-occipital-nerve block (GONB) can help relieve the pain and reduce the frequency of headaches. Our study assessed the efficacy of ultrasound-guided greater-occipital-nerve block (USgGONB) in chronic migraines (CM) and its relationship to serum CGRP levels. Methods: Forty chronic migraineurs who underwent bilateral USgGONB using 40 mg triamcinolone and 1 mL lidocaine were recruited and interictal serum CGRP samples were collected immediately before and one month after GONB. The clinical response was evaluated using headache diaries before and one month after USgGONB. The patient response was determined after USgGONB according to the reduction in headache days as a good responder (>50% reduction), poor responder (<50%) or non-responder. Results: Monthly headache days after GONB showed a significant reduction (median, 10 days; range, 8−14.7) compared to before the block (median, 18 days; range, 17−22; p < 0.001). Across all patients, interictal serum CGRP levels after USgGONB were significantly lower than before the block (median, 40 pg/mL (range, 25−60) vs. 145 pg/mL (range, 60−380) (p = 0.001). The pre-treatment interictal CGRP levels showed a significant difference (p = 0.003), as their levels in non-responders (median, 310 pg/mL; interquartile range, 262−350) were significantly higher than those seen in responders, whether poor responders (median, 135 pg/mL; interquartile range, 100−200 pg/mL) or good responders (median, 140 pg/mL; interquartile range, 80−150 pg/mL). Conclusion: the study showed the beneficial effect of USgGONB in chronic migraines that was associated with lowering interictal CGRP levels, implying a potential role for CGRP in the mechanism of action of GONB in CM, and the interictal CGRP level may be used as a predictor for the response to GONB.

Peripheral magnetic theta burst stimulation to muscles can effectively reduce spasticity: a randomized controlled trial.

BACKGROUND: Spasticity is a common complication of many neurological diseases and despite contributing much disability; the available therapeutic options are limited. Peripheral magnetic stimulation is one promising option. In this study, we investigated whether peripheral intermittent theta burst stimulation (piTBS) will reduce spasticity when applied directly on spastic muscles. METHODS: In this sham-controlled study, eight successive sessions of piTBS were applied directly to spastic muscles with supra threshold intensity. Assessment was done by modified Ashworth scale (mAS) and estimated Botulinum toxin dose (eBTD) at baseline and after the 8th session in both active and sham groups. RESULTS: A total of 120 spastic muscles of 36 patients were included in the analysis. Significant reduction of mAS and eBTD was found in the active compared to sham group (p < 0.001). The difference in mAS was also significant when tested in upper limb and lower limb subgroups. The degree of reduction in mAS was positively correlated with the baseline scores in the active group. CONCLUSION: piTBS could be a promising method to reduce spasticity and eBTD. It consumes less time than standard high frequency protocols without compromising treatment efficacy. TRIAL REGISTRATION: Clinical trial registry number: PACTR202009622405087. Retrospectively Registered 14th September, 2020.

Navigated perilesional transcranial magnetic stimulation can improve post-stroke visual field defect: A double-blind sham-controlled study.

BACKGROUND: Visual field defects (VFD) usually do not show improvement beyond 12 weeks from their onset. It has been shown that repetitive presentation of a stimulus to areas of residual vision in cases of visual field defect can improve vision. The counterpart of these areas in the brain are the partially damaged brain regions at the perilesional areas where plasticity can be enhanced. OBJECTIVE: We aimed to study the effect of navigated repetitive transcranial magnetic stimulation (rTMS) applied to perilesional areas on the recovery of patients with cortical VFD. METHODS: Thirty-two patients with cortical VFD secondary to stroke of more than 3 months duration received 16 sessions of either active or sham high frequency navigated perilesional rTMS. Automated perimetry and visual functioning questionnaire (VFQ-25) were performed at baseline and after completion of the sessions. RESULTS: The active group showed significant improvement after intervention, compared to the sham group, in both mean deviation (MD), visual field index (VFI) and in the VFQ-25 scores. CONCLUSIONS: Navigated rTMS is a new treatment option for post-stroke VFD as it can selectively stimulate areas of residual vision around the infarcted tissue, improving the threshold of visual stimulus detection which could be used alone or in combination with existing therapies.

Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations-is the term "thyroblastoma" more appropriate?

Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45 years) and one male (17 years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known "hotspot" pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that "blastoma" is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term "thyroblastoma" might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed.

Impact of FLT3 Receptor (CD135) Detection by Flow Cytometry on Clinical Outcome of Adult Acute Myeloid Leukemia Patients.

BACKGROUND: The significance of FMS-like tyrosine kinase 3 (FLT3)-ITD mutation in acute myeloid leukemia (AML) prognosis has been well established. The aims of this study were to investigate the prognostic impact of the FLT3 protein (CD135) expression and its association with FLT3-ITD mutation, and to identify its role in minimal residual disease. PATIENTS AND METHODS: CD135 was measured by flow cytometry on leukemic blasts of 257 adults with de novo AML. High expression of CD135 ≥ 20% was correlated with clinical, laboratory, and other prognostic factors that influenced treatment outcome. FLT3-ITD mutation was tested by PCR. RESULTS: The frequency of CD135 expression was 138 (53.7%) of 257. FLT3-ITD was detected in (21.4%). Positive CD135 expression was associated with high total leukocyte count (P = .006), platelet count (P = .003), monocytic leukemia (P < .001), and CD34 (P = .008) and CD117 (P = .006) expression. CD135 expression ≥ 25% was a predictor of FLT3-ITD mutation (P = .03). CD135 overexpression was a negative predictor of complete remission and of postinduction minimal residual disease at days 14 and 28 (P < .001). CD135 had an adverse impact on overall and disease-free survival (68.5% vs. 15%, P = .002). Multivariate analysis indicated CD135 was the sole independent prognostic factor for overall survival (hazard ratio = 2.49; 95% confidence interval, 1.855-3.345; P < .001). CONCLUSION: CD135 is emerging as a prognostic factor, a new marker for minimal residual disease, and a potential novel therapeutic target of AML.

Mice expressing a "hyper-sensitive" form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption.

We recently characterized S426A/S430A mutant mice expressing a desensitization-resistant form of the CB1 receptor. These mice display an enhanced response to endocannabinoids and ∆9-THC. In this study, S426A/S430A mutants were used as a novel model to test whether ethanol consumption, morphine dependence, and reward for these drugs are potentiated in mice with a "hyper-sensitive" form of CB1. Using an unlimited-access, two-bottle choice, voluntary drinking paradigm, S426A/S430A mutants exhibit modestly increased intake and preference for low (6%) but not higher concentrations of ethanol. S426A/S430A mutants and wild-type mice show similar taste preference for sucrose and quinine, exhibit normal sensitivity to the hypothermic and ataxic effects of ethanol, and have normal blood ethanol concentrations following administration of ethanol. S426A/S430A mutants develop robust conditioned place preference for ethanol (2 g/kg), morphine (10 mg/kg), and cocaine (10 mg/kg), demonstrating that drug reward is not changed in S426A/S430A mutants. Precipitated morphine withdrawal is also unchanged in opioid-dependent S426A/S430A mutant mice. Although ethanol consumption is modestly changed by enhanced CB1 signaling, reward, tolerance, and acute sensitivity to ethanol and morphine are normal in this model.

Mice Expressing a "Hyper-Sensitive" Form of the Cannabinoid Receptor 1 (CB1) Are Neither Obese Nor Diabetic.

Multiple lines of evidence implicate the endocannabinoid signaling system in the modulation of metabolic disease. Genetic or pharmacological inactivation of CB1 in rodents leads to reduced body weight, resistance to diet-induced obesity, decreased intake of highly palatable food, and increased energy expenditure. Cannabinoid agonists stimulate feeding in rodents and increased levels of endocannabinoids can disrupt lipid metabolism. Therefore, the hypothesis that sustained endocannabinoid signaling can lead to obesity and diabetes was examined in this study using S426A/S430A mutant mice expressing a desensitization-resistant CB1 receptor. These mice display exaggerated and prolonged responses to acute administration of phytocannabinoids, synthetic cannabinoids, and endocannabinoids. As a consequence these mice represent a novel model for determining the effect of enhanced endocannabinoid signaling on metabolic disease. S426A/S430A mutants consumed equivalent amounts of both high fat (45%) and low fat (10%) chow control diet compared to wild-type littermate controls. S426A/S430A mutants and wild-type mice fed either high or low fat control diet displayed similar fasting blood glucose levels and normal glucose clearance following a 2 g/kg glucose challenge. Furthermore, S426A/S430A mutants and wild-type mice consumed similar amounts of chow following an overnight fast. While both THC and JZL195 significantly increased food intake two hours after injection, this increase was similar between the S426A/S430A mutant and wildtype control mice Our results indicate that S426A/S430A mutant mice expressing the desensitization-resistant form of CB1 do not exhibit differences in body weight, food intake, glucose homeostasis, or re-feeding following a fast.

LKB1 protein expression in neuroendocrine tumors of the lung.

During a recent investigation of LKB1 gene abnormality in lung lesions, strong expression of LKB1 protein in normal neuroendocrine (NE) cells of the bronchial epithelium was found. Because LKB1 functions as a tumor suppressor gene, the question of whether alteration of LKB1 expression is related to the development of pulmonary NE tumors of various grades was investigated. LKB1 immunohistochemistry was examined in a total of 68 primary pulmonary NE tumors consisting of 30 specimens of small cell lung carcinoma (SCLC), 23 large cell neuroendocrine carcinomas (LCNEC), two atypical carcinoids, and 13 typical carcinoids. Loss or low expression (<20% immunoreactive cells) of LKB1 protein expression was more frequently observed in high-grade NE tumors (SCLC and LCNEC; 45/53, 84.9%) than in typical and atypical carcinoids (3/15; 20%). The difference in LKB1 immunoreactivity between the high-grade NE tumors and the carcinoid group was statistically significant (P < 0.0001). In conclusion, marked reduction of LKB1 expression in high-grade NE tumors of the lung suggests a possible role of LKB1 inactivation in its tumorigenesis. Although a few previous studies indicated rare genetic alterations of LKB1 in SCLC, further studies including analysis of other NE tumors and focusing on epigenetic abnormalities of LKB1 gene are warranted.

Role of the PI3K/Akt, mTOR, and STK11/LKB1 pathways in the tumorigenesis of sclerosing hemangioma of the lung.

Although the histogenesis of sclerosing hemangioma (SH) of the lung is now thought to be respiratory epithelial in origin, the genetic abnormalities that mediate its development are not known. Because pathophysiology of several syndromes associated with benign tumors may converge on the tuberous sclerosis complex (TSC), serine/threonine kinase 11 (STK11), and mammalian target of rapamycin (mTOR) pathways, the purpose of the present paper was to investigate their roles in the development of SH. Semiquantitative immunohistochemical analysis was done to assess the expression of phospho-mTOR, phospho-S6 ribosomal protein, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), phospho-Akt, STK11, tuberin, hamartin, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1alpha (HIF-1alpha) in 19 cases of typical SH. To determine whether genetic alteration of STK11 is involved in the development of SH, all encoding exons of STK11 were analyzed by polymerase chain reaction (PCR) amplification and direct sequencing of genomic DNA of six specimens. The six specimens were also investigated for whether promoter hypermethylation exists as an alternative inactivating mechanism for STK11. All specimens showed moderate to marked reaction to phospho-S6 ribosomal protein and PTEN; 16 specimens (84%) showed slight to moderate reaction to phospho-mTOR, negative reaction to STK11, and slight to moderate reaction to hamartin; 11 (58%) showed slight to moderate reaction to phospho-Akt; 18 (95%) showed slight to moderate reaction to tuberin and positive reaction for HIF-1alpha; and 17 (90%) showed moderate reaction to VEGF. No somatic mutation of STK11 was found and the six specimens were unmethylated in the promoter region. These data imply that aberrant mTOR signaling may play a role in the development of SH, and its vascular nature may be due partially to high levels of VEGF caused by dysregulation of mTOR signaling.

Risk factors and independent predictors of survival in patients with pulmonary epithelioid haemangioendothelioma. Review of the literature and a case report.

Pulmonary epithelioid haemangioendothelioma (PEH) is a rare pulmonary neoplasm. A patient with PEH with lymph node and pleural metastases that were discovered incidentally is described. An abnormal left upper lobe shadow was noticed on CXR in a 70-year-old woman during an assessment for the sudden onset of nausea and vomiting. Transbronchial lung biopsy did not provide a diagnosis. Lobectomy and lymph node resection were performed. The histological diagnosis of PEH was confirmed immunohistochemically by positive reactions to factor VIII-related antigen and CD34. Data on 93 patients with PEH including the present case report were analysed by Cox regression analysis using forward stepwise method to identify the risk factors, and the independent predictors of survival in patients with PEH. It revealed that male, symptomatic patients, presence of cough, haemoptysis, chest pain, multiple unilateral nodules, pleural effusion, metastases to more than one site and lymph node metastases were all significant risk factors for PEH (P<0.05). Symptomatic patients and presence of pleural effusion were the independent predictors of survival in patients with PEH.

Metastatic germ cell tumor of the lung masquerading as primary rhabdomyosarcoma.

Two years after testicular resection was carried out in a 40-year-old man that revealed mixed germ cell tumor of more than one histological type (seminoma, embryonal cell carcinoma, and yolk sac tumor), he presented with an asymptomatic pulmonary nodule in his left lower lobe. Video-assisted thoracoscopic partial resection of the tumor revealed a 24 x 20 mm teratoma with somatic-type malignancy in which pleomorphic rhabdomyosarcoma was a major element. One year later, asymptomatic tumor recurrence occurred at both edges of the stapler line as 22 x 20 mm and 10 x 5 mm nodules composed only of pleomorphic rhabdomyosarcoma. Throughout the course there was no abdominal lymph node swelling detected by computed tomography (CT) and tumor markers were normal. Adjuvant chemotherapy was started after the tumor recurrence. Currently, the patient is still undergoing chemotherapy 5 months after the tumor recurrence. In conclusion, despite the fact that primary pulmonary rhabdromyosarcoma is a rare neoplasm, metastatic pulmonary germ cell tumor with somatic-type malignancy showing predominantly rhabdomyosarcomatous differentiation should be considered in the differential diagnosis of such lesions of the lung.