Langerhans cell histiocytosis of the mandible in a six-year-old child

Histiocytosis is a term applied to a group of rare disorders of the reticuloendothelial system. Eosinophilic granuloma, the most benign and localized of the three Langerhans cell histiocytosis entities, may be solitary or multiple. Eosinophilic granuloma can affect almost any bone, but commonly involves the mandible when the jaws are affected. Conventional treatment of LCH is with surgery, radiotherapy, chemotherapy and steroid injections, alone or in combination. Spontaneous regression of localized disease has also been reported. We report a six and a half-year-old patient with Langerhans cell histiocytosis--solitary eosinophilic granuloma of the mandible that initially regressed but rapidly recurred even after radical treatment and had a fatal outcome.     

Dysregulated CXCR4 expression promotes lymphoma cell survival and independently predicts disease progression in germinal center B-cell-like diffuse large B-cell lymphoma

Abnormal expression of the chemokine receptor CXCR4 plays an essential role in tumor cell dissemination and disease progression. However, the significance of CXCR4 overexpression in de novo diffuse large B cell lymphoma (DLBCL) is unknown. In 743 patients with de novo diffuse large B cell lymphoma (DLBCL) who received standard Rituximab-CHOP immunochemotherapy, we assessed the expression of CXCR4 and dissected its prognostic significance in various DLBCL subsets. Our results showed that CXCR4⁺ patients was associated with male, bulky tumor, high Ki-67 index, activated B-cell-like (ABC) subtype, and Myc, Bcl-2 or p53 overexpression. Moreover, CXCR4⁺ was an independent factor predicting poorer progression-free survival in germinal-center B-cell-like (GCB)-DLBCL, but not in ABC-DLBCL; and in patients with an IPI of ≤2, but not in those with an IPI>2. The lack of prognostic significance of CXCR4 in ABC-DLBCL was likely due to the activation of p53 tumor suppressor attenuating CXCR4 signaling. Furthermore, concurrent CXCR4⁺ and BCL2 translocation showed dismal outcomes resembling but independent of MYC/BCL2 double-hit DLBCL. Gene expression profiling suggested that alterations in the tumor microenvironment and immune responses, increased tumor proliferation and survival, and the dissemination of CXCR4⁺ tumor cells to distant organs or tissues were underlying molecular mechanisms responsible for the CXCR4⁺ associated poor prognosis.     

When is a bispectral index of 60 too low?: Rational processed electroencephalographic targets are dependent on the sedative-opioid ratio

BACKGROUND: Opioids are commonly used in conjunction with sedative drugs to provide anesthesia. Previous studies have shown that opioids reduce the clinical requirements of sedatives needed to provide adequate anesthesia. Processed electroencephalographic parameters, such as the Bispectral Index (BIS; Aspect Medical Systems, Newton, MA) and Auditory Evoked Potential Index (AAI; Alaris Medical Systems, San Diego, CA), can be used intraoperatively to assess the depth of sedation. The aim of this study was to characterize how the addition of opioids sufficient to change the clinical level of sedation influenced the BIS and AAI. METHODS: Twenty-four adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the modified Observer's Assessment of Alertness/Sedation score, BIS, and AAI were measured at each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for each pharmacodynamic endpoint. RESULTS: Response surface models adequately characterized all pharmacodynamic endpoints. Despite the fact that sevoflurane-remifentanil interactions were strongly synergistic for clinical sedation, BIS and AAI were minimally affected by the addition of remifentanil to sevoflurane anesthetics. CONCLUSION: Although clinical sedation increases significantly even with the addition of a small to moderate dose of remifentanil to a sevoflurane anesthetic, the BIS and AAI are insensitive to this change in clinical state. Therefore, during "opioid-heavy" sevoflurane-remifentanil anesthetics, targeting a BIS less than 60 or an AAI less than 30 may result in an unnecessarily deep anesthetic state.     

Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera

Alzheimer's disease is a neurodegenerative disorder characterized by progressive dementia. Bacopa monniera is described in the Ayurvedic Materia Medica, as a therapeutically useful herb for the treatment of cognitive impairment, thus supporting its possible anti-Alzheimer's properties. Our studies have shown that Bacopa monniera reduces beta-amyloid deposits in the brain of an Alzheimer's disease animal model. The objective of this study was to establish the presence of endogenous substances in Bacopa monniera extract (BmE) that will impact components of the oxidative stress cascade such as the reduction of divalent metals, scavenging of reactive oxygen species, alterations of lipoxygenase activity and hydrogen peroxide-induced lipid peroxidation. The extract contained polyphenols and sulfhydryl contents suggestive of endogenous antioxidant activity. The results demonstrated that BmE reduced divalent metals, dose-dependently scavenged reactive oxygen species, decreased the formation of lipid peroxides and inhibited lipoxygenase activity. These data combined with our previous studies that have shown that BmE treatment reduces beta-amyloid levels in the brain of an Alzheimer's disease doubly transgenic mouse model of rapid amyloid deposition (PSAPP mice) suggesting mechanisms of action relevant to the treatment of Alzheimer's disease.     

Correlation between clinical and histological findings in parathyroid tumors suspicious for carcinoma

Carcinoma of the parathyroid is a rare malignancy that can be cured surgically if the proper diagnosis and treatment is given initially. Arriving to the clinical suspicion of a malignancy preoperatively is by far the most important step for a good prognosis. Our goal is to review the correlation between clinical and final histopathological findings that can arouse the suspicion of such malignancy and their true predictive value in the diagnosis. All patients that underwent surgical removal of the parathyroid mass between March of 1992 and March of 2003 were reviewed retrospectively at Providence Hospital and Medical Centers. Among 168 patients who underwent parathyroid excision, 14 (8.3%) had hyperplasia of the parathyroid, 121 (72%) had benign adenoma, 25 (14.8%) had other benign lesions, and 8 (4.7%) patients had primary carcinoma of the parathyroid confirmed by pathology. Our mean serum calcium level was 11.57 mg/dL, which was lower than the mean level (12 mg/dL) for benign hyperparathyroidism. The mean tumor size was 2.18 cm, smaller than the proposed for malignant criteria, and none of the eight patients (0%) had any symptoms of hypercalcemia at the time of diagnosis. Seven of eight patients (87.5%) had frank signs of invasion together with other histological features, and two patients had associated papillary carcinoma of the thyroid. Five patients from our series did not meet clinical criteria for malignancy (tumor size > 3 cm, palpable mass, and serum calcium > 14 mg/dL), but had undisputable histological findings (high mitotic pattern, fibrous trabeculae, capsular invasion, vascular invasion, and nodular involvement). On the other hand, 17 patients with benign histology had tumors greater than 3 cm, and an additional 18 had palpable masses on physical examination. We believe that these patients need to be followed closely. The patients with diagnosis of parathyroid carcinoma, their kindred, and those with large adenomas may benefit from genetic screening for HRTP2 gene mutations in search of early detection of tumors suspicious for malignancy. This is based on the fact that we did not find correlation between the clinical presentation and the histological features in our patients with proven malignancy.     

Opioid-Volatile Anesthetic Synergy: A Response Surface Model with Remifentanil and Sevoflurane as Prototypes

Background: Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane.

Methods: Sixteen adult volunteers received a target-controlled infusion of remifentanil (0-15 ng/ml) and inhaled sevoflurane (0-6 vol%) at various target concentration pairs. After reaching pseudo-steady state drug levels, the Observer's Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observer's Assessment of Alertness/Sedation score >= 4) for anesthetics lasting 30-900 min.

Results: Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil.     

Preliminary results from the LUX-Dx insertable cardiac monitor remote programming and performance (LUX-Dx PERFORM) study

Despite the wide adoption of insertable cardiac monitors (ICMs), high false-positive rates, suboptimal signal quality, limited ability to detect atrial flutter, and lack of remote programming remain challenging. The LUX-Dx PERFORM study was designed to evaluate novel technologies engineered to address these issues. Here, we present preliminary results from the trial focusing on the safety of ICM insertion, remote monitoring rates, and the feasibility of remote programming. LUX-Dx PERFORM is a multicenter, prospective, single-arm, post-market, observational study with planned enrollment of up to 827 patients from 35 sites in North America. A preliminary cohort consisting of the first 369 patients who were enrolled between March and October 2021 was selected for analysis. Three hundred sixty-three (363) patients had ICM insertions across inpatient and outpatient settings. The mean time followed was 103.4 ± 61.8 days per patient. The total infection rate was 0.8% (3/363). Interim results show high levels of remote monitoring with a median 94% of days with data transmission (interquartile range: 82–99). Thirteen (13) in-clinic and 24 remote programming sessions were reported in 34 subjects. Reprogramming examples are presented to highlight signal quality, the ability to detect atrial flutter, and the positive impact of remote programming on patient management. Interim results from LUX-Dx PERFORM study demonstrate the safety of insertion, high data transmission rates, the ability to detect atrial flutter, and the feasibility of remote programming to optimize arrhythmia detection and improve clinical workflow. Future results from LUX-Dx PERFORM will further characterize improvements in signal quality and arrhythmia detection.     

Malignant melanoma and levodopa in Parkinson's disease: causality or coincidence?

Levodopa is the major drug used in the treatment of patients with Parkinson's disease. However, levodopa continues to be ‘contra-indicated’ for patients with Parkinson's disease associated with malignant melanoma. Case reports have suggested that levodopa has a causal relationship with malignant melanoma due to their shared dopamine biochemical pathway. Clinical characteristics of 54 patients with both Parkinson's disease and melanoma were analyzed (43 cases from the literature and 11 from our institution). The results suggest that the occurrence of both Parkinson's disease and melanoma in these patients is coincidental rather than causal. It did not appear that the Parkinson's disease patients on levodopa therapy were predisposed to melanoma, nor did levodopa therapy appear to exaggerate melanoma if it were previously present.     

Cerebrospinal fluid acetylcholinesterase and choline measurements in Huntington's disease

Summary The caudate nucleus has the highest acetylcholinesterase (AChE) activity in the brain and it has been shown that autopsied brain tissue of patients with Huntington's disease (HD) have reduced levels of acetylcholine. Because of these findings, the cholinergic function in HD was studied by measuring cerebrospinal fluid (CSF) choline levels and AChE activity during a randomized, double-blind, cross-over, placebo-controlled clinical trial of isoniazid. While mean choline levels adjusted for age were lower compared with controls (P=0.0007), AChE activity did not differ between HD patients and normal controls. Treatment with isoniazid had no significant effect on CSF choline levels or CSF AChE activity. CSF AChE activity showed a statistically significant increase with advancing age. The reduced level of choline in CSF of HD patients may reflect either a defect in choline transport into the brain or a decrease of choline-phospholipid output from the brain.