CD19 + CD21lo/neg cells are increased in systemic sclerosis-associated interstitial lung disease

Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017–6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21^lo/neg cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p = 0.002) or healthy controls (5.0 ± 0.5%, p < 0.0001). While CD21^lo/neg B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21^lo/neg cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21^lo/neg B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.

     

Nerve growth factor and substance P regulation in nasal sensory neurons after toluene diisocyanate exposure

Toluene diisocyanate (TDI) exposure produces rhinitis and nasal irritation, and increases the synthesis and release of substance P (SP) from airway sensory nerves. The mechanism leading to enhanced SP production following irritant inhalation remains unclear, but may involve actions of nerve growth factor (NGF). NGF binds trkA receptors located on sensory nerve terminals. Activation of trkA receptors initiates kinase-signaling cascades, which ultimately may increase SP. However, the effects of inhaled irritants on NGF release are not known. In this study, NGF levels in nasal lavages were examined following instillation of 10% TDI into both nasal cavities. NGF was significantly increased 2, 6, 12, and 24 h after TDI exposure compared with controls. The increase in NGF preceded the neuronal and mucosal increases in SP. Pretreatment with K252a, a nonselective tyrosine-kinase inhibitor, prevented the increase in SP-immunoreactivity in TG neurons and epithelial nerve fibers and the inflammatory response to TDI exposure. Because NGF binds to trkA tyrosine-kinase receptors, the NGF released during TDI exposure may mediate SP upregulation in airway sensory neurons, innervating the nasal cavity.     

Fetal expression of the angiotensinogen gene

To determine whether the angiotensinogen (Ao) gene is expressed in multiple organs of the fetal rat and the changes associated with maturation, fetal (15-20 days of gestation), newborn (1-10 days old), and adult (90 days old) rat tissues were subjected to Northern analysis and hybridization with a full length Ao complementary DNA (cDNA). Whereas Ao messenger RNA (mRNA) was undetectable in fetal livers, Ao sequences were readily detectable 1 h after birth and reached a peak at 24 h of birth. Levels remained elevated at 5 and 10 days after birth to decrease slightly at 90 days of postnatal life. Poly A+ enriched liver RNA was subjected to a similar analysis demonstrating that fetal liver Ao mRNA levels were 50-fold less than the corresponding adult levels. In contrast to the finding in the fetal liver, Ao mRNA was found in fetal brown fat, brains, and kidneys. We conclude that 1) Expression of the Ao gene is developmentally regulated in a tissue-specific manner; 2) Unlike the adult animal, the liver may not be the primary source of Ao in the fetus; 3) Alternate sources of Ao synthesis include fetal brown fat, brain, and kidneys.     

Study of the reproductive effects in rats surgically implanted with depleted uranium for up to 90 days

In 2001, the Naval Health Research Center Toxicology Detachment was funded by the U.S. Army Medical Research Acquisition Activity (USAMRAA) to conduct a study of the effects of surgically implanted depleted uranium (DU) pellets on adult rat reproductive success and development across two successive generations. This article presents some of the findings for the group of offspring from adult rats mated at 30 d post surgical implantation of DU pellets. Adult male and female Sprague-Dawley rats (P1 generation) were surgically implanted with 0, 4, 8, or 12 DU pellets (1 x 2 mm). The P1 generation was then cross-mated at 30 d post surgical implantation. Urine collected from P1 animals at 27 d post surgical implantation showed that DU was excreted in the urine of DU-implanted animals in a dose-dependent manner. DU surgical implantation did not have a negative impact on P1 reproductive success, survival, or body weight gain through post surgical implantation d 90. There were no statistically significant differences in F1 birth weight, survival, and litter size at postnatal day (PND) 0, 5, and 20. No gross physical abnormalities identified in the offspring were attributable to neonatal DU exposure. A series of neurodevelopment and immune function assessments were also conducted on F1 offspring. No group differences were observed that were related to parental DU exposure. Studies are ongoing on the impact of leaving DU embedded in soft tissue for 120 d on rat reproduction and subsequent offspring survival and development.     

Disposition of 2,6-di-tert-butyl-4-nitrophenol (DBNP), a submarine atmosphere contaminant, in male Sprague-Dawley rats

The phenol 2,6-di-tert-butyl-4-nitrophenol (DBNP) is a contaminant found onboard submarines and is formed by the nitration of an antioxidant present in turbine lubricating oil TEP 2190. DBNP has been found on submarine interior surfaces, on eating utensils and dishes, and on the skin of submariners. DBNP exposure is a potential health concern because it is an uncoupler of mitochondrial oxidative phosphorylation. Adult male rats were dosed once by oral gavage with 15 or 40 mg/kg DBNP mixed with 14C-DBNP in kanola oil and 0.8% v/v DMSO (n = 16/group). The distribution of 14C in major tissues was measured over time for up to 240 h post-dose. Unexpectedly, 6/16 (40%) of the rats gavaged with 40 mg/kg DBNP died within 24 h of dosing. Prostration, no auditory startle response, reduced locomotor activity, and muscular rigidity persisted in survivors for up to 8 days after dosing. For animals dosed with 15 mg/kg DBNP, radioactivity levels were significantly elevated in the following tissues 24h after dosing: fat>liver>kidneys>heart>lungs>brain>striated muscle>spleen. Radioactivity levels were elevated for fat, liver, kidney, heart, and lungs of animals euthanized 144 h post-dosing and in the liver of animals euthanized 240 h post-dosing. These findings suggest that DBNP may accumulate in the body as a result of continuous or repeat exposures of short interval to DBNP.     

Zonisamide monotherapy for epilepsy in children and young adults

Several of the newer antiepilepsy drugs have not been tested as monotherapy in controlled trials. Zonisamide is a broad-spectrum antiepilepsy drug indicated for the adjunctive treatment of partial seizures in adults. However, several small, open-label studies have indicated that it may be safe and effective as monotherapy. The present chart review study was conducted to evaluate the safety and effectiveness of zonisamide monotherapy in a pediatric and young adult patient group. Patient records at the Blue Bird Circle Clinic for Pediatric Neurology were reviewed to identify patients receiving zonisamide monotherapy. Efficacy was assessed from seizure diaries and patients' subjective evaluations. Safety and tolerability were evaluated by analysis of adverse events and change in body weight. The study included 131 patients aged 1 to 21.8 years with a broad spectrum of seizure types and epilepsy syndromes. A total of 101 patients (77.1%) achieved a 50% or greater decrease in seizure frequency, including 39 patients who achieved seizure freedom. Zonisamide monotherapy was well tolerated, with three patients (2.3%) discontinuing for adverse events. These results support open-label studies from Japan reporting that zonisamide monotherapy is safe and effective in pediatric and young adult patients.     

Dual pathology in Rasmussen's encephalitis: A study of seven cases and review of the literature

Dual pathology has previously been reported in less than 10% of cases of Rasmussen's encephalitis (RE). Given the rarity of RE, it appears unlikely that dual pathology in RE is merely a coincidence. We therefore reviewed all cases of RE experienced in our institution to assess for an additional/associated pathology. A total of seven patients with RE were identified in our archives. Seven children (4 boys and 3 girls, age range: 3–16 years, mean: 9.5 years) with medically refractory epilepsy underwent surgical resection for intractable seizures. The surgical specimens were examined with routine neurohistological techniques, and immunohistochemistry was performed with an extensive panel of antibodies for viruses, lymphocytes, microglia/macrophages, human leukocyte antigen (HLA)‐DR, astrocytes, and neurons. Relevant literature was reviewed. Microscopically, all seven cases demonstrated the inflammatory pathology of RE in the cortex and white matter with leptomeningeal and perivascular lymphocytic infiltration, microglial nodules with/without neuronophagia, neuronal loss and gliosis. The HLA‐DR antibody was extremely helpful in highlighting the extent of microglial cell proliferation/activation that was not appreciable with standard histology. An unexpected finding in all seven cases was the presence of cortical dysplasia. In our series of seven cases, there was co‐occurrence of the inflammatory/destructive pathology of RE with malformative/dysplastic features in cortical architecture in 100% of cases, raising questions about the possible relationships between the two entities. Awareness of the possibility of dual pathology in RE is important for clinical and pathological diagnosis, and may affect the management and outcome of these patients. Immunohistochemistry is very helpful to make a definitive diagnosis of both pathologies.     

Use of the newer antiepileptic drugs in pediatric epilepsies

Children with epilepsy, particularly infants, differ from adults not only in the clinical manifestations of their seizures but also in the presence of unique electroencephalographic patterns, etiologies, and response to antiepileptic drugs (AEDs). There is a growing list of newer AEDs and nonpharmacologic therapies available to manage childhood epilepsy. These newer AEDs may not be overall more efficacious than the older drugs, but they do appear to be safer, better tolerated, and to have fewer drug-drug interactions. Selection of the AED for initial therapy must be based upon clinical judgment and patient-specific circumstances, such as the specific epilepsy syndrome being treated, anticipated duration of treatment, presence of comorbidities, ability to use certain formulations, and overall cost effectiveness. In some cases, seizures may be aggravated by the use of certain AEDs. Overall, oxcarbazepine is the first-line treatment for localization-related epilepsy with partial-onset seizures. For generalized epilepsies, the AED choice is highly dependent upon which specific syndrome is being treated. For generalized epilepsies with primarily absence seizures, lamotrigine is the AED of first choice. For mixed generalized epilepsies such as Lennox-Gastaut syndrome or juvenile myoclonic epilepsy, zonisamide or topiramate are the first-line agents. For infants with West syndrome, treatment is based upon the underlying etiology: vigabatrin for tuberous sclerosis; adrenocorticotropic hormone for children with no specific etiology uncovered (cryptogenic); and zonisamide for those with a severe symptomatic etiology other than tuberous sclerosis. Single drug therapy (monotherapy) is the goal of epilepsy treatment because this is associated with better compliance, fewer adverse effects, and lower cost. If the seizures prove intractable or adverse effects are encountered with the first AED, then a second monotherapy trial is undertaken. Once three appropriate medications at therapeutic doses have failed, other modalities should be considered, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet.     

Decremental motor responses to repetitive nerve stimulation in ALS

Repetitive nerve stimulation (RNS) of the trapezius muscle at slow rates was performed on 192 patients with amyotrophic lateral sclerosis (ALS). Fifty-six patients (29%) showed classical neuromuscular decrement of 10–43% (mean 16.8%) while 44 patients (23%) had a borderline decrement of 5–9%. The trapezius was significantly more sensitive in revealing the defect than the distal hypothenar muscles. In 30 patients followed serially, the decremental response remained constant or increased with time. However, 25% of patients continued to show no decrement in spite of progression of disease. No statistical correlation was found between decrement and clinical severity, disease staging, or disease progression. The finding that at least 50% of ALS patients show some degree of decrement on RNS of the trapezius muscle suggests that functional alterations of the neuromuscular junction accompany this disease. © 1994 John Wiley & Sons, Inc.