Mild to moderate COVID-19 illness in adult outpatients: Characteristics, symptoms, and outcomes in the first 4 weeks of illness.

ABSTRACT: Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness.At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness.We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms.Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.

Why Does Clostridium difficile Infection Recur?

Clostridium (or Clostridioides) difficile infection affects more than 500,000 people annually in the United States, one-third of whom have recurrent symptoms. The evolution of C difficile as a resilient pathogen has to do with its ability to persist in the environment and in the host, leading to recurrence and environmental spread. Understanding the mechanisms by which this microbe interacts with the environment, the host, and the gut microbiota are critical to solving this problem. This article presents a brief clinical vignette; discusses the current state of understanding of colonization, transmission, and recurrence; and considers the role the host plays in eliminating this infection. The understanding of these mechanisms and application of osteopathic principles has the potential to improve patient outcomes.

Alcohol Consumption and Bone Mineral Density in People with HIV and Substance Use Disorder: A Prospective Cohort Study.

BACKGROUND: People living with HIV (PLWH) commonly have low bone mineral density (BMD) (low bone mass and osteoporosis) and are at high risk for fractures. Fractures and low BMD are significant causes of morbidity and mortality, increasingly relevant as PLWH age. Alcohol use is common among PLWH and known to affect bone health. The association between alcohol use and changes in BMD among PLWH is not well understood. METHODS: We conducted a 3.5-year prospective cohort study of 250 PLWH with substance use disorder or ever injection drug use. Annual alcohol consumption was measured as a mean of grams per day of alcohol, mean number of heavy drinking days per month, mean number of days abstinent per month, and any heavy drinking, using the 30-day Timeline Followback method twice each year. The primary outcome was annual change in BMD measured each year by dual energy X-ray absorptiometry in grams per square centimeter (g/cm2 ) at the femoral neck. Additional dependent variables included annual change in total hip and lumbar spine BMD, >6% annual decrease in BMD at any site, and incident fractures in the past year. Regression models adjusted for relevant covariates. RESULTS: The median age of participants was 50 years. The median duration of HIV infection was 16.5 years and the mean time since antiretroviral therapy initiation was 12.3 years. At study entry, 67% of participants met criteria for low BMD (46% low bone mass, 21% osteoporosis). Median follow-up was 24 months. We found no significant associations between any measure of alcohol consumption and changes in BMD (g/cm2 ) at the femoral neck (adjusted ß for g/d of alcohol = -0.0032, p = 0.7487), total hip, or lumbar spine. There was no significant association between any measure of alcohol consumption and >6% annual decrease in BMD at any site, or incident fractures. CONCLUSIONS: In this sample of PLWH and substance use disorders or ever injection drug use, we detected no association between any of the alcohol measures used in the study and changes in BMD or incident fractures.

Lifetime and recent alcohol use and bone mineral density in adults with HIV infection and substance dependence.

Low bone mineral density (BMD) is common in people living with HIV infection (PLWH), increasing fracture risk. Alcohol use is also common in PLWH and is a modifiable risk factor for both HIV disease progression and low BMD. In PLWH, alcohol's effect on BMD is not well understood.We studied adult PLWH with substance dependence. We measured lifetime alcohol use (kg) and recent (i.e., past 30-day) alcohol use (categorized as: abstinent, low risk, or high risk). In adjusted multivariable regression analyses, we tested associations between lifetime and recent alcohol use and (i) mean BMD (g/cm) at the femoral neck, total hip, and lumbar spine and (ii) low BMD diagnosis (i.e., osteopenia or osteoporosis). We also examined associations between 2 measures of past alcohol use (i.e., total consumption [kg] and drinking intensity [kg/year]) and BMD outcome measures during 3 periods of the HIV care continuum: (i) period before first positive HIV test, (ii) period from first positive HIV test to antiretroviral therapy (ART) initiation, and (iii) period following ART initiation.We found no significant associations between lifetime alcohol use and mean femoral neck (ß -0.000, P = .62), total hip (ß -0.000, P = .83) or lumbar spine (ß 0.001, P = .65) BMD (g/cm), or low BMD diagnosis (adjusted odds ratio [aOR] = 0.98, 95% Confidence Interval [CI]: 0.95-1.01). There was no significant correlation between past 30-day alcohol use and mean BMD (g/cm). Past 30-day alcohol use was associated with low BMD diagnosis (P = .04); compared to abstainers, the aOR for high risk alcohol use was 1.94 (95% CI: 0.91-4.12), the aOR for low risk alcohol use was 4.32 (95% CI: 1.30-14.33). Drinking intensity (kg/year) between first positive HIV test and ART initiation was associated with lower mean BMD (g/cm) at the femoral neck (ß -0.006, P = .04) and total hip (ß -0.007, P = .02) and increased odds of low BMD (aOR = 1.18, 95% CI = 1.03-1.36).In this sample of PLWH, we detected no association between lifetime alcohol use and BMD. However, recent drinking was associated with low BMD diagnosis, as was drinking intensity between first positive HIV test and ART initiation. Longitudinal studies should confirm these associations.

Neuroinvasive St. Louis Encephalitis Virus Infection in Solid Organ Transplant Recipients.

In summer 2015, three unrelated solid organ transplant recipients in Phoenix, Arizona, had meningoencephalitis suggestive of West Nile virus (WNV) infection. Testing was inconclusive but was later confirmed as St. Louis encephalitis (SLE). We retrospectively reviewed clinical manifestations, treatment, and outcomes of these transplant recipients. Common symptoms were fever, rigors, diarrhea, headache, and confusion. One patient died 3 days after hospitalization. Therapy for the other two patients was initiated with interferon α-2b (IFN) and intravenous IgG (IVIG; IFN plus IVIG in combination). Both patients tested positive for WNV by serologic assay, but SLE virus (SLEV) infection was later confirmed by plaque reduction neutralization test at a reference laboratory. Clinical improvement was observed within 72 h after initiation of IFN plus IVIG. SLEV has been an uncommon cause of neuroinvasive disease in the United States. Accurate, timely diagnosis is hindered because of clinical presentation similar to neuroinvasive WNV and SLE, serologic cross-reactivity, and lack of a commercially available serologic assay for SLEV. There is currently no approved therapy for flaviviral neuroinvasive disease. Anecdotal reports indicate varying success with IFN, IVIG, or IFN plus IVIG in WNV neuroinvasive disease. The same regimen might be of value for immunocompromised persons with neuroinvasive SLEV infection.

Screening and brief intervention for drug use in primary care: the ASPIRE randomized clinical trial.

IMPORTANCE: The United States has invested substantially in screening and brief intervention for illicit drug use and prescription drug misuse, based in part on evidence of efficacy for unhealthy alcohol use. However, it is not a recommended universal preventive service in primary care because of lack of evidence of efficacy. OBJECTIVE: To test the efficacy of 2 brief counseling interventions for unhealthy drug use (any illicit drug use or prescription drug misuse)-a brief negotiated interview (BNI) and an adaptation of motivational interviewing (MOTIV)-compared with no brief intervention. DESIGN, SETTING, AND PARTICIPANTS: This 3-group randomized trial took place at an urban hospital-based primary care internal medicine practice; 528 adult primary care patients with drug use (Alcohol, Smoking, and Substance Involvement Screening Test [ASSIST] substance-specific scores of ≥4) were identified by screening between June 2009 and January 2012 in Boston, Massachusetts. INTERVENTIONS: Two interventions were tested: the BNI is a 10- to 15-minute structured interview conducted by health educators; the MOTIV is a 30- to 45-minute intervention based on motivational interviewing with a 20- to 30-minute booster conducted by master's-level counselors. All study participants received a written list of substance use disorder treatment and mutual help resources. MAIN OUTCOMES AND MEASURES: Primary outcome was number of days of use in the past 30 days of the self-identified main drug as determined by a validated calendar method at 6 months. Secondary outcomes included other self-reported measures of drug use, drug use according to hair testing, ASSIST scores (severity), drug use consequences, unsafe sex, mutual help meeting attendance, and health care utilization. RESULTS: At baseline, 63% of participants reported their main drug was marijuana, 19% cocaine, and 17% opioids. At 6 months, 98% completed follow-up. Mean adjusted number of days using the main drug at 6 months was 12 for no brief intervention vs 11 for the BNI group (incidence rate ratio [IRR], 0.97; 95% CI, 0.77-1.22) and 12 for the MOTIV group (IRR, 1.05; 95% CI, 0.84-1.32; P = .81 for both comparisons vs no brief intervention). There were also no significant effects of BNI or MOTIV on any other outcome or in analyses stratified by main drug or drug use severity. CONCLUSIONS AND RELEVANCE: Brief intervention did not have efficacy for decreasing unhealthy drug use in primary care patients identified by screening. These results do not support widespread implementation of illicit drug use and prescription drug misuse screening and brief intervention. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00876941.

Fulminant hepatitis due to human adenovirus.

PURPOSE: To describe the demographics, clinical manifestations, treatment and outcomes of patients with human adenovirus (HAdV) hepatitis. METHODS: A case of fulminant HAdV hepatitis in a patient with chronic lymphocytic leukemia receiving rituximab and fludarabine is described. We conducted a comprehensive review of the English-language literature through May, 2012 in search of definite cases of HAdV hepatitis. RESULTS: Eighty-nine cases were reviewed. Forty-three (48 %) were liver transplant recipients, 19 (21 %) were bone marrow transplant recipients, 11 (12 %) had received chemotherapy, five (6 %) had severe combined immunodeficiency, four (4 %) were HIV infected, two had heart transplantation, and two were kidney transplant recipients. Ninety percent (46/51) of patients presented within 6 months following transplantation. Fever was the most common initial symptom. Abdominal CT scan revealed hypodense lesions in eight of nine patients. Diagnosis was made by liver biopsy in 43 (48 %), and on autopsy in 46 (52 %). The HAdV was isolated at other sites in 54 cases. Only 24 of 89 patients (27 %) survived: 16 whose immunosuppression was reduced, six with liver re-transplantation, and two who received cidofovir and intravenous immunoglobulin. CONCLUSION: HAdV hepatitis can manifest as a fulminant illness in immunocompromised hosts. Definitive diagnosis requires liver biopsy. Early consideration of a viral etiology, reduction in immunosuppression, and liver transplantation can be potentially life-saving.

Chronic care management for dependence on alcohol and other drugs: the AHEAD randomized trial.

IMPORTANCE: People with substance dependence have health consequences, high health care utilization, and frequent comorbidity but often receive poor-quality care. Chronic care management (CCM) has been proposed as an approach to improve care and outcomes. OBJECTIVE: To determine whether CCM for alcohol and other drug dependence improves substance use outcomes compared with usual primary care. DESIGN, SETTING, AND PARTICIPANTS: The AHEAD study, a randomized trial conducted among 563 people with alcohol and other drug dependence at a Boston, Massachusetts, hospital-based primary care practice. Participants were recruited from September 2006 to September 2008 from a freestanding residential detoxification unit and referrals from an urban teaching hospital and advertisements; 95% completed 12-month follow-up. INTERVENTIONS: Participants were randomized to receive CCM (n=282) or no CCM (n=281). Chronic care management included longitudinal care coordinated with a primary care clinician; motivational enhancement therapy; relapse prevention counseling; and on-site medical, addiction, and psychiatric treatment, social work assistance, and referrals (including mutual help). The no CCM (control) group received a primary care appointment and a list of treatment resources including a telephone number to arrange counseling. MAIN OUTCOMES AND MEASURES: The primary outcome was self-reported abstinence from opioids, stimulants, or heavy drinking. Biomarkers were secondary outcomes. RESULTS: There was no significant difference in abstinence from opioids, stimulants, or heavy drinking between the CCM (44%) and control (42%) groups (adjusted odds ratio, 0.84; 95% CI, 0.65-1.10; P=.21). No significant differences were found for secondary outcomes of addiction severity, health-related quality of life, or drug problems. No subgroup effects were found except among those with alcohol dependence, in whom CCM was associated with fewer alcohol problems (mean score, 10 vs 13; incidence rate ratio, 0.85; 95% CI, 0.72-1.00; P=.048). CONCLUSIONS AND RELEVANCE: Among persons with alcohol and other drug dependence, CCM compared with a primary care appointment but no CCM did not increase self-reported abstinence over 12 months. Whether more intensive or longer-duration CCM is effective requires further investigation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00278447.

Opportunistic infections in patients with pulmonary alveolar proteinosis.

OBJECTIVES: To describe the demographics, clinical manifestations, treatment, and outcomes of patients with pulmonary alveolar proteinosis (PAP) who developed an opportunistic infection with Nocardia spp., mycobacteria or fungal pathogens. METHODS: A case of PAP and Nocardia spp. brain abscess is described. A comprehensive review of the English-language literature was conducted to identify all reported cases of PAP and opportunistic infections between 1950 and July, 2010. RESULTS: Seventy five cases were reviewed. Thirty two patients (43%) had nocardial infection, 28 (37%) mycobacterial infection, and 15 (20%) fungal infection. Thirty nine patients (65%) were male. Seventeen patients (23%) were immunosuppressed. Twenty patients (27%) were active smokers. PAP was the initial diagnosis in 19 patients (33%), while infection presented first in 23 patients (40%); 16 patients (27%) had a concurrent diagnosis of PAP and infection. The average interval between PAP diagnosis and an opportunistic infection was 16 months. Lungs were the most common site of infection; extra-pulmonary infection was present in 27 patients (32%). Thirty nine patients (57%) survived through the follow-up period, while 31 died. CONCLUSIONS: Opportunistic infections can either precede or follow a diagnosis of PAP. PAP should be considered in apparently immunocompetent patients who present with an opportunistic infection and diffuse alveolar infiltrates.

A whole new way of looking at things: the use of Dark Reader technology to detect fluorophors.

The Dark Reader optical system (Clare Chemical Research, Denver, CO, USA) uses relatively low intensity broad-band visible blue light in combination with broad-band optical filters to detect fluorescence with a level of sensitivity that often surpasses that of UV transilluminators and can rival that of laser-based scanners. Applications of DR (Clare Chemical Research) devices include the detection of DNA and SYBR-stained protein samples following, and also during, electrophoresis. Unlike laser-based imaging systems, the fluorescence is directly visible to the user as well as being fully compatible with charge-coupled device (CCD) and Polaroid camera-based detection and imaging. Additionally, the DR optical system functions well in multicolor fluorophor environments. Because the Dark Reader does not emit any UV light, the extent of DNA damage incurred when visualizing DNA samples is drastically reduced compared to the damage produced by a UV device and this can have a significant benefit on downstream cloning protocols. Furthermore, dye photobleaching is minimal, extending the length of time that a fluorescent sample is visible. The inherent flexibility of the DR optical system allows many different configurations of the Dark Reader to be constructed such as transilluminators, hand lamps and integrated transilluminator-electrophoresis units.

A DNA polymerase III holoenzyme-like subassembly from an extreme thermophilic eubacterium.

We have purified a novel DNA polymerase from Thermus thermophilus. This was enabled by use of general gap filling assays to monitor polymerase activity and cross-reactive monoclonal antibodies against the alpha catalytic subunit of E. coli DNA polymerase III holoenzyme to distinguish a novel polymerase from the well characterized DNA polymerase I-like Thermus thermophilus DNA polymerase. Two proteins migrating with the polymerase after three chromatographic steps were isolated and subjected to partial amino acid sequencing. The amino termini of both were homologous to the two products of the E. coli dnaX gene, the gamma and tau subunits of the DNA polymerase III holoenzyme. Using this information and sequences conserved among dnaX-like genes, we isolated a gene fragment by PCR and used it as a probe to isolate the full length Thermus thermophilus dnaX gene. The deduced amino acid sequence is highly homologous to the DnaX proteins of other bacteria. Examination of the sequence permitted identification of a frameshift site similar to the one used in E. coli to direct the synthesis of the shorter gamma DnaX-gene product. Based on this information, we conclude that a conventional replicase exists in extreme thermophilic eubacteria. The general biological and practical technological implications of this finding are discussed.

Fluorometric assay for DNA polymerases and reverse transcriptase.

We report a quick, easy and inexpensive fluorometric assay that measures the activity of replication enzymes using Pico-GreenTM. The systems tested include replication of the natural template M13 Gori by E. coli DNA polymerase III holoenzyme and the replication of a synthetic homopolymer by human immunodeficiency virus reverse transcriptase. A direct comparison of the fluorometric assay with the conventional isotopic assay shows that the fluorometric assay accurately reflects the extent of replication. By performing the assay reactions directly in 96-well plates and using a fluorescence plate reader to determine the extent of reaction, the time required to measure replication activities is significantly shortened.

Early metabolic changes during m-Dinitrobenzene neurotoxicity and the possible role of oxidative stress.

m-Dinitrobenzene (m-DNB) is an industrial chemical causing gliovascular lesions in the brain stem similar to those produced by nitroimidazoles and by thiamine deficiency. To identify early preneuropathic indices of toxicity we examined the action of m-DNB on glycolysis and on measures of oxidative stress in the brain both in vivo and in vitro. Significant increases in local cerebral glucose utilization were seen in 14 of 30 brain regions prior to development of lesions. Rat brain astrocyte cultures also showed increases in both glucose consumption and lactic acid formation in the first 24 h following exposure to 0.5 mM m-DNB and prior to the development of cytotoxicity. The concentration of reduced glutathione in these cultures was decreased to about half of control values over a 2-h incubation period, indicating an early disturbance of redox balance. The rate of reduction of nitroblue tetrazolium increased eightfold during a 1-h incubation period, suggesting a free radical-mediated process. Superoxide dismutase partially prevented this increase, although other protective agents failed to do so possibly due to lack of cellular penetration. These observations show that m-DNB neurotoxicity involves early metabolic stimulation and redox disruption that may be causally associated with the production of free radicals.

Movement of the F40 domain of flagellin during the morphological transition of bacterial flagella.

Flagella from Salmonella typhimurium were labeled with various amounts of fluorescein isothiocyanate. The site of labeling was identified as being predominantly in the exterior F40 domain. The fluorescence intensity decreased as the fluorescein density on the flagella increased, indicating self energy transfer between fluoresceins. The fluorescence of modified flagella was measured during the normal-to-curly morphological transition induced by alkaline pH. The morphological transition itself was simultaneously monitored by dark-field microscopy. Concomitant with the transition was a 25% increase in fluorescence for flagella heavily labeled with fluorescein. This was shown to be due to a decrease in the efficiency of energy transfer between fluoresceins on proximal flagellin subunits, implying that the F40 domains undergo relative movement apart during the morphological transition. Closer inspection of the domain movement and morphological transition as a function of pH reveals that the two processes are not exactly concomitant. This indicates the existence of intermediates during the transition. The fluorescence technique, outlined here, provides a means of directly monitoring an organizational 'switch' in the flagellin subunits during the actual morphological transition of flagella.

beta-Amyloid precursor protein fragments and lysosomal dense bodies are found in rat brain neurons after ventricular infusion of leupeptin.

Infusion of the serine and thiol protease inhibitor, leupeptin, is known to cause a reduction of fast axoplasmic transport, and accumulation of lysosomal dense bodies in neuronal perikarya. We have found these dense bodies in hippocampal and cerebellar neurons contain ubiquitin conjugated proteins. We now demonstrate that these accumulated neuronal lysosomes are labeled by antisera to the cytoplasmic, transmembrane and extracellular domains of beta-amyloid precursor protein (APP) and also that lysosomal APP is fragmented. This in vivo model confirms that neurons can process APP via a lysosomal pathway and that neuronal lysosomes in vivo contain both N-terminal and potentially amyloidogenic C-terminal fragments of APP. We also show that increased APP immunoreactivity after leupeptin treatment is seen first in neurons and later in astrocytes. On recovery from infusion, APP N-terminal immunoreactivity diminishes whilst C-terminal reactivity remains in neurons. These findings are consistent with production in whole brain of potentially amyloidogenic fragments of APP within neuronal lysosomes in perikarya and dendrites implying that neurons may play a role in forming the beta-amyloid of plaques.

Significant improvement to the catalytic properties of aspartate aminotransferase: role of hydrophobic and charged residues in the substrate binding pocket.

The substrate specificity of tyrosine aminotransferase (eTAT) from Escherichia coli has been tested by transferring the critically different residues Leu39, Glu141, and Arg293 into equivalent positions of aspartate aminotransferase (eAAT). These residues are not directly involved in the catalytic process. The single mutant eAAT V39L possesses greater values of kcat/KM not only for tyrosine but also for aspartate and glutamate. In contrast, the double mutant eAAT P141E,A293R and also the triple mutant eAAT V39L,P141E,A293R exhibit smaller changes of kcat/KM. The converse mutants of tyrosine aminotransferase, in which critical residues of eAAT (Val39) and of mitochondrial AAT (Ala39, Val37) were transferred into equivalent positions of eTAT, exhibited generally decreased values of kcat/KM for both dicarboxylic and aromatic substrates. On the basis of the known structures of eAAT and eAAT V39L as well as of a refined model of eTAT, these results indicate that the different substrate specificities of eAAT and eTAT are due to multiple side chain differences and minor rearrangements of the backbone. The generally improved catalytic efficiency of the mutant eAAT V39L appears to be due to an indirect effect, namely, the facilitated closure of the active site upon substrate binding.

The effect of sugars on the morphology of the bacterial flagellum.

Using dark-field microscopy, we have found that certain sugars cause the normal-to-curly helical transition of bacterial flagella. Titration of flagella isolated from Salmonella typhimurium with 16 different carbohydrates showed that: (i) only certain sugars cause the transition. There is no obvious relationship between the simple physico-chemical properties of the sugar and whether the sugar causes the transition or not; (ii) the efficacies of sugars that do cause the transition differ markedly. For these sugars there is a relationship between efficacy and molecular size. These results suggest that the specific, though weak, binding of sugars to sites on flagella cause the morphological transition.

Routes of excretion of neuronal lysosomal dense bodies after ventricular infusion of leupeptin in the rat: a study using ubiquitin and PGP 9.5 immunocytochemistry.

To determine the rate and routes of removal of lysosomal, lipofuscin-like dense bodies from neurons, the protease inhibitor, leupeptin, was infused into the lateral ventricle of rats for up to nine days. After seven days a number of animals were then allowed to recover. The formation and later disappearance of dense bodies was followed by morphology and immunocytochemistry. After 48 h of infusion lysosomal dense bodies in large numbers appeared in cortical, hippocampal and cerebellar neurons, which also showed increased ubiquitin immunoreactivity, as well as in other cell types. By 3-4 days ubiqutin-immunoreactive dense bodies were equally distributed between neurons and astroglia. After seven to nine days of infusion ubiquitin immunoreactive dense bodies filled neuronal perikarya, dendrites and expanded initial segments of many axons and were abundant in glial processes. All dense bodies studied by electron microscopy were ubiquitin immunoreactive. After four days of recovery dense bodies were markedly fewer in neuronal perikarya, and virtually all were now within glial processes. From 7 to 28 days of recovery, when most neurons appeared normal, lipofuscin bodies remained in axon initial segments and in reduced numbers in glial processes, particularly around blood vessels and beneath the pia of hippocampus and of cerebellar cortex. Thus, neurons probably have a steady passage of short lived proteins through the lysosomal excretory pathway. The observed temporal sequence of events on recovery suggests that secondary lysosomes probably pass rapidly from neuronal perikarya and dendrites to astrocytes and thus to the vascular bed or pia-arachnoid. The mechanism of cell-to-cell transfer is not clear from this study.

The neurotoxicity of alpha-chlorohydrin in rats and mice: I. Evolution of the cellular changes.

Mice and rats are found to be equally susceptible to developing symmetrical brain stem lesions on exposure to alpha-chlorohydrin and in both species the earliest neurotoxic changes are strictly confined to glial cells, particularly astrocytes; haemorrhages are not found in either species. Minimal evidence of increased vascular leakage of horse-radish peroxidase (HRP) in rats is shown by increased HRP content of perivascular cells within the lesions. Later macrophage invasion and capillary proliferation is accompanied by rare focal leakiness of HRP. Gross astrocytic damage, therefore, does not necessarily impair integrity of the blood-brain barrier. While early in intoxication, astrocytes are severely distended with fluid and their organelles seriously disorganized, they do not die but rapidly regenerate their processes. They thus appear to undergo a process of 'clasmatodendrosis' from which they recover. Comparisons are made with the genesis of symmetrical brain stem lesions in other acute energy deprivation syndromes, including Wernicke's encephalopathy.

Vascular factors in the neurotoxic damage caused by 1,3-dinitrobenzene in the rat.

Using a 3 x 10 mg/kg dose schedule of 1,3-dinitrobenzene (DNB) over two days in Fischer rats, we have found the following changes in vascular function and structure during the early phase of the symmetrical brain stem lesions. 1. Marked increase in cerebral blood flow generally but especially in the inferior colliculi, from 6 h after the final dose of DNB. 2. Increasing incidence of petechial haemorrhages in inferior colliculi, cerebellar roof, vestibular and superior olivary nuclei from 12 h. 3. Focal leakage of horseradish peroxidase and many sleeve-like arteriolar haemorrhages seen in vibratome sections and by scanning electron microscopy (SEM) in these regions from 12 h. 4. Periarteriolar oedema and protein leakage present in step-serial sections in these regions from 12 h, with astrocyte swelling and occasional small infarcts. These changes suggest that the vascular bed may play an important role in the pathogenesis of these lesions, perhaps in parallel with early astroglial damage. They are discussed in relation to (i) the known presence of xanthine oxidase in the vascular bed of the brain and the likelihood of "useless redox cycling' with free radical generation from this enzyme's interaction with nitroheterocyclic compounds, and (ii) the possible role of free radical damage to endothelial cells in this intoxication and in the analogous lesions of natural and experimental Wernicke's encephalopathy.