Geography but not alternative host species explain the spread of raccoon rabies virus in Vermont.

In North America, the raccoon-associated variant of rabies virus (RRV) is of special concern, given its relatively rapid spread throughout the eastern USA and its potential public health impact due to high raccoon host densities in urban areas. Northward expansion of this epizootic included an outbreak in the Canadian province of Quebec in 2006-2009 due to trans-border spread from the State of Vermont. To inform a more proactive approach to future control efforts, this study uses phylogenetic analyses to explore the role of geography and alternative carnivore hosts in the dynamics of RRV spread within Vermont. Specifically, we sought to examine whether striped skunks, a species frequently infected by RRV, could be part of the maintenance host community. Whole genome sequencing of 160 RRV samples from Vermont and neighbouring US states were used for fine-scale phylogeographic analyses. Results, together with the complete surveillance record of raccoon rabies since its entry into Vermont in 1994, document incursions by two distinct viral lineages and identify topographical features of the landscape which have significantly influenced viral spread, resulting in a complex distribution pattern of viral variants throughout the state. Results of phylogenetic cluster analysis and discrete state reconstruction contained some evidence of skunk-to-skunk and skunk-to-raccoon transmission but overall failed to support a role for skunks as alternative maintenance hosts.

Human immune response to immunization with a structurally defined polypeptide fragment of streptococcal M protein.

We tested the ability of pepsin-extracted, highly purified M protein to induce type-specific immunity in experimental animals and humans. M protein was prepared from limited peptic digests of whole group A type 24 streptococci and was purified to chemical homogeneity as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, quantitative amino acid analysis, and Edman degradation. For vaccination, the lyophilized M24 protein preparation (pep M24) was precipitated in aluminum hydroxide. When injected into laboratory animals, alum-precipitated pep M24 produced type-specific protective antibodies and was free of non-type-specific immunoreactivity. In man, skin tests with 1-microgram doses of pep M24 were negative in all 37 adults tested. 12 adult human volunteers received two-four subcutaneous injections of 100-200 micrograms of alum-precipitated pep M24 at intervals of at least 2 wk. The immune response to pep M24 was measured by a variety of assays designed to detect (a) type-specific humoral antibodies (opsonophagocytic, long chain, and mouse protection tests); (b) total humoral antibodies (complement fixation and enzyme-linked immunosorbent assay); (c) cellular immunity (skin tests); and (d) heart cross-reactive antibodies (immunofluorescence). Type-specific opsonic antibodies developed in 10 of the 12 vaccinees, and positive delayed-type skin tests developed in 11. Immune sera from two of the vaccinees were effective in mouse-protection tests against challenge with M24 but not M6 streptococci. None of the volunteers developed heart-reactive antibodies or antibodies to non-type-specific M protein antigens. Alum-precipitated pep M24 was well-tolerated in man, and no serious local or systemic reactions were observed. Thus, pep M24 induces type-specific, protective antibodies in doses that are well-tolerated in man.

Mineralogy and geochemistry of efflorescent minerals on mine tailings and their potential impact on water chemistry.

In the gold mining Witwatersrand Basin of South Africa, efflorescent mineral crusts are a common occurrence on and nearby tailings dumps during the dry season. The crusts are readily soluble and generate acidic, metal- and sulphate-rich solutions on dissolution. In this study, the metal content of efflorescent crusts at an abandoned gold mine tailings dump was used to characterise surface and groundwater discharges from the site. Geochemical modelling of the pH of the solution resulting from the dissolution of the crusts was used to better understand the crusts' potential impact on water chemistry. The study involved two approaches: (i) conducting leaching experiments on oxidised and unoxidised tailings using artificial rainwater and dilute sulphuric acid and correlating the composition of crusts to these leachates and (ii) modelling the dissolution of the crusts in order to gain insight into their mineralogy and their potential impact on receiving waters. The findings suggested that there were two chemically distinct discharges from the site, namely an aluminium- and magnesium-rich surface water plume and an iron-rich groundwater plume. The first plume was observed to originate from the oxidised tailings following leaching with rainwater while the second plume originated from the underlying unoxidised tailings with leaching by sulphuric acid. Both groups of minerals forming from the respective plumes were found to significantly lower the pH of the receiving water with simulations of their dissolution found to be within 0.2 pH units of experimental values. It was observed that metals in a low abundance within the crust (for example, iron) had a stronger influence on the pH of the resulting solutions than metals in a greater abundance (aluminium or magnesium). Techniques such as powder X-ray diffraction (PXRD) and in situ mineral determination techniques such as remote sensing can effectively determine the dominant mineralogy. However, the minerals or metals incorporated through solid solution into bulk mineralogy that dominates the chemistry of the solutions upon their dissolution may occur in minor quantities that can only be predicted using chemical analysis. Their mineralogy can be predicted using geochemical modelling and can provide a set of hypothetical minerals that upon dissolution yield a solution similar to that of the actual crusts. This realisation has a bearing on decision-making such as in risk assessment and designing pollutant mitigation strategies.

Diagnosis of miliary tuberculosis by cerebral computerized tomography.

We report a case of miliary tuberculosis with symptoms and signs of an intracranial mass. These were found to be multiple tuberculomas by computerized axial tomography (CT scan). We review the pathophysiologic features of intracranial tuberculomas. The CT scan allows a rapid and sensitive diagnosis of intracranial tuberculosis without utilizing invasive neurodiagnostic techniques. The value of using CT scans following treatment was confirmed.

Invasive sinusitis with intracranial extension caused by Curvularia lunata.

Curvularia lunata has previously been linked to localized sinus infection in immunocompetent hosts. We treated a case of pansinusitis with extensive bone destruction and intracranial extension caused by C lunata. Curvularia lunata was identified when typical fungal macroconidia appeared on culture. Numerous surgical procedures, in addition to a 12-month course of antifungal therapy consisting of 4 g of intravenous amphotericin B and an 8-month course of 400 mg of oral ketoconazole daily, were required to control the infection. This unusual case of invasive sinusitis caused by C lunata alerts the treating physician to the presence of this mold and gives an overview of diagnostic method as well as the management.

Fluconazole therapy in coccidioidal meningitis maintained with intrathecal amphotericin B.

BACKGROUND: Meningitis follows approximately 0.15% to 0.75% of cases of extrapulmonary coccidioidomycosis. Successful treatment of coccidioidal meningitis (CM) has generally required intrathecal therapy with amphotericin B, which often causes significant toxic effects and discomfort to the patient. Prior to fluconazole, azoles had not been efficacious in CM either because of toxicity at elevated doses or because of poor cerebrospinal fluid distribution. Fluconazole however, has been found to have both good cerebrospinal fluid penetration and a favorable side effect profile. METHODS: We studied 11 patients with CM who were maintained with amphotericin B and were then switched to oral fluconazole therapy alone at a dosage of 400 mg/d for a period of up to 19 months. The patients were evaluated clinically for evidence of deterioration measured by need for hospitalization, development of extrameningeal disease during the study period, need to reinstitute intrathecal amphotericin B therapy because of worsening disease, cerebrospinal fluid leukocyte count, protein level, and serologic tests for complement-fixing antibody. RESULTS: Three patients required hospitalization during the study, two patients for reasons unrelated to CM. No patient developed extrameningeal disease or required discontinuation of fluconazole therapy because of deteriorating disease. Patients at exit reported no symptoms related to meningitis or adverse effects related to fluconazole therapy. There was no deterioration in general health or neurologic status. CONCLUSIONS: Our study demonstrates that conversion from amphotericin B to fluconazole was associated with a stable disease course of CM for up to 19 months. Further studies delineating both optimal dosage and characteristics of patients likely to respond to fluconazole therapy alone are needed.

Disability in multiple sclerosis and the provision of social and medical services: findings in Wellington, New Zealand.

A study of the incapacity and socioeconomic scales in 120 patients with multiple sclerosis (MS) living in Wellington, New Zealand, is described. The questionnaire has been compared by different health professionals. There was good correlation between the observations of different professionals on incapacity analysis and this may be improved by reducing the questions to six. The findings on the socioeconomic scale, however, cannot be predicted accurately from the incapacity scale. The socioeconomic survey revealed major improvement in patient support in New Zealand during the last decade. We consider that our New Zealand findings indicate the value of field officers concerned with co-ordination of services and provision of information for patients with MS. Future research should be directed towards assessment of support systems.

Effects of ethanol on plasma catecholamines and norepinephrine clearance.

Plasma catecholamines were measured in nine men after they had drunk either 0.5 or 1 ml/kg ethanol. Ethanol was found to induce a dose-dependent rise in plasma norepinephrine concentrations. Epinephrine concentrations were also raised in the initial intoxication phase. To determine whether ethanol raises plasma norepinephrine through increased release or decreased clearance (Cl), we infused norepinephrine into eight male subjects with and without prior ethanol, each subject acting as his own control. During infusions after ethanol, norepinephrine concentrations rose higher, and the mean circulatory Cl of norepinephrine was reduced from 76 to 47 ml/kg/min. This was associated with a prolongation of norepinephrine t 1/2 from 1.7 to 2.05 min. No significant difference in circulatory input of norepinephrine was found between infusions with and without ethanol. These results indicate that ethanol consumption increases plasma norepinephrine by reducing its circulatory Cl.

Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection.

To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours [AUC(0-8)] for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x h, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC(0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.

Comparative trial of valproate sodium and clonazepam in chronic epilepsy.

A crossover comparative study of valproate sodium and clonazepam in the treatment of 32 adult epileptic patients receiving multiple drug therapy is described. Serum concentrations of other anticonvulsant drugs were unchanged by the addition of clonazepam. However, patients receiving high doses of other anticonvulsant drugs had lower serum concentrations of clonazepam (p less than .01). With valproate sodium, phenobarbital concentrations increased (P less than .05) in patients receiving phenobarbital but not significantly in patients receiving primidone. Phenytoin concentrations were reduced (P less than .05) during treatment with valproate sodium. Both drugs significantly reduced the frequency of minor seizures, with valproate sodium having the greater effect. However, it is important to monitor serum concentrations of other anticonvulsant drugs during treatment with valproate sodium since changes in these may influence seizure control or cause side effects.

Visceral fungal infections due to Petriellidium boydii (allescheria boydii). In vitro drug sensitivity studies.

Four patients with visceral infections due to the fungus Petriellidium boydii, who were recently hospitalized in our institutions, are described. Three of the patients were compromised hosts; in the fourth patient, infection occurred after trauma. All had received prior steroid and antibiotic therapy. Studies of patients with mycetoma or secondary infection of a pulmonary cavity due to this organism and of patients with visceral infections are reviewed. Because of histologic similarities to Aspergillus species, infections due to P. boydii may have been misdiagnosed in the past if the infecting fungus was not isolated in culture. The fungus has been shown to be resistant in vitro to currently available antifungal agents. Resistance to amphotericin and 5-fluorocytosine is demonstrated in our studies. There are few reports of successful chemotherapy of any manifestation of this infection, and no such reports of visceral disease. We demonstrate in vitro sensitivity of isolates in our cases and in others to micronazole, a new antimicrobial agent; this drug may be indicated for treatment of disease due to P. boydii.

Drugs and folate metabolism.

Folates are a group of compounds which are required in the diet and are important in DNA, amino acids and possibly also amine metabolism. The biologically active folates are in the tetrahydro form. Tetrahydrofolates are produced from unreduced dietary folates by the enzyme dihydrofolate reductase. A number of drugs such as aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim and triamterene act as folate antagonists and produce folate deficiency by inhibiting this enzyme. With other drugs which produce low serum and tissue concentrations of folate such as anticonvulsants, antituberculosis drugs, alcohol and oral contraceptives, the mechanism of this effect is uncertain. Possible mechanism include reduced absorption, prevention of release of folate from tissue stores, altered plasma protein binding, or increased folate metabolism in the liver. Treatment with folic acid antagonists such as methotrexate readily causes megaloblastic anaemia; this can be prevented by therapy with folinic acid (5-formyltetrahydrofolate). The role of other drugs in producing megaloblastic anaemia is less certain, e.g. it occurs in less than 0.75% of patients receiving anticonvulsants. The possible neurological and psychiatric effects of folate deficiency are also uncertain. However, in patients with folate deficiency who have neuropsychiatric symptoms, neuropathy or myelopathy, and normal vitamin B12 levels, it may be of value to try therapy with folic or folinic acid.

Radiation retinopathy after orbital irradiation for Graves' ophthalmopathy.

Recent reports indicate that orbital irradiation for Graves' ophthalmopathy is sometimes beneficial, particularly for dysthyroid optic neuropathy, and is not associated with serious complications. We are aware, however, of four patients who were found to have radiation retinopathy after orbital irradiation for Grave's ophthalmopathy. All four patients have decreased central acuity, and three of the four are legally blind in one or both eyes. Computer reconstruction of the dosimetry, based on computed tomography and beam profiles, shows that errors in dosage calculations and radiotherapy technique probably account for the radiation retinopathy in three of the four patients. Radiotherapy for Graves' ophthalmopathy should be administered only by competent radiotherapists who are experienced in the treatment of this disease. Similar errors in dosage calculations and treatment techniques may account for other reports of radiation retinopathy after reportedly safe dosages.

Radiation litigation in retrospect.

Most of the radiation litigation filed against the United States pursuant to the Federal Tort Claims Act has been defended by asserting federal sovereign immunity or by proving that the plaintiff's injury is unrelated to his radiation exposure. This paper reports that the second defense is best advanced by comprehensive pretrial investigation of the plaintiff's claim, which frequently results in voluntary dismissal of the legal action.

Coccidioidomycosis in pregnancy during an epidemic in California.

OBJECTIVE: To determine presentation, clinical course, and outcome of a cohort of pregnant women with coccidioidomycosis and compare findings with common observations reported in the literature. METHODS: Thirty-two women who delivered live infants or aborted fetuses in 1993 and had confirmed diagnoses of coccidioidomycosis were included in the study. Medical records were evaluated retrospectively for clinical characteristics, laboratory results, and disease course. RESULTS: Dissemination occurred in three of 32 cases. The most common management was supportive and symptomatic care. At 1 year, 26 of 32 had recovered. There were no maternal deaths. CONCLUSION: The common depiction of coccidioidomycosis in pregnancy has overstated morbidity and mortality likely because of reporting bias. Many women will have favorable outcomes without drug treatment, and the practice of abortions or early delivery in subjects with active infection should be rare.

Community-acquired pneumonia: etiology, diagnosis, and treatment.

Pneumonia is an important cause of morbidity and mortality. A variety of conditions that damage the airways and weaken host defense mechanisms increase the susceptibility of the individual to bacterial colonization of the pulmonary tree. Because the clinician frequently cannot determine the etiologic agent, pneumonia is often treated empirically. Cefonicid, a long-acting cephalosporin, is a useful and cost-effective antibiotic that is active against many of the common pathogens that cause community-acquired pneumonia, such as Streptococcus pneumoniae and Haemophilus influenzae. It is also active against less common community-acquired pathogens, such as Klebsiella pneumoniae, Escherichia coli, and some anaerobic mouth flora. Erythromycin is useful when Mycoplasma or Legionella species are suspected. Cefonicid's demonstrated safety and efficacy, its low cost, and its long half-life, permitting once-daily dosing, make this antibiotic an ideal parenteral choice for empiric therapy of community-acquired pneumonia.

MR findings in acute and chronic coccidioidomycosis meningitis.

PURPOSE: To characterize MR findings in acute and chronic coccidioidomycosis meningitis and relate the imaging features to the clinical course. METHODS: We reviewed MR scans and clinical findings of 12 patients with coccidioidal meningitis. RESULTS: Patients with active or untreated disease were found to have hydrocephalus and intense enhancement of the cervical subarachnoid space, basilar, sylvian, and interhemispheric cisterns on postcontrast MR scans. Focal parenchymal signal abnormalities suggesting ischemia or infarction were common. Abnormal MR enhancement decreases during therapy, although patients develop cortical and/or brain stem atrophy. CONCLUSIONS: Widespread cisternal and cervical subarachnoid meningeal involvement is common in coccidioidal meningitis. Serial contrast MR imaging reflects the effects of therapy in patients with coccidioidal meningitis.

Metabolic changes during glucose tolerance tests in migraine attacks.

(1) Intravenous glucose tolerance tests have been carried out on 6 migraine sufferers on two occasions. The first study was carried out during a migraine attack and the second was performed in an attack-free period. The patients had fasted overnight and the investigations were carried out in the morning. Samples of venous blood were taken for measurement of concentrations of glucose, lactate, pyruvate, free fatty acids (FFA), glycerol, ketone-bodies, insulin and growth hormone. (2) an impaired tolerance to glucose was found during the migraine attacks compared with the control studies. Elevated ketone and FFA levels were found during the attacks and may have accounted for the glucose intolerance. The elevation of plasma FFA levels during the migraine attacks paralleled changes in blood glycerol concentrations suggesting increased lipolysis during the attacks. Growth hormone and cortisol were raised and insulin was depressed during attacks. (3) Our observations, in which the patients acted as their own controls, imply increased lipolysis during migraine attacks and are in contrast to previously reported studies. The patterns of metabolic and hormonal changes are consistent with a stress response during the attacks and the significance in relation to the causation of the attacks is discussed.

The role of folate deficiency in the development of peripheral neuropathy caused by anticonvulsants.

To investigate the role of folate deficiency in neuropathy caused by anticonvulsants, electrophysiological studies of peripheral nerve function were carried out on 29 epileptic patients on long-term anticonvulsant therapy. All but three patients showed abnormalities in one or more electrophysiological measurements, the main abnormality being in amplitude of sensory nerve action potential--this was reduced or absent in 76% of patients. All patients had low concentrations of folate in serum and CSF, these being below the normal ranges in 19 patients. These 19 patients were treated with folate, either 5-formyltetrahydrofolate (10 patients) or folic acid (9 patients), over a period of one month. After therapy all patients had normal levels of folate in serum and CSF, slightly higher levels in CSF being obtained in those receiving 5-formyltetrahydrofolate. Folate therapy significantly reversed abnormalities in motor and sensory nerve distal latencies; the effect was greater with 5-formyltetrahydrofolate, apparently because this produced higher CSF folate concentrations than folic acid. We conclude that folate deficiency may be involved in the development of peripheral neuropathy due to anticonvulsants.