Repeated low-dose exposures to sarin, soman, or VX affect acoustic startle in guinea pigs.

Chemical warfare nerve agents (CWNAs) are known to cause behavioral abnormalities in cases of human exposures and in animal models. The behavioral consequences of single exposures to CWNAs that cause observable toxic signs are particularly well characterized in animals; however, less is known regarding repeated smaller exposures that may or may not cause observable toxic signs. In the current study, guinea pigs were exposed to fractions (0.1, 0.2, or 0.4) of a medial lethal dose (LD50) of sarin, soman, or VX for two weeks. On each exposure day, and for a post-exposure period, acoustic startle response (ASR) was measured in each animal. Although relatively few studies use guinea pigs to measure behavior, this species is ideal for CWNA-related experiments because their levels of carboxylesterases closely mimic those of humans, unlike rats or mice. Results showed that the 0.4 LD50 doses of soman and VX transiently increased peak startle amplitude by the second week of injections, with amplitude returning to baseline by the second week post-exposure. Sarin also increased peak startle amplitude independent of week. Latencies to peak startle and PPI were affected by agent exposure but not consistently among the three agents. Most of the changes in startle responses returned to baseline following the cessation of exposures. These data suggest that doses of CWNAs not known to produce observable toxic signs in guinea pigs can affect behavior in the ASR paradigm. Further, these deficits are transient and usually return to baseline shortly after the end of a two-week exposure period.

Carrier status of leptospirosis among cattle in Sri Lanka: a zoonotic threat to public health.

Leptospirosis is a zoonotic disease of global importance and one of the notifiable diseases in Sri Lanka. Recent studies on human leptospirosis have suggested that the cattle could be one of the important reservoirs for human infection in the country. However, there is a dearth of local information on bovine leptospirosis, including its implications for human transmission. Thus, this study attempted to determine the carrier status of pathogenic Leptospira spp in cattle in Sri Lanka. A total of 164 cattle kidney samples were collected from the meat inspection hall in Colombo city during routine inspection procedures conducted by the municipal veterinary surgeons. The DNA was extracted and subjected to nested PCR for the detection of leptospiral flaB gene. Amplicons were sequenced, and phylogenic distances were calculated. Of 164 samples, 20 (12.2%) were positive for flaB-PCR. Sequenced amplicons revealed that Leptospira species were deduced to L. borgpetersenii (10/20, 50%), L. kirschneri (7/20, 35%) and L. interrogans (3/20, 15%). The results indicate that a high proportion of the sampled cattle harbour a variety of pathogenic Leptospira spp, which can serve as important reservoirs for human disease.

The M694V mutation in Armenian-Americans: a 10-year retrospective study of MEFV mutation testing for familial Mediterranean fever at UCLA.

Familial Mediterranean fever (FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever (MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis.

The anticholinergic and antiglutamatergic drug caramiphen reduces seizure duration in soman-exposed rats: synergism with the benzodiazepine diazepam.

Therapy of seizure activity following exposure to the nerve agent soman (GD) includes treatment with the anticonvulsant diazepam (DZP), an allosteric modulator of γ-aminobutyric acid A (GABA(A)) receptors. However, seizure activity itself causes the endocytosis of GABA(A) receptors and diminishes the inhibitory effects of GABA, thereby reducing the efficacy of DZP. Treatment with an N-methyl-d-aspartic acid (NMDA) receptor antagonist prevents this reduction in GABAergic inhibition. We examined the efficacy of the NMDA receptor antagonist caramiphen edisylate (CED; 20mg/kg, im) and DZP (10mg/kg, sc), administered both separately and in combination, at 10, 20 or 30min following seizure onset for attenuation of the deleterious effects associated with GD exposure (1.2 LD(50); 132µg/kg, sc) in rats. Outcomes evaluated were seizure duration, neuropathology, acetylcholinesterase (AChE) activity, body weight, and temperature. We also examined the use of the reversible AChE inhibitor physostigmine (PHY; 0.2mg/kg, im) as a therapy for GD exposure. We found that the combination of CED and DZP yielded a synergistic effect, shortening seizure durations and reducing neuropathology compared to DZP alone, when treatment was delayed 20-30min after seizure onset. PHY reduced the number of animals that developed seizures, protected a fraction of AChE from GD inhibition, and attenuated post-exposure body weight and temperature loss independent of CED and/or DZP treatment. We conclude that: 1) CED and DZP treatment offers considerable protection against the effects of GD and 2) PHY is a potential therapeutic option following GD exposure, albeit with a limited window of opportunity.

The effect of mechanical stress on cartilage energy metabolism.

Cartilage is routinely subjected to varying mechanical stresses which are known to affect matrix turnover by a variety of pathways. Here we show that mechanical loads which suppress sulphate incorporation or protein synthesis by articular chondrocytes, also inhibit rates of oxygen uptake and of lactate production. Although the mechanisms have not been definitively identified, it has been shown that high hydrostatic pressures reduce the activity of the glucose transporter GLUT. Furthermore, fluid expression consequent on static loading changes intracellular pH and ionic strength; intracellular changes which would reduce the activity of glycolytic enzymes. Both pathways would thus lead to a fall in rates of glycolysis and a reduction in intracellular ATP, and - since ATP concentrations directly affect sulphation of proteoglycans - a rapid fall in sulphate incorporation. Our results suggest that load-induced changes in matrix synthesis in cartilage can occur by means other than changes in gene expression.

Department of defense eye injuries from fiscal year 1988-1998.

BACKGROUND: The U.S. Army Safety Center, U.S. Navy Safety Center, and U.S. Air Force Safety Center collect data on occupational injuries that occur in each respective military service. METHODS: An 11-year retrospective study of ground eye injuries collected by the Army Safety Center, Navy Safety Center, and Air Force Safety Center, from Fiscal Year (FY) 1988 through FY 1998 was performed. Demographic data analyzed included rank, gender, age, and military/civilian status. Injury data analyzed included severity of injury, eye protection use, injury cost, work days lost due to injury, and days hospitalized due to injury. RESULTS: Statistics for Department of Defense (DoD) eye injuries indicate the average military individual who sustains an eye injury is a 20- to 24-year-old male, E3-E5. This individual is not wearing eye protection and will lose an average of 5.9 days from work at a cost averaging $6,295. The average civil service employee who sustains an eye injury is a WG6-10 who is a 30- to 39-year-old male. This individual is not wearing eye protection and will lose an average of 3.5 days from work at a cost averaging $1,598. Statistically significant differences in the numbers of eye injuries were observed between military occupational groups. In addition, incidence rates between military occupational groups were statistically significant. Category 1, Infantry, Gun Crews, and Seamanship Specialists, has the highest count of injuries and Category 7, Craftsworkers, has the highest incidence. CONCLUSIONS: Proactive vision conservation education at local levels needs to focus on these military occupational groups.

Cytolethal distending toxin demonstrates genotoxic activity in a yeast model.

Cytolethal distending toxins (CDTs) are multisubunit proteins produced by a variety of bacterial pathogens that cause enlargement, cell cycle arrest, and apoptosis in mammalian cells. While their function remains uncertain, recent studies suggest that they can act as intracellular DNases in mammalian cells. Here we establish a novel yeast model for understanding CDT-associated disease. Expression of the CdtB subunit in yeast causes a G2/M arrest, as seen in mammalian cells. CdtB toxicity is not circumvented in yeast genetically altered to lack DNA damage checkpoint control or that constitutively promote cell cycle progression via mutant Cdk1, because CdtB causes a permanent type of damage that results in loss of viability. Finally, we establish that CDTs are likely to be potent genotoxins, as indicated by in vivo degradation of chromosomal DNA associated with expression of CdtB-suggesting that the varied distribution of CDT in bacteria implicates many human pathogens as possessors of genotoxic activity.

The surgical spectrum of pulmonary neuroendocrine neoplasms.

OBJECTIVES: The purpose of this study is to review our experience with the spectrum of neuroendocrine neoplasms of the lung with emphasis on the histopathologic classification and surgical therapy of each class of neoplasm. DESIGN: This retrospective review covers the entire spectrum of neuroendocrine neoplasms of the lung over an 11-year period (January 1985 to December 1995) in a university hospital setting. Only patients who underwent surgical resection were included in this review. PATIENTS: During this period, a total of 77 patients underwent lung resection for the following neuroendocrine neoplasms: typical carcinoid (TC), 50 patients; atypical carcinoid (AC), 5 patients; large cell neuroendocrine carcinoma (LCNEC), 9 patients; mixed large-small cell neuroendocrine carcinoma (LSNEC), 4 patients; or small cell neuroendocrine carcinoma (SCC), 9 patients. There were 37 men (48.1%) and 40 women (51.9%) among the patients, with a mean age of 57.9 years (range, 14 to 87 years). INTERVENTIONS: Primary surgical resection consisted of the following procedures: 52 lobectomies (67.5%); 10 pneumonectomies (13%); 13 limited resections (16.9%); 1 left main bronchus sleeve resection; and 1 carinal resection. Six patients had the following concomitant procedures: pericardiectomy, 2 patients; mediastinoscopy, 1 patient; chest wall resection, 1 patient; stapling blebs, 1 patient; and transdiaphragmatic liver biopsy, 1 patient. Four patients underwent bilobectomies, and two patients underwent multiple wedge resections. RESULTS: The hospital mortality rate was 2.6% (2 of 77 patients), and both patients died of pulmonary failure. Follow-up was obtained in 62 of 77 patients (80.9%) for an average of 38.1 months (range, 2 to 132 months). There were a total of 13 deaths, and 8 were disease-related (LCNEC, 4 deaths; SCC, 2 deaths; LSNEC, 1 death; and AC tumor, 1 death. The mean disease-free intervals for patients with these neoplasms were the following: TC tumor, 41.3 months; AC tumor, 20 months; LCNEC, 20.4 months; LSNEC, 25 months; and SCC, 48 months. The overall 3-year survival rate was 45.2% (28 of 62 patients). CONCLUSION: This report will emphasize the classification, surgical management, and treatment considerations of pulmonary neuroendocrine neoplasms. Despite the poor overall prognosis in high-grade neuroendocrine tumors of the lung, surgery remains a viable adjunct in the early stages of this disease.

The pathophysiology of the intervertebral disc.

After a review of disk structure, the pivotal role of disk cells in producing and renewing the extracellular disk matrix is emphasized. Disk cells rely on nutrients that diffuse through the vertebral endplates. Microelectrode methods have been developed to study nutrient diffusion and endplate permeability. Mechanical stimuli modify disk cell activity. Scoliosis is associated with decreased endplate permeability, a factor that may play a role in disk degeneration and scoliosis progression.

Fracture resistance of all-ceramic and metal-ceramic inlays.

PURPOSE: Metal-ceramic inlay designs were developed to determine if the esthetic qualities of all-ceramic inlays could be duplicated and at the same time improve their strength and stability. The objectives of this study were to: (1) compare the fracture resistance of metal-ceramic inlays with that of all-ceramic inlays; (2) determine the correlation between the degree of preparation taper and fracture resistance; and (3) determine the correlation between marginal gap width and fracture resistance. MATERIALS AND METHODS: Inlay preparations were made on 60 Dentoform teeth, with 30 teeth allocated for metal-ceramic inlays and 30 teeth for all-ceramic inlays. Each group was further subdivided into 5-, 10-, and 20-degree taper preparations. Metal-ceramic inlays were fabricated using Goldtech Bio 2000 metal and Ceramco porcelain extending to the margin, while all-ceramic inlays were made from Empress II ceramic. Marginal gap widths were measured at six critical areas after fabrication. The load at failure was measured using an Instron Universal Testing Machine. RESULTS: The mean fracture load for all-ceramic inlays and metal-ceramic inlays at 5, 10, and 20 degrees was 70+/-40 N, 48+/-37 N, 33+/-7 N, and 40+/-23 N, 29+/-22 N, and 14+/-4 N, respectively. The mean gap width was 105 microm and 126 microm for all-ceramic and metal-ceramic inlays, respectively. CONCLUSION: The mean fracture load for Empress inlays was significantly higher than that for metal-ceramic inlays. Inlays with a 5-degree taper were significantly more fracture resistant than those with a 20-degree taper. There was no relation between marginal gap width and fracture resistance.

A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study.

BACKGROUND: Some endometrial cancers are hormonally dependent. A principal source of circulating estrogen is conversion of adrenal androstenedione by aromatase. Anastrozole (Arimidex) is an oral nonsteroidal aromatase inhibitor which is active in recurrent breast cancer. This Phase II study was undertaken to evaluate anastrozole in recurrent endometrial carcinoma. METHODS: Patients with advanced or recurrent endometrial cancer not curable with either surgery or radiation therapy and with measurable disease, a GOG (Zubrod) performance status of < or = 2, no more than one prior hormonal therapy regimen, and no prior chemotherapy were eligible. Anastrozole was administered at a dose of 1 mg/day orally for at least 28 days. RESULTS: Twenty-three patients were entered on this trial. On central pathology review, 9 of them had grade 2 and 14 had grade 3 tumors. One to 24 courses (median: 1) of therapy were administered. Two partial responses were noted (9%; 90% confidence interval 3 to 23%). Two additional patients had short-term stable disease. With the exception of 1 case of venous thrombosis, the toxicity profile was mild. Median durations of progression-free survival and overall survival are 1 and 6 months, respectively. CONCLUSIONS: Anastrozole has minimal activity in an unselected population of patients with recurrent endometrial cancer.

Intratracheal instillation of zinc-cadmium sulfide (ZnCdS) in Fischer 344 rats.

The purpose of this study was to assess the bioavailability and pulmonary toxicity of ZnCdS in rats. Groups of 30 male Fischer 344 rats each were anesthetized and dosed via intratracheal instillation with 5 mg of either ZnCdS, quartz (positive control), or titanium dioxide (TiO(2), negative control) suspended in 0.5 ml saline. A vehicle control group received 0.5 ml saline. Ten animals from each test group were sacrificed at 1 day, 1 wk, and 14 wk after dosing for bronchoalveolar lavage fluid (BALF) analysis and histopathology. The BALF was analyzed for alkaline phosphatase, acid phosphatase, lactate dehydrogenase (LDH), beta-glucuronidase (beta-glu), total protein, and cell counts. Two separate groups of 24 rats each were dosed as already described with either ZnCdS or saline. Eight rats from each group were sacrificed at 1 day, 1 wk, and 14 wk after dosing for determination of cadmium (Cd) and zinc (Zn) concentrations in the lung, liver, kidney, and blood. Results indicate that at 1 day after dosing, all enzyme activities (except acid phosphatase) and cell counts in BALF from the quartz and ZnCdS groups were significantly higher than in the TiO(2) and saline groups. At 7 days after dosing, high enzyme activity persisted in the quartz group, while the ZnCdS group showed only LDH and total protein levels significantly higher than the saline group. At 14 wk after dosing, LDH, total protein, beta-glu, and cell counts in the quartz group were significantly higher than all other groups. Histologic examination revealed interstitial inflammation and accumulation of foreign material in the lungs and mediastinal lymph nodes of quartz-, TiO(2)-, and ZnCdS-treated rats. Metal analyses in tissues showed profuse Cd and Zn concentrations in the lung 1 day after dosing, followed by a successive decline at 7 days and 14 wk after dosing. A very small, but statistically significant, amount of Cd and Zn was found in the kidneys at 14 wk after dosing. In conclusion, ZnCdS appears to cause temporary lung inflammation, is cleared slowly, and is poorly bioavailable.

Surgical palliation of airway obstruction resulting from lung cancer.

Bronchogenic carcinoma remains a relentless plague of modern society causing far more deaths than the well-popularized "AIDS epidemic" and secondary only to cardiovascular disease as a cause of death in America. Despite medical advances and treatment breakthroughs, only 40% of newly identified lung cancer patients are "potentially curable". Therefore, a large portion of this patient population will require palliative care and treatment. Surgical palliation is somewhat a misnomer in that most endobrachial lesions causing significant obstruction that result in dyspnea are not amenable to surgical intervention, i.e., operative resectional therapy. The palliative management options of airway obstruction resulting from advanced stage lung cancer will be reviewed, including the historical aspects, development and current use of laser resection, airway stenting, and endobrachial brachytherapy for management of unresectable airway tumors. These modalities frequently are used simultaneously in the same patient and may be used in conjunction with current chemotherapeutic and conventional external-beam radiation protocols.

A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions.

BACKGROUND: The purpose of this study was to compare the effectiveness and safety of a chronic indwelling pleural catheter with doxycycline pleurodesis via tube thoracostomy in the treatment of patients with recurrent symptomatic malignant pleural effusions (MPE). METHODS: In this multi-institutional study conducted between March 1994 and February 1997, 144 patients (61 men and 83 women) were randomized in a 2:1 distribution to either an indwelling pleural catheter or doxycycline pleurodesis. Patients receiving the indwelling catheter drained their effusions via vacuum bottles every other day or as needed for relief of dyspnea. RESULTS: The median hospitalization time was 1.0 day for the catheter group and 6.5 days for the doxycycline group. The degree of symptomatic improvement in dyspnea and the quality of life was comparable in each group. Six of 28 patients who received doxycycline (21%) had a late recurrence of pleural effusion, whereas 12 of 91 patients who had an indwelling catheter (13%) had a late recurrence of their effusions or a blockage of their catheter after the initially successful treatment (P = 0.446). Of the 91 patients sent home with the pleural catheter, 42 (46%) achieved spontaneous pleurodesis at a median of 26.5 days. CONCLUSIONS: A chronic indwelling pleural catheter is an effective treatment for the management of patients with symptomatic, recurrent, malignant pleural effusions. When compared with doxycycline pleurodesis via tube thoracostomy, the pleural catheter requires a shorter hospitalization and can be placed and managed on an outpatient basis.

Cutaneous uptake of 14C-HD vapor by the hairless guinea pig.

The hairless guinea pig (HGP) is used by our laboratory to model the human cutaneous response to sulfur mustard (HD), bis(2-chloroethylsulfide), exposure. We determined the HD content in the skin of HGP after a 7-min exposure to vapors saturated with a mixture of HD and 14C-HD. Concentration/time (CT) values in the range of 2 micrograms/cm2/min were determined by counting skin 14C disintegrations per min (dpm) in animals euthanized immediately after exposure. These values are similar to human penetration rates obtained by other investigators. A rate curve monitoring the reduction in skin 14C dpm was developed for animals euthanized between 0 and 24 hr post- exposure. This curve showed the greatest change after 1 hr. The epidermal (62%) to dermal (38%) ratio of 14C at 24 hr was measured for two animals. We saw no site preference for HD penetration among the 8 sites used. The 14C content of template adhesive tape was determined to follow HD distribution. These results contribute to a better understanding of the cutaneous response to HD in the HGP model.

Comparison of hematologic consequences and efficacy of p-aminophenones in mice.

Controlled methemoglobin (MHb) formation is one strategy employed to counter cyanide (CN) toxicity. Currently available MHb formers present certain drawbacks and limitations. The purpose of this study was to characterize, in mice, the hematologic effects of the MHb-forming compound p-aminopropiophenone (PAPP), and two structurally-related p-aminophenones, p-aminoheptanoylphenone (PAHP) and p-aminooctanoylphenone (PAOP). Although these three p-aminophenones have been shown previously to be efficacious as pretreatments against CN, a more complete understanding of their hematologic effects is lacking. In addition, because the active form of PAPP has been shown to be its N-hydroxy metabolite, the N-hydroxy metabolites of PAPP, PAHP and PAOP were also tested. Using a hemoximeter, blood samples obtained -2 to +180 min relative to intramuscular (i.m.) or intraperitoneal (i.p.) drug injections were evaluated. Sodium nitrite (NaNO(2)) and the appropriate solvents served as the positive and negative controls, respectively. Dose-, time-, route-, and compound-related effects were observed. MHb and sulfhemoglobin levels increased, whereas levels of those parameters related to oxygen-carrying capacity of the blood, such as, oxygen saturation and oxyhemoglobin decreased. In general, the effects of PAHP and PAOP were longer lasting than those of PAPP and NaNO(2). Furthermore, PAPP and NaNO(2) were equally effective with either route of administration. Conversely, PAHP and PAOP showed larger effects when administered i.p. versus i.m. The animals treated with N-hydroxy metabolites of the p-aminophenones also showed similar changes in the hematological parameters measured. N-hydroxy PAPP was shown to be the most rapidly acting MHb-forming compound examined in this series. It could achieve therapeutic concentrations of MHb within 2 min and thus may be considered as a treatment for CN intoxication. Although additional work is needed, these data provide information that will be useful for the successful development of improved anti-CN MHb formers.

Evaluation of treatment modalities for thoracic empyema: a cost-effectiveness analysis.

BACKGROUND: Empyema thoracis is treated with a multitude of therapeutic options. Optimal therapy and cost-containment requires selection of the most appropriate initial intervention. METHODS: A retrospective review of treatment modalities was performed on 77 patients diagnosed with empyema thoracis from 1990 to 1997 at one institution. Mean age was 59 years (range, 21 to 90 years); 52 were men and 25 were women. RESULTS: Sixty-five percent (50/77) were parapneumonic and 68% (52/77) were multiloculated. Treatment modalities were as follows: group 1, antibiotics only (n = 4); group 2, primary intervention: image-directed catheter (n = 20) or tube thoracostomy (n = 24); and group 3, secondary intervention: decortication (n = 17), rib resection or muscle interposition (n = 12). Thirty-four percent (9/20 image-directed catheter and 8/24 tube thoracostomy) had failure of initial intervention. Patients undergoing decortication more often had multiloculated empyema thoracis (16 of 17) compared with those undergoing image-directed catheters (8 of 20) or tube thoracotomy (16 of 24). Length of stay was reduced for decortication patients (17 days) compared with those having image-directed catheters (21.8 days), failed image-directed catheters (29.7 days), or tube thoracostomies (19.6 days). Hospital charges per patient between decortication and image-directed catheter ($34,770.79 versus $37,869.41) were comparable, but charges were significantly decreased in decortication patients as compared with failed image-directed catheters ($55,609.32; p < 0.05). CONCLUSIONS: Our series revealed that early decortication has charges similar to those of primary intervention (image-directed catheter or tube thoracostomy) but is more cost-effective than failed image-directed catheter. We advocate the use of early surgical intervention as the most optimal and cost-effective initial modality for the treatment of empyema thoracis.