Developmental toxicity of perfluorononanoic acid in mice.

Perfluorononanoic acid (PFNA) is a ubiquitous and persistent environmental contaminant. Although its levels in the environment and in humans are lower than those of perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA), a steady trend of increases in the general population in recent years has drawn considerable interest and concern. Previous studies with PFOS and PFOA have indicated developmental toxicity in laboratory rodent models. The current study extends the evaluation of these adverse outcomes to PFNA in mice. PFNA was given to timed-pregnant CD-1 mice by oral gavage daily on gestational day 1-17 at 1, 3, 5 or 10mg/kg; controls received water vehicle. Dams given 10mg/kg PFNA could not carry their pregnancy successfully and effects of this dose group were not followed. Similar to PFOS and PFOA, PFNA at 5mg/kg or lower doses produced hepatomegaly in the pregnant dams, but did not affect the number of implantations, fetal viability, or fetal weight. Mouse pups were born alive and postnatal survival in the 1 and 3mg/kg PFNA groups was not different from that in controls. In contrast, although most of the pups were also born alive in the 5mg/kg PFNA group, 80% of these neonates died in the first 10 days of life. The pattern of PFNA-induced neonatal death differed somewhat from those elicited by PFOS or PFOA. A majority of the PFNA-exposed pups survived a few days longer after birth than those exposed to PFOS or PFOA, which typically died within the first 2 days of postnatal life. Surviving neonates exposed to PFNA exhibited dose-dependent delays in eye opening and onset of puberty. In addition, increased liver weight seen in PFNA-exposed offspring persisted into adulthood and was likely related to the persistence of the chemical in the tissue. Evaluation of gene expression in fetal and neonatal livers revealed robust activation of peroxisome proliferator-activated receptor-alpha (PPARα) target genes by PFNA that resembled the responses of PFOA. Our results indicate that developmental toxicity of PFNA in mice is comparable to that of PFOS and PFOA, and that these adverse effects are likely common to perfluoroalkyl acids that persist in the body.

The course of toxicity in the pregnant mouse after exposure to the cyanobacterial toxin cylindrospermopsin: clinical effects, serum chemistries, hematology, and histopathology.

Cylindrospermopsin (CYN) is a toxin produced by a variety of fresh-water cyanobacterial species worldwide and induces significant adverse effects in both livestock and humans. This study investigated the course of CYN-induced toxicity in pregnant mice exposed daily during either the period of major organogenesis (gestation days [GD] 8-12) or fetal growth (GD13-17). Endpoints include clinical signs of toxicity, serum analyses to evaluate hepatic and renal function, histopathology of liver and kidney, and hematology. Study animals were administered 50 µg/kg CYN once daily by ip route and euthanized 24 h after 1, 2, 3, 4, or 5 consecutive doses, or 6 or 13 d after the dosing period. The course of the CYN-induced effects was determined at all euthanasia times for the endpoints just outlined. Results indicated that CYN is a toxin, producing lethality in dams during the early part of gestation, significant weight loss, and bleeding in the gastrointestinal tract, tail tip, and peri-orbital tissues. Effects also included alterations in serum markers for liver function, histopathological changes in liver and kidney tissues, electrolyte abnormalities, leukocytosis, and posttreatment thrombocytopenia and reticulocytosis. The onset of symptoms was rapid, producing reductions in weight gain in GD8-12 animals, bleeding in the vaginal area in GD13-17 animals, and significant increases in sorbitol dehydrogenase (SDH) in both groups after a single dose. Although the GD8-12 dams displayed a 50% lethality, in GD13-17 animals only a single death occurred. Alterations seen in hepatic and renal function or histopathology do not appear to be of sufficient severity to produce death. Evidence indicates that bleeding may play a critical role in the onset of symptoms and eventually, in the observed lethality.

Cholinesterase inhibition and depression of the photic after discharge of flash evoked potentials following acute or repeated exposures to a mixture of carbaryl and propoxur.

Previously, we reported that acute treatment with propoxur or carbaryl decreased the duration of the photic after discharge (PhAD) of flash evoked potentials (FEPs). In the current studies, we compared the effects of acute or repeated exposure to a mixture of carbaryl and propoxur (1:1.45 ratio; propoxur:carbaryl) on the duration of the PhAD and brain ChE activity in Long Evans rats. Animals were exposed (po) either to a single dose (0, 3, 10, 45 or 75 mg/kg), or 14 daily dosages (0, 3, 10, 30, 45 mg/kg), of the mixture. Acute and repeated treatment with 3mg/kg (or greater) of the mixture produced dose-related inhibition of brain ChE activity. Compared to controls, the PhAD duration decreased after acute administration of 75 mg/kg or repeated treatment with 30 mg/kg of the mixture. The linear relationship between the percent of control brain ChE activity and the PhAD duration was similar for both exposure paradigms. Dose-response models for the acute and repeated exposure data did not differ for brain ChE activity or the duration of the PhAD. Repeated treatment with the mixture resulted in slightly less (13-22%) erythrocyte ChE inhibition than acute exposure. Both acute and repeated treatment resulted in dose-additive results for the PhAD duration and less than dose-additive responses (6-16%) for brain ChE activity for the middle range of dosages. Acute treatment resulted in greater than dose-additive erythrocyte ChE inhibition (15-18%) at the highest dosages. In contrast, repeated treatment resulted in less than dose-additive erythrocyte ChE inhibition (16-22%) at the middle dosages. Brain and plasma levels of propoxur and carbaryl did not differ between the acute and repeated dosing paradigms. In summary, a physiological measure of central nervous system function and brain ChE activity had similar responses after acute or repeated treatment with the carbamate mixture, and brain ChE showed only small deviations from dose-additivity. Erythrocyte ChE activity had larger differences between the acute and repeated treatment paradigms, and showed slightly greater deviations from dose-additivity. Because these treatments utilized larger dosages than anticipated environmental exposures, concern for non-additive effects in humans is minimized. The small magnitude of the deviations from dose-additivity also suggest that in the absence of repeated exposure data, results from an acute study of readily reversible carbamate toxicity can be used to estimate the response to repeated daily exposures.

Toxicity and recovery in the pregnant mouse after gestational exposure to the cyanobacterial toxin, cylindrospermopsin.

Cylindrospermopsin (CYN) is a tricyclic alkaloid toxin produced by fresh water cyanobacterial species worldwide. CYN has been responsible for both livestock and human poisoning after oral exposure. This study investigated the toxicity of CYN to pregnant mice exposed during different segments of gestation. The course of recovery and individual responses to the toxin were evaluated. Adverse effects of CYN were monitored up to 7 weeks post-dosing by clinical examination, histopathology, biochemistry and gene expression. Exposure on gestational days (GD) 8-12 induced significantly more lethality than GD13-17 exposure. Periorbital, gastrointestinal and distal tail hemorrhages were seen in both groups. Serum markers indicative of hepatic injury (alanine amino transferase, aspartate amino transferase and sorbitol dehydrogenase) were increased in both groups; markers of renal dysfunction (blood urea nitrogen and creatinine) were elevated in the GD8-12 animals. Histopathology was observed in the liver (centrilobular necrosis) and kidney (interstitial inflammation) in groups exhibiting abnormal serum markers. The expression profiles of genes involved in ribosomal biogenesis, xenobiotic and lipid metabolism, inflammatory response and oxidative stress were altered 24 h after the final dose. One week after dosing, gross, histological and serum parameters had returned to normal, although increased liver/body weight ratio and one instance of gastrointestinal bleeding was found in the GD13-17 group. Gene expression changes persisted up to 2 weeks post-dosing and returned to normal by 4 weeks. Responses of individual animals to CYN exposure indicated highly significant inter-animal variability within the treated groups.

Modeling single and repeated dose pharmacokinetics of PFOA in mice.

Perfluorooctanoic acid (PFOA) displays complicated pharmacokinetics in that serum concentrations indicate long half-lives despite which steady state appears to be achieved rapidly. In this study, serum and tissue concentration time-courses were obtained for male and female CD1 mice after single, oral doses of 1 and 10 mg/kg of PFOA. When using one- and two-compartment models, the pharmacokinetics for these two dosages are not consistent with serum time-course data from female CD1 mice administered 60 mg/kg, or with serum concentrations following repeated daily doses of 20 mg/kg PFOA. Some consistency between dose regimens could be achieved using the saturable resorption model of Andersen et al. In this model PFOA is cleared from the serum into a filtrate compartment from which it is either excreted or resorbed into the serum by a process presumed transporter mediated with a Michaelis-Menten form. Maximum likelihood estimation found a transport maximum of T(m) = 860.9 (1298.3) mg/l/h and half-maximum concentration of K(T) = 0.0015 (0.0022) mg/l where the estimated standard errors (in parentheses) indicated large uncertainty. The estimated rate of flow into and out of the filtrate compartment, 0.6830 (1.0131) l/h was too large to be consistent with a biological interpretation. For these model parameters a single dose greater than 40 mg/kg, or a daily dose in excess of 5 mg/kg were necessary to observe nonlinear pharmacokinetics for PFOA in female CD1 mice. These data and modeling analyses more fully characterize PFOA in mice for purposes of estimating internal exposure for use in risk assessment.

The cyanobacterial toxin, cylindrospermopsin, induces fetal toxicity in the mouse after exposure late in gestation.

Cylindrospermopsin (cyn) is a cyanobacterial toxin implicated in human and wildlife poisonings. We have completed studies investigating the potential of purified cyn to induce developmental toxicity in mammals. The teratology study involved intraperitoneal injections (8.0-128 microg kg(-1)) on gestational days (GD) 8-12 with subsequent examination of term fetuses for viability, weight and morphological anomalies. Cyn was lethal to a significant portion of the dams receiving > or = 32 microg kg(-1). Surviving pregnant females were killed and fetuses removed for examination. Analysis indicates no adverse effects on litter size, fetal weight, or incidence of anomalies. Subsequently, 50 microg kg(-1) cyn was administered on GD 8-12 or 13-17. Animals were allowed to give birth and litters monitored for growth and viability. A reduction in litter size occurred in treated groups. Avg. pup wt. was only affected in the GD 13-17 group. GD 13-17 dams did not exhibit the toxicity noted in the GD 8-12 group but gave birth significantly earlier than controls. There was a significant number of dead GD 13-17 pups and incidences of blood in the gastrointestinal tract and hematomas in the tips of the tails in survivors. Pups were cross-fostered to control mothers in litters of 10. On postnatal days (PND) 5-6 there were no significant differences in weight gain or viability in GD 8-12 litters, while GD 13-17 litters had significantly reduced weight gain and viability. GD 13-17 exposed male pups still weighed significantly less than the controls after 15 months.

Phase II trial of liposomal doxorubicin (Doxil) in advanced soft tissue sarcomas.

PURPOSE: To assess the objective response rate, toxicity experienced, progression-free survival, and overall survival of patients with previously untreated advanced soft tissue sarcomas treated with a liposomal doxorubicin formulation (Doxil). METHODS: Patients with metastatic or recurrent soft tissue sarcoma who had received no prior chemotherapy for advanced disease were treated with liposomal doxorubicin (Doxil) according to a two stage accrual design. Doxil was administered at 50 mg/m2 every 4 weeks. A total of 15 patients were treated and are evaluable for response and toxicity. RESULTS: The male/female ratio was 7/8, the median age was 60 years (34-75) and the ECOG performance status was 0-1 in >90% of patients. Leiomyosarcoma (7/15) and malignant fibrous histiocytoma (2/15) were the most common histologic diagnoses. No objective responses were observed in the 15 evaluable patients. No lethal toxicity occurred. Grade 3-4 leukopenia or neutropenia were reported in 3/15 (20%) patients. Grade 3 mucositis or hand-foot syndrome occurred in 2/15 (13%) and 1/15 (7%) patients respectively and seemed more severe in older patients. The median time to progression was 1.9 months (range 0.9-6.2). Twelve patients have now died. The Kaplan-Meier estimate of median overall survival is 12.3 months. As called for in the study design, accrual was terminated because no responses were obtained in the first 15 patients. CONCLUSION: Though well-tolerated, Doxil given according to this dose and schedule to patients with advanced soft tissue sarcoma had no significant therapeutic activity. A correlation between older age and skin/mucosal toxicity of Doxil is suggested in this study but needs confirmation. Future investigations of Doxil in soft tissue sarcomas should use a different schedule and dose.

Treatment options for orthopaedic oncologic entities.

Over the past 2 decades, tremendous advancement in the understanding of tumor natural history and treatment has occurred. If the basic principles are followed, the evaluation and appropriate treatment of musculoskeletal tumors can be reproduced successfully by any conscientious surgeon. Many benign bone and soft-tissue tumors can and probably should be treated by the community orthopaedic surgeon, and this chapter is biased toward treatment of those lesions. The encounter of a malignant lesion is probably beyond the scope of practice of most practicing orthopaedic surgeons. The assessment of the patient and treatments rendered in the first meetings may well dictate the ultimate outcome of survival and limb preservation: thus, patients with such lesions should be treated by experienced orthopaedic oncologists. With the small numbers of these lesions and the extreme consequences of mishandling them, it would be imprudent to do otherwise.

The effect of Danquah Communication System (DanCS) boards on maladaptive behaviours among individuals with severe intellectual impairment and non-verbal communication skills.

There is evidence that some individuals with severe intellectual impairment who are non-verbal may, out of frustration, display such inappropriate behaviour as aggression and self-injury as a means of communicating their needs to caregivers. The purpose of this study was to develop an inexpensive augmented communication device and to teach individuals with multiple impairment to use this method to communicate their needs in order to reduce their aggressive behaviours. The Dan Communication System (DanCS) symbol boards were therefore designed with computerized voice interface to help the individuals communicate to caregivers by means of audio and visual signs. A working DanCS board has been successfully developed and can now be mass produced by a manufacturer. The DanCS board is illustrated and described. A measurement device called the Goal Attainment Scale (GAS) that focused on three target behaviours; pressing of symbols, control of aggression, and social interaction with caregivers, was used to evaluate progress in the participating subjects (N = 30). Results showed that the multiply impaired individuals in the study significantly improved in all the targeted behaviours through the use of the DanCS. Details of the study are reported.

Allograft-prosthesis composite versus megaprosthesis in proximal femoral reconstruction.

A review of 33 patients who underwent proximal femoral resection for primary bone tumor and reconstruction with an allograft-prosthesis composite or a megaprosthesis is presented to consider the relative merits of the 2 procedures. Clinical function, reconstruction survival, and associated complications were analyzed. Eighteen composites in 16 patients and 18 megaprosthesis in 17 patients were analyzed. Infection in the composite group and instability in the megaprosthesis group were the common causes of failure and removal of reconstructions. The average functional evaluation in 14 surviving patients with composites was 87% of normal. In 10 surviving patients with megaprostheses, the average function was 80% when complications were avoided. Survival analysis of the patients with reconstructions showed a 10 year survival of 76% for the patients with composites and 58% for those with megaprostheses. Both composite and megaprosthetic reconstruction of the proximal femur seem to function equally well from the perspective of function and survival because no statistically significant difference could be shown by this review.

Adamantinoma.

This is an unusual case of an adamantinoma in an early phase of evolution. It was much smaller than adamantinomas typically seen at presentation, although it was located in the usual anterior tibial cortical region. Slow growth and a prolonged period of symptoms are common with adamantinoma and were also observed in this patient. The multifocal presentation within the same bone is unusual. This case illustrated the need to consider adamantinoma in the differential diagnosis of any pre-tibial cortical lesion despite the small size, benign presentation, or the longevity of symptoms.

Two-dimensional and Doppler echocardiography alone can adequately define preoperative anatomy and hemodynamic status before repair of complete atrioventricular septal defect in infants < 1 year old.

OBJECTIVES: We sought to assess the ability of two-dimensional and Doppler echocardiography alone, without cardiac catheterization, to evaluate infants < 1 year of age for complete open heart repair of complete balanced atrioventricular (AV) septal defect. BACKGROUND: Two-dimensional echocardiographic-Doppler examinations provide accurate anatomic detail in patients with AV septal defect. Lung biopsy data have shown that patients rarely develop significant inoperable pulmonary vascular disease before 7 months of age. Although calculated pulmonary arteriolar resistance is often elevated in young infants with this heart defect, this elevation rarely reflects significant pulmonary vascular changes in infants < 7 to 12 months of age. METHODS: We performed a retrospective review of 34 patients who underwent complete repair of AV septal defect at our institution between January 1, 1988 and September 1, 1992. Some patients had both catheterization and echocardiographic-Doppler studies (group I, n = 16); others had only echocardiographic-Doppler studies (group II, n = 18). RESULTS: The groups were comparable with regard to age at echocardiography and operation, days in the hospital, days with ventilatory and inotropic support and occurrence of postoperative pulmonary hypertension. One child (2.9%) died during the early postoperative period, and one child in each group (5.8%) died within the 1st year of life. Preoperative echocardiography allowed better detailing of anatomy, valve commitment and regurgitation than was possible with catheterization alone. Knowledge of preoperative pulmonary resistance did not alter the surgical decision or predict postoperative pulmonary hypertension. There was no apparent difference in mortality between the two groups (0 vs. 5.5%), but the small number of patients in each group provides for a very low power (beta = 0.04) calculation. This mortality rate is not different from that reported in recent studies. CONCLUSIONS: Patients with AV septal defect can safely undergo surgical correction of this defect on the basis of echocardiographic-Doppler data alone.

Evaluation of temporary atrial pacing leads.

Thirty-five patients were randomized to receive either the Medtronic 6500 or one of two braided multifilament temporary pacing leads in the atrium following open heart surgery. Sensing performance was judged by amplitude, slew rate, and the proportion of patients with an adequate sensing threshold. Pacing performance was assessed with measures of impedance, threshold voltage, current, and energy. The Medtronic 6500 demonstrated superior sensing and lower energy consumption compared to braided multifilament leads. This type of lead may offer advantages when using atrial synchronous temporary pacing systems.

Juxta-articular osteoid osteoma.

Osteoid osteomas that arise at the end of a long bone, within the insertion of the joint capsule (juxta-articular, intra-articular), may cause misleading clinical, radiographic, and histologic findings, resulting in unnecessary diagnostic tests and a delay in definitive treatment. To clarify optimum diagnostic procedures, we reviewed 20 cases of juxta-articular osteoid osteomas and found a mean delay from presentation to correct diagnosis of 24 months. Plain radiographs were either negative or showed only secondary changes. A periosteal reaction and proliferative synovitis with chronic inflammation was common, which could be misinterpreted as rheumatoid arthritis. Optimum diagnostic procedures were a bone scan followed by plain tomograms and an excisional biopsy of the nidus.

Ki-67 and grading of malignant fibrous histiocytomas.

Although generally considered to be of high grade, malignant fibrous histiocytomas (MFH) show a range of histologic appearances and a diverse biologic behavior. More precise grading of this type of sarcoma is desirable. The rate of cell proliferation may reflect clinical behavior. A more sensitive measure of cell proliferation is the expression of the Ki-67 antigen. Frozen sections were prepared from 29 cases of MFH. Sections were immunohistochemically stained for Ki-67, and the results were quantitated by image analysis (CAS 100). The Spearman rank correlation test was used to compare the extent of the Ki-67 staining with the conventional histologic grade, nuclear grade, number of mitoses, extent of necrosis, and overall cellularity. There was a significant correlation between the extent of Ki-67 staining and the nuclear grade (cc = 0.56; P = 0.002) and overall histologic grade (correlation coefficient = 0.58; P = 0.001), but there was no significant, independent correlation between Ki-67 and prognosis.

Round atelectasis in an elderly man: the role of thoracotomy.

In summary, a case of round atelectasis appearing subsequent to a pleural effusion in an elderly man 6 months after open heart surgery is reported. Although plain roentgenograms and linear and computerized tomography could help the physician make the diagnosis with confidence, a needle biopsy of the lesion at the very least or exploratory thoracotomy may sometimes still be justified for the properly selected patient.