The role of veterinary medicine regulatory agencies.

An effective animal medicine regulatory programme includes a systematic, evidence-based means of documenting the safety and effectiveness of products before they are produced, marketed or used in a particular country or region. The programme must also include adequate monitoring and controls over the use of these substances. It is clearthat such programmes provide veterinarians, farmers and other animal medicine users with greater assurance that veterinary drugs and biologicals will be safe and effective in preventing and mitigating disease. It is important that these regulatory controls include programmes to ensure that human food obtained from treated animals is safe and that all potential toxicological and microbiological hazards that may be associated with the use of veterinary medicines have been adequately evaluated. There is a great need worldwide for veterinary medicines that provide needed therapies for vast numbers of animals and animal species and, in the case of food-producing animals, for medicinal products that enhance the productivity and efficiency of food production and ensure food safety when they are used in accordance with their approval specifications. The public health mission of regulatory agencies succeeds when they are able to put into the hands of the user an approved, safe and effective, well-manufactured and appropriately labelled medicine, and when there are adequate controls in place to assure proper compliance.

Development of a quick reference guide to accommodate vegetarianism in diet therapy for multiple disease conditions.

With more Americans adopting vegetarian lifestyles, health-care professionals will encounter more patients whose vegetarian dietary practices must be reconciled with the therapeutic diets required by a variety of disease conditions. The development of a quick reference guide was undertaken to address several areas of concern unique to vegetarian patients and provide an expandable clinical resource. For the disease conditions examined, nutrition care goals were found to be met without compromising vegetarian practices.

Description of acute ozone response as a function of exposure rate and total inhaled dose.

The magnitude of respiratory responses to short-term ozone exposure is known to be a function of the exposure variables concentration (C), duration of exposure (T), and minute ventilation (VE) during exposure. The purpose of this study was to identify a mathematical model that described ozone-induced mean decrements in forced expiratory volume in 1 s (FEV1) as a function of exposure rate (C x VE) and total inhaled dose (C x VE x T). Three hundred seventy-four young male nonsmokers participated in 504 exposures to several concentrations of ozone for 2 or 6.6 h. Mean percent change in FEV1 was calculated for each hour of exposure and was fit to the exposure variables by use of nonlinear models. We identified a general sigmoid-shaped model that well described the observed mean response in terms of exposure rate and total inhaled dose over a wide range of C and T. By fixing the value of a single parameter, this model reduces to a simpler form, which was adequate for description of responses over narrower ranges of exposure conditions. We concluded that the observed mean responses to short-term ozone exposure were adequately described by the nonlinear models identified in this study and that models of this form may be useful for description of responses over a wide range of C and T.

Prediction of carboxyhemoglobin formation due to transient exposure to carbon monoxide.

Fifteen men were exposed to 6,683 ppm C18O for 3.09-6.65 min. Arterial and antecubital vein blood samples were drawn at 1-min intervals beginning at the start of C18O inhalation and ending 10 min later. Simultaneously, alveolar ventilation was calculated from the measured values of minute ventilation and dead space. All other parameters of the Coburn-Forster-Kane equation (CFKE), except the Haldane affinity ratio, were measured separately in each subject. Means of CFKE predictions of increases in venous HbCO (delta HbCO) in samples collected approximately 2 min after cessation of exposure were accurate, but the range in errors of prediction for individual subjects was +/- 3.8% HbCO, depending on the time after exposure cessation. Increases in venous and arterial HbCO were inaccurately predicted during and immediately after HbCO formation, however. Venous blood was overestimated during CO uptake because of a delayed appearance of HbCO. Individual subjects differed markedly in the degree of delay of HbCO appearance in venous blood. Arterial delta HbCO was consistently underestimated either by the CFKE or by predictions based on venous blood samples. Thus, exposure of such organs as brain or heart to HbCO may be substantially higher than expected during transient high-level CO exposure.

Effect of regional circulation patterns on observed HbCO levels.

In an earlier experiment, we briefly exposed 15 young men to high levels of CO while simultaneously monitoring arterial and peripheral venous HbCO levels. The arterial HbCO levels were considerably higher than the venous levels during the CO exposure. Furthermore, great variation in the difference between arterial and venous HbCO levels was observed, with the maximal difference for each subject ranging from 2.3 to 12.1% HbCO. In the present paper, we suggest an explanation for the observed differences between arterial and venous HbCO on the basis of the regional circulation of the forearm, where both samples were taken. Because regional circulation patterns are known to vary with physical training, the differences in physical training between subjects may account for the observed variation. An expanded model was derived from the Coburn-Forster-Kane equation, which reflects the above hypothesis. Most of the parameter values for the expanded model were measured on individual subjects. Literature values were used for other parameters. Two parameters were estimated using five of the subjects and were then used in the predictions of the expanded model for the remaining subjects.

Thalamically projecting cells of the lateral cervical nucleus in monkey.

The number, location, and morphology of thalamically projecting lateral cervical nucleus (LCN) cells were determined in monkey using retrograde transport of wheatgerm agglutinin-conjugated horseradish peroxidase. These data were compared to the total population of LCN neurons as determined by Nissl stain. In 4 Macaca fascicularis and one Saimiri sciureus the average size of the thalamic projection from LCN was found to be 506 +/- 94 cells contralateral to the injections. Thalamically projecting LCN neurons were located between the lower medulla and the third cervical segment; approximately 90% of these cells were in the first two cervical segments. Morphologic analysis of thalamically projecting LCN cells showed that they were smaller in size, and more oblong in shape in caudal regions of the nucleus. In 3 macaques, the average total number of LCN cells was determined to be 1617 +/- 908 on one side, in Nissl material. In these Nissl-stained preparations LCN neurons were found as far caudal as the fourth cervical segment; 68% were located in the first two cervical segments. Hence, thalamically projecting LCN neurons in the monkey are located in the rostral portion of the nucleus and comprise about one-third of the total population. Comparison of these data with reports in the literature imply that, unlike the cat, the major projection from LCN in monkeys is to the mesencephalon rather than to the thalamus.

Giant cervical epidural veins after craniectomy for head trauma.

Markedly dilated cervical epidural veins and right upper extremity weakness developed in a 43-year-old man 4 months after contralateral craniectomy for head trauma. After cranioplasty, his symptoms improved markedly and the size of the veins returned to normal. These findings suggest that enlarged cervical epidural veins may occur without an underlying vascular lesion and that upper extremity weakness may occasionally be attributable to spinal cord venous stasis.

Magnetic resonance imaging measurements of pituitary stalk compression and deviation in patients with nonprolactin-secreting intrasellar and parasellar tumors: lack of correlation with serum prolactin levels.

Prolactin (PRL) Levels are frequently elevated in patients with non-PRL-secreting adenomas or other intrasellar and parasellar diseases ("pseudoprolactinomas"). This phenomenon is believed to result from a loss of dopaminergic inhibition on pituitary lactotrophs and is known as the "stalk-section effect." Using magnetic resonance imaging scans and a high-magnification sella technique, we measured a number of parameters indicative of the disruption of normal sellar structures. The investigator was blind to the patient's diagnosis and PRL level while collecting the data. Parameters measured were the tumor size, the angular deviation of the pituitary stalk, and the degree of compression of the pituitary stalk. Measurements were obtained from 44 patients with pathologically confirmed tumors that had no immunohistochemical reactivity to PRL. PRL levels were often higher than expected. Four patients (9%) had a PRL level of more than 150 ng/ml, and three patients (7%) had a PRL level of 200 ng/ml or more. One patient with a plasmacytoma eroding the sella floor had a PRL level as high as 504 ng/ml. There was no significant correlation of PRL level and the degree of pituitary stalk compression, stalk deviation, or tumor size. PRL levels were found to be markedly elevated in some patients with a tumor causing little distortion of the pituitary stalk. Conversely, PRL levels were often normal despite evidence of massive distortion of the stalk. Therefore, magnetic resonance imaging evidence of pituitary stalk distortion cannot be used to determine the diagnosis of prolactinoma versus pseudoprolactinoma in most cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Endoscopic colloid cyst surgery.

OBJECTIVE: The purpose of this report is to discuss the technical aspects of operating on colloid cysts through a transventricular approach, with rigid endoscopes. METHODS: Twelve patients underwent 14 endoscopic operations in attempts to treat their colloid cysts. All patients were symptomatic, with headache being the most common complaint (8 of 12 patients). Six patients in this series exhibited enlarged ventricles associated with their colloid cysts. Using rigid endoscopes of < or =3.5-mm diameter, the cysts were inspected and fenestrated. Both hard and soft cyst contents were evacuated, and then the walls of the cysts were coagulated inside and outside. External ventriculostomy tubes were usually placed. Technical obstacles to successful completion of endoscopic colloid cyst surgery are discussed. RESULTS: For 11 of the 12 patients, the colloid cysts could be treated via an endoscopic approach. The mean follow-up time was 173 weeks, and the median follow-up time was 125 weeks. For the 12th patient, bilateral scarring of the foramina of Monro precluded direct surgery; therefore, a septostomy was performed and a ventriculoperitoneal shunt was placed. CONCLUSION: Endoscopic transventricular surgery should be considered for the treatment of colloid cysts.

Transnasal endoscopic surgery of the pituitary gland: technical note.

OBJECTIVE: An approach to transnasal transsphenoidal debulking of pituitary tumors using endoscopic guidance is presented. METHODS: Technical details of this approach using an endoscope inserted through one nostril and operating instruments inserted through a submucosal tunnel created via the other nostril are discussed. RESULTS: Ten patients who had operations are tabulated. Illustrative cases are presented. CONCLUSION: Endoscopic debulking of pituitary tumors can provide good results with minimal operative morbidity.

Dose response for UV-induced immune suppression in people of color: differences based on erythemal reactivity rather than skin pigmentation.

Ultraviolet radiation (UVR) is known to suppress immune responses in human subjects. The purpose of this study was to develop dose responses across a broad range of skin pigmentation in order to facilitate risk assessment. UVR was administered using FS 20 bulbs. Skin pigmentation and UVR sensitivity were evaluated using Fitzpatrick classifications, minimal erythemal dose (MED), slope of the erythemal dose response curve (sED), baseline pigmentation and tanning response. To assess immune responses dinitrochlorobenzene (DNCB) was applied to irradiated buttock skin 72 h after irradiation. Two weeks later DNCB was applied to the inside upper arm. Skin thickness was measured before and after challenge. Dose response was modeled (to obtain a regression line) for the entire group of 185 subjects. With the exception of sED none of the above-mentioned pigmentation indicators contributed significantly to variability around the regression line. Thus, differences in sensitivity for multiple skin types based on Fitzpatrick classification or MED were not observed. However, differences in immune sensitivity to UVR were detected between subjects with steep erythemal dose response curves and those with moderate or flat responses. For subjects with steep erythemal responses the dose calculated to suppress the immune response by 50% was 114 mJ/cm2. This group included individuals with Fitzpatrick skin types I-V, MED for these subjects ranged from 30 to 80 mJ/cm2. The 50% suppression dose for subjects with weak or no erythemal response could not be computed (the dose response was flat). This resistant group included subjects with skin types IV-VI and MED for these subjects ranged from 41 to > 105 mJ/cm2. This study provides a human dose response for UVR suppression of contact sensitivity that will be useful in risk assessment. It is the first study to provide this information using the FS sun lamp and is the first study to include people of color. The sED appears to be a new variable for identifying sensitive subjects at risk of UVR-induced immune suppression.

The role of spatial filtering in sensitivity regulation.

The role of spatial filtering in controlling sensitivity to increments is hard to evaluate under normal viewing conditions because eye movements lead to a confounding of spatial and temporal transients. We measured sensitivity to increments on different sized backgrounds in photopic and scotopic vision when the backgrounds were stabilized on the retina, thus eliminating temporal transients. The saturating effect of small fields on photopic thresholds was preserved under these conditions indicating that spatial filtering by retinal cells is critical in maintaining photopic sensitivity. Some effect of spatial pattern on sensitivity in stabilized vision was also observed in scotopic vision, although it was much smaller than was observed in photopic vision. The interaction effects between rod and cone systems that are observed with small backgrounds were also preserved in stabilized vision, implicating a very peripheral site for the generation of these interactions.

Compensatory tracking in humans with elevated carboxyhemoglobin.

A total of seventy-four men divided into five groups performed a compensatory tracking task for 4 hr with group mean carboxyhemoglobin (COHb) levels of 0.9, 5.6, 6.1, 11.4 or 16.6%. In all but one group, COHb was formed in approximately 5 min by having the subject breathe a high concentration of carbon monoxide (CO) from a Douglas bag. An appropriate low level of CO in the exposure/test chamber maintained the elevated COHb for the 4-hr duration of the experiment. A slow COHb formation group, not exposed to CO during bag breathing, which was only exposed to low-level CO in the exposure/testing chamber, served as a positive control. Even though mean tracking error scores increased in a nearly monotone manner as a function of COHb, the effects were not statistically significant. Even at the highest dose, the increase in tracking error was small. The increased mean error score due to rapid formation was virtually the same as that due to slow formation.

Response properties of upper cervical spinothalamic neurons in cats. A possible explanation for the unusual sensory symptoms associated with upper cervical lesions in humans.

Lesions in the foramen magnum and upper cervical spinal cord often cause an unusual array of sensory changes and atrophic weakness, primarily involving the ipsilateral forelimb. Furthermore, small midline myelotomies performed at C1 often lead to widespread analgesia covering most of the body in patients with chronic pain. These observations challenge physicians' understanding of anatomy and physiology in the upper cervical region. Using single cell recording techniques the authors have shown that spinothalamic neurons in the second cervical segment of cats have complex response properties, often responding to stimuli throughout the body. These findings together with a review of clinical and basic science literature are used to provide explanations for the unusual signs and symptoms observed in patients with upper cervical and foramen magnum lesions.

Comparing solutions to the linear and nonlinear CFK equations for predicting COHb formation.

The Coburn, Forster, Kane model of COHb formation as a result of exposure to CO exists in two forms: the linear CFK equation that assumes a constant level of oxyhemoglobin; and the nonlinear CFK equation that allows the oxyhemoglobin level to vary with the carboxyhemoglobin level. Although both equations are currently used, no rigorous analysis exists to show under what conditions the two models determine substantially different solutions. This paper provides such an analysis and shows that the linear model may be used as a reasonable approximation over a much wider range of carboxyhemoglobin levels than had been supposed on physiological grounds.

Incorporating observability thresholds of tumors into the two-stage carcinogenesis model.

This paper discusses a general way of incorporating the growth kinetics of malignant tumors with the two-stage carcinogenesis model. The model is presented using time-homogeneous rate parameters. In that case, the differential equations comprising the model are straightforward to solve using standard numerical techniques and software. An extension of the method to time-dependent rate parameters is included in Appendix A. Allowing the rate parameters to be time-dependent does incur computational cost. An expression is given for the expected time without visible tumor, a generalization of the expected time to an observable tumor that includes the possibility of tumor regression. The model is illustrated using incidental liver tumor data in control rats from NTP rodent carcinogenicity studies, using linear birth-death kinetics of tumors combined with a non-absorbing detection limit. The approach is also shown to be potentially useful with tumor observability thresholds having more complicated features.

Chronic pulmonary artery balloon counterpulsation in sheep via percutaneous route.

BACKGROUND: In clinical practice pulmonary artery balloon counterpulsation (PABC) has been utilized only in the operative setting with the balloon housed in a graft attached to the pulmonary artery. Clearly, percutaneous insertion of a dedicated pulmonary artery balloon is a desirable goal for patients requiring temporary assist for right ventricular failure. METHODS: To address the question of right sided cardiopulmonary tolerance for a chronic indwelling pulmonary artery balloon, six adult ewes underwent percutaneous placement of an 11 ml pulmonary artery balloon, via the femoral vein. Effective pumping and timing were monitored for 48 hours at which time the animals were sacrificed. At autopsy gross and microscopic study of all right heart structures, the pulmonary arteries and the lungs were studied for adverse effects. RESULTS: There were inconsequential minor abrasions to right heart structures in most animals. The pulmonary artery in five of six animals revealed ecchymoses and some transmural hemorrhage, but no necrosis or perforation. There was no pulmonary injury that could not be ascribed to postoperative atelectasis. CONCLUSIONS: This study demonstrates that chronic pulmonary artery balloon counterpulsation can be carried out for a period of 48 hours without significant injury to right heart and pulmonary structures in the ovine model

Determination of the Transmittance Uniformity of Optical Filter Standard Reference Materials.

An instrument based on a scientific grade charge-coupled device (CCD) camera system is performance-qualified to evaluate the transmittance homogeneity of solid optical filter standard reference materials. Measurement results are presented for the new instrument, and compared, where appropriate, with an older, scanning instrument, for a variety of filters spanning transmittances down to 0.01. The new instrument is found to give comparable results with the older instrument, with reduced random uncertainty and improved information content.

High resolution MR technique in the diagnosis of mesial temporal sclerosis. Correlative MRI and pathological features.

Mesial temporal sclerosis, otherwise known as hippocampal sclerosis, is the most common entity associated with medically intractable temporal lobe epilepsy. The neuronal loss and gliosis of the hippocampus that is pathologically characteristic of this disorder is thought to serve as an epileptogenic substrate. Accurate identification and localization of this pathology is crucial before surgery is considered to potentially cure medically intractable seizures. Magnetic resonance imaging plays a central role in the presurgical work-up. We present a 44-year-old man with a history of intractable partial complex seizures secondary to right-sided mesial temporal sclerosis and discuss the magnetic resonance imaging findings utilizing a high resolution technique.

A statistical model for FEV1 response to arbitrary dynamic ozone exposure conditions.

Lung function response to inhaled ozone at ambient air pollution levels is known to be a function of ozone concentration, exposure duration, and minute ventilation. Most data-driven exposure-response models address exposures under static condition (i.e., with a constant ozone concentration and exercise pattern). Such models are simplifications, as both ambient ozone concentrations and normal human activity patterns change with time. The purpose of this study was to develop a dynamic model of response with the advantages of a statistical model (a relatively simple structure with few parameters). A previously proposed mechanistic model for changes in specific airways resistance was adapted to describe the percent change in forced expiratory volume in one second (FEV1). This model was then reduced using the fit to three existing exposure-response data sets as criterion. The resulting model consists of a single linear differential equation together with an algebraic logistic equation. Under restricted static conditions the model reduces to a logistic model presented earlier by the authors.