Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity.

Monensin, a monovalent ion-selective ionophore, facilitates the transmembrane exchange of principally sodium ions for protons. The outer surface of the ionophore-ion complex is composed largely of nonpolar hydrocarbon, which imparts a high solubility to the complexes in nonpolar solvents. In biological systems, these complexes are freely soluble in the lipid components of membranes and, presumably, diffuse or shuttle through the membranes from one aqueous membrane interface to the other. The net effect for monensin is a trans-membrane exchange of sodium ions for protons. However, the interaction of an ionophore with biological membranes, and its ionophoric expression, is highly dependent on the biochemical configuration of the membrane itself. One apparent consequence of this exchange is the neutralization of acidic intracellular compartments such as the trans Golgi apparatus cisternae and associated elements, lysosomes, and certain endosomes. This is accompanied by a disruption of trans Golgi apparatus cisternae and of lysosome and acidic endosome function. At the same time, Golgi apparatus cisternae appear to swell, presumably due to osmotic uptake of water resulting from the inward movement of ions. Monensin effects on Golgi apparatus are observed in cells from a wide range of plant and animal species. The action of monensin is most often exerted on the trans half of the stacked cisternae, often near the point of exit of secretory vesicles at the trans face of the stacked cisternae, or, especially at low monensin concentrations or short exposure times, near the middle of the stacked cisternae. The effects of monensin are quite rapid in both animal and plant cells; i.e., changes in Golgi apparatus may be observed after only 2-5 min of exposure. It is implicit in these observations that the uptake of osmotically active cations is accompanied by a concomitant efflux of H+ and that a net influx of protons would be required to sustain the ionic exchange long enough to account for the swelling of cisternae observed in electron micrographs. In the Golgi apparatus, late processing events such as terminal glycosylation and proteolytic cleavages are most susceptible to inhibition by monensin. Yet, many incompletely processed molecules may still be secreted via yet poorly understood mechanisms that appear to bypass the Golgi apparatus. In endocytosis, monensin does not prevent internalization. However, intracellular degradation of internalized ligands may be prevented.(ABSTRACT TRUNCATED AT 400 WORDS)

Resistance to ivermectin by Haemonchus contortus in goats and calves.

Efficacy of ivermectin on susceptible or resistant populations of the parasitic nematode Haemonchus contortus was determined in cattle and goats held in a barn. Goats were each infected with 3000 infective, ivermectin-susceptible or -resistant H. contortus larvae on day 0 and reinfected with 2000 infective larvae on day 24. Goats were treated orally with 600 micrograms kg-1 ivermectin on day 31. No significant differences were detected in blood packed cell volume (PCV) or total protein (TP), prepatent period, or epg among the four groups of goats that were each infected with one of four parasite strains (one susceptible, three resistant). There were no differences among the four parasite strains in the numbers of infective larvae that developed to the third larval stage from fecal cultures or in the viability of cultured infective larvae when held in the laboratory at 27 +/- 1 degrees C for 14 weeks. After treatment with ivermectin, there were significant differences among the parasite strains in PCV, TP, and epg. Total worm counts were reduced by 94 to 97% with three times the recommended dose. Immature and adult Skrjabinema ovis were also present in two treated goats. In a second test, one goat infected once with 10,000 infective larvae of a resistant strain of H. contortus and then treated with nine doses of ivermectin, increasing from 500 to 2000 micrograms kg-1 over a period of 133 days, had 35 adult worms at necropsy. In a third test, three calves were readily infected with an ivermectin-resistant strain of H. contortus from goats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of cadmium on ethanol self-administration using a sucrose-fading procedure.

Rats were exposed for 70 days to either a diet containing 100 ppm cadmium (Group Cadmium) or a control diet with no additives (Group Control). Subsequently, all animals were trained to lever press for a 20% sucrose solution. Across several phases, sucrose was faded out as the reinforcer and gradually replaced with a 10% ethanol solution. A subsequent operant choice (concurrent) test, during which pressing one lever resulted in a dipper presentation of ethanol and the other lever provided water, was followed by a single-lever test where sucrose was reinstated as the reinforcer. The results showed that although cadmium-treated rats lever pressed more than controls during the early phases of the sucrose-fading procedure, animals exposed to cadmium lever pressed at lower rats than controls for ethanol during the concurrent test. There were no group differences on the final sucrose test. The possibility that cadmium may alter sensitivity to ethanol is discussed.

Effects of T-2 toxin on saccharin aversion and food consumption in adult rats.

The present experiment used a saccharin aversion paradigm to evaluate the potential aversive action of T-2 toxin, a trichothecene mycotoxin that induces emesis and weight loss. Adult male rats were fed either a control diet or a diet adulterated with 640 ppm lithium chloride (positive control) or with 2.5, 5.0 or 10.0 ppm T-2 toxin and given access to a 0.1% saccharin solution and to tap water during four training days. The rats were then shifted to the control diet during three extinction days. Moderate saccharin aversion induced by the positive control diet and the 5.0 and 10.0 ppm T-2 diets was apparent on the third day of exposure and the aversion to the saccharin solution abated during the extinction trials. Saccharin aversion was evident at levels of T-2 toxin that did not induce obvious tissue pathology.

Bronchial adenoma: a malignant misnomer.

Bronchial adenomas are a histologically and clinically diverse group of respiratory tract neoplasms arising from mucous glands and ducts of the tracheobronchial tree. They represent 1% of pulmonary malignancies. The traditional concept of a single, histologically benign form is challenged and the malignant potential of these tumors is stressed. Three main cell types with their characteristic histopathologic and clinical features are discussed: carcinoid, adenoid cystic carcinoma, and mucoepidermoid carcinoma. A case of bronchial carcinoid with hepatic metastases is reported, emphasizing the malignant potential of this controversial group of tumors. The appropriate diagnostic evaluation is outlined and aggressive surgical management is stressed. Chemotherapy and radiation therapy which are reserved mainly for palliation do not add to overall five year survival rates.

Computed tomography in maxillofacial trauma.

Computed tomography (CT) has become the key diagnostic modality in the evaluation of head trauma. Experience with CT in the operative assessment of maxillofacial injuries is limited, however. Plain films and multidirectional tomography have been used until now to define fractures in the facial region. We examined 27 patients sustaining maxillofacial trauma with CT scans. Ten patients were studied in the coronal plane, 12 in the axial plane, and the remaining 5 in both the axial and coronal planes. Polycycloidal tomography in the coronal and/or sagittal plane was obtained in 18 patients for comparison with the CT scan. Fracture lines, bony fragments, and associated skeletal deformities were clearly identified by CT scan in all 27 patients permitting the diagnosis of zygomatic, orbital floor, nasoethmoidal complex, LeFort, temporal bone, frontal sinus, and mandible fractures. More importantly, concomitant intracranial injuries including epidural and intracerebral hematomas, traumatic encephalocoele, and pneumocephalus were readily seen. In addition, facial and orbital soft tissue structures including the globe, optic nerve, orbital fat, and extraocular muscles were easily examined by adjusting the CT level and window settings. Overall, CT yielded additional information not available from polytomography in 15 of 18 cases when both modalities were used. Multidirectional tomography is currently superior to CT scanning if fine, intrinsic bone detail is required. However, we have found that complex fractures with fragmentation are more easily identified on CT scans than conventional tomography because of superior contrast resolution of computed tomography. With improved spatial resolution, CT scanning may totally supplant multidirectional tomography in the evaluation of maxillofacial trauma.

Adenocarcinoma of the ethmoid following radiotherapy for bilateral retinoblastoma.

Adenocarcinoma of the ethmoid sinus is rare, representing only 4-8% of malignancies of the paranasal sinuses. An extraordinary case of papillary adenocarcinoma of the ethmoid sinus arising 30 years following high-dose radiotherapy for bilateral retinoblastoma is presented. Retinoblastoma, though occurring only once in every 23,000 to 34,000 births, is the most common malignant intraocular tumor of childhood. Second fatal mesenchymal and epithelial primaries have been described in 8.5% of patients with bilateral retinoblastomas previously treated with radiotherapy; however, papillary adenocarcinoma arising within the paranasal sinuses has not been reported. Histologically, the findings of a papillary pattern of poorly differentiated, mucicarmine-staining cells enclosing gland-like spaces, and the absence of pseudorosettes, melanin, mesenchymal and peripheral neural elements supports an epithelial origin of this tumor. Agressive treatment including partial maxillectomy, radical pansinusectomy, radical neck dissection followed by regional radiotherapy and systemic chemotherapy failed to prevent the development of fatal hepatic metastases. The high incidence of second fatal primary neoplasms in patients with bilateral retinoblastomas receiving radiation suggests an innate susceptibility that may add to the risk of radiotherapy. Careful long-term head and neck surveillance is mandatory if early aggressive management of these extremely lethal tumors is to be successful.

Continuous measurements of skin surface oxygen and carbon dioxide tensions in obstructive sleep apnea.

We have found that skin surface electrodes for continuously measuring oxygen (PSO2) and carbon dioxide (PSCO2) tensions provide reliable means of determining whether infants with apnea due to airway obstruction during sleep require treatment. Nine patients referred for evaluation of aqnea during sleep were studied. In 6 patients with PSO2 less than 50 torr during sleep, the hypoxic episodes were clearly associated with partial or total airway occlusion as judged by increasing respiratory effort without concomitant airflow. PSCO2 was found to increase during the episodes of obstruction in all 6 patients. These patients were treated with 1. tracheotomy, 2. tonsillectomy and adenoidectomy in 2 patients, 3. bilateral mandibular condylotomies, 4. pharyngeal flap release, and 5. discontinuing topical nasal decongestants. After treatment, all had decreased hypoxia, hypercarbia, or airway obstruction. Two of the remaining 3 patients had no alterations of PSO2 or PSCO2 associated with airway obstruction during sleep. The third exhibited hypoxia and hypercarbia secondary to central apnea. We conclude, therefore, that continuous monitoring of skin surface oxygen and carbon dioxide tensions is useful in evaluating children with obstructive sleep apnea.

Transbronchial drainage of pulmonary abscesses with the flexible fiberoptic bronchoscope.

Flexible fiberoptic bronchoscopy with multiplanar fluoroscopic control is shown to be effective in the transbronchial drainage of pulmonary abscesses. A new technique which permits the intracavitary placement of brush forceps and fine arterial catheters is described. This has facilitated the rapid defervescence of fever and established immediate endobronchial drainage. Seventy percent of patients had complete radiographic closure of their abscess cavities at three months. Clinical findings are presented and the role of aspiration in pathogenesis of pulmonary abscess is stressed.

The effects of naltrexone on cadmium-induced increases in oral ethanol self-administration.

Adult male rats were exposed to a standard laboratory diet (N = 20), or an adulterated diet containing 100 ppm added cadmium (N = 20), for 60 days. On Day 61, half the animals from each dietary condition received subcutaneous implants of two 30 mg naltrexone pellets, and the remaining half the animals received identical implants of 30 mg placebo pellets. One week later, animals from groups created by this interaction (Groups Control-Placebo, Control-Naltrexone, Cadmium-Placebo, Cadmium-Naltrexone) were tested in an ethanol self-administration paradigm that presented a 10% ethanol solution (v/v) in both a choice and nonchoice format. The results indicated that cadmium exposure increased the oral self-administration of ethanol in the choice setting where water was offered as an alternative, and the opiate antagonist naltrexone failed to attenuate this effect.

Spatial analysis of midfacial fractures with multidirectional and computed tomography: clinicopathologic correlates in 44 cases.

The use of conventional tomography and recent application of computed tomography to the assessment of facial injuries permit a more precise preoperative spatial analysis of complex midfacial fractures. Forty-four patients sustaining Le Fort I, II, or III maxillary fractures underwent multidirectional or computed tomography (CT) or both. The patterns of fractures of the maxilla and associated fractures of the mandible, zygomas, nasoethmoidal complex, frontal sinus, skull base, and cranial vault were correlated with surgical or clinical findings or both. In 91% of cases, CT or multidirectional tomography or both correctly identified the spatial pattern of fracture of the maxilla and its supporting pillars. Pure Le Fort II fractures were seen in only nine patients, while an isolated pure Le Fort I or III fracture was not encountered. Le Fort II and III fractures were commonly associated with additional tripod, frontal sinus, or nasoethmoidal complex dislocations.

Progressive neonatal airway obstruction secondary to cervical thymic cyst.

Cervical thymic cysts are extremely unusual neoplasms that only rarely produce signs and symptoms of upper airway tract compromise. Less than 7% of patients initially have dyspnea or hoarseness. We report the first known case of progressive neonatal airway obstruction secondary to a rapidly enlarging cervical thymic cyst. Because one half of these benign tumors may demonstrate mediastinal extension, computed axial tomography or B-mode ultrasonography or both is recommended prior to surgical excision. Review of the literature confirms that the majority are successfully removed via a transcervical approach without recurrence.

Computerized axial tomography in inflammatory pseudotumor of the orbit.

Although thyrotoxicosis and orbital complications of acute ethmoid or frontal sinusitis are among the most common causes of unilateral exophthalmos, inflammatory pseudotumor is frequently accompanied by progressive acute unilateral proptosis. Because the associated chemosis, scleral erythema, and ophthalmoplegia constitute a spectrum of clinical findings present in numerous inflammatory orbital disorders and systemic diseases, the diagnosis of inflammatory pseudotumor is one of exclusion, often requiring orbital biopsy. Four patients without evidence of sinusitis, endocrinopathy, collagen vascular disease, or Wegener's granulomatosis are described. The diagnosis of orbital pseudotumor was disclosed by computed axial tomography, thus avoiding orbitotomy. The finding of scleral and choroidal thickening with enhancement following intravenous contrast injection represents a select group of patients with orbital pseudotumor and differentiates them from patients with endocrine exophthalmopathy or neoplasms. This noninvasive technique is extremely valuable because early diagnosis is critical for successful treatment. All four patients responded dramatically to high-dose corticosteroid therapy. In the absence of significant clinical response, however, Wegener's granulomatosis, lymphoma, and rhabdomyosarcoma, especially in younger patients, must be carefully excluded. Orbital exploration or decompression or both are used when proptosis, headache, or orbital pain does not resolve promptly, visual acuity deteriorates, or the diagnosis remains unknown.

Adaptation in the function of pharyngeal constrictor muscles.

The palatopharyngeus and pharyngeal constrictor muscles were studied by electromyography (EMG) and by direct observation with a flexible fiberoptic scope in the anesthetized as well as in the alert rhesus monkey. The muscles were monitored to determine the change in their discharge with nasal obstruction, head posture, head extension, and swallowing. The results indicated that certain regions of the middle and inferior pharyngeal constrictors never discharged during deglutition. Extending the head could induce a tonic discharge in fibers of the middle pharyngeal constrictor for the duration of head extension. Placement of water in the hypopharynx not only induced a sustained laryngospasm but also a tonic discharge in the select fibers of the superior and middle pharyngeal constrictors. Changing from a supine to an upright posture, or obstructing the nasal cavity, could induce a rhythmic discharge. These studies indicate that there are functional components of fibers within each of the anatomically recognized pharyngeal constrictors.

Severe upper airway obstruction caused by bullous pemphigoid: diagnostic usefulness of the flow-volume curve.

The site and severity of upper airway obstruction accurately determined by analysis of the flow-volume curve obtained from a dyspneic patient with bullous pemphigoid. The limitation of maximum inspiratory flow to 0.5 L/s and of maximum expiratory flow to 0.7 L/s over most of the vital capacity suggested that the lumen of the extrathoracic trachea was narrowed to a diameter of 3 mm. The marked improvement in flow with the patient breathing a helium-oxygen mixture further confirmed that flow was limited in a large central airway. The predictions made from analysis of the flow-volume curve were confirmed by fiberoptic bronchoscopic examination and by computerized axial tomography, which revealed severe supraglottic obstruction. After a tracheostomy was performed, maximal inspiratory and expiratory flows were normal.

Evaluation and treatment of frontal sinus fractures.

We treated twenty-three patients with blunt or penetrating wounds of the frontal sinus from 1978 through 1983. Nondisplaced anterior wall fractures were observed or explored. Posterior table fractures--with displacement confirmed by computed tomography or polycycloidal tomography--were explored. Either obliteration of the sinus or nasofrontal duct reconstruction with a Sewall-Boyden-McKnaught flap was selected, depending on the magnitude of duct injury. In all cases, the anterior wall was primarily reconstructed. All penetrating wounds with posterior table involvement were treated by cranialization of the frontal sinus and temporalis muscle obliteration of the nasofrontal ducts. Only one case of meningitis occurred, resulting in prolonged hospitalization.

Upper airway obstruction in infectious mononucleosis.

Life-threatening upper respiratory obstruction is an unusual complication of infectious mononucleosis. Although the majority of fatalities result from progressive bulbar paralysis or the Guillain-Barré syndrome, airway impairment primarily occurs as a result of pharyngeal lymphoid hyperplasia and associated faucial arch edema. Recent experience in a young child with infectious mononucleosis who exhibited progressive hypersomnolence, sleep apnea, and stridor during sleep is presented. In addition, a retrospective analysis of 72 cases of respiratory complications of infectious mononucleosis provides guidelines for specific airway management. Mild upper respiratory obstruction with persistent fever, severe odynophagia, and malaise is treated with parenteral corticosteroids. Immediate tonsillectomy using a halothane and oxygen induction technique is recommended for severe airway occlusion. Tracheotomy is currently reserved for those patients with progressive alveolar hypoventilation, hypercarbia, atelectasis, and bulbar paralysis. In general, tonsillectomy is well-tolerated, eliminating airway obstruction, improving swallowing function, and rapidly resolving pharyngeal discomfort.

Tracheotomy for infant botulism.

Botulism is a serious intoxication caused by ingestion of food containing preformed botulinus toxin and characterized by rapidly progressive bulbar paralysis, generalized weakness, and respiratory insufficiency. In 1976 a distinct clinical entity of infant botulism was recognized. The disease apparently results from intraintestinal toxin production which produces a defect in neuromuscular transmission by interfering with release of acetylcholine at cholinergic synapses. Five cases of infant botulism were identified at the Children's Hospital of Philadelphia between 1975 and 1977. Initial symptoms included constipation, slow feeding, lethargy and weak cry. Four of the patients progressed to respiratory insufficiency requiring nasotracheal intubation. Three of the infants with respiratory failure required tracheotomy. Because infants with respiratory failure may require support for months, we recommend that a tracheotomy be performed early in the management to avoid the complications associated with prolonged intubation. The effectiveness of antitoxin or antibiotics to treat infant botulism remains questionable and therefore prolonged respiratory supportive care is the mainstay of therapy. In addition, we offer guidelines for decannulation in cases of infant botulism. None of the patients in our series could be decannulated prior to initial discharge from the hospital.

Value of radionucleotide scanning in the staging of head and neck carcinoma.

The presence or absence of distant metastases in squamous cell carcinoma of the head and neck is critical in making rational therapeutic decisions. Radionucleotide bone and liver scans are frequently utilized in the initial evaluation of these patients for possible distant metastases. The true value of routine bone and liver scans in the initial staging of primary squamous cell carcinoma of the head and neck is unknown. One hundred eighteen patients with primary squamous cell carcinoma of the head and neck, evaluated during a five-year period, were retrospectively reviewed. Eight percent were stage I, 18% stage II, 21% stage III, 53% stage IV. Because metastatic carcinoma of the head and neck is primarily regional or pulmonary, the low prevalence of liver and bone metastases limits the usefulness limits the usefulness of these radionucleotide scans. We conclude that routine bone and liver scanning is not a valuable diagnostic technique in the initial staging of head and neck carcinoma when clinical or biochemical evidence of distant metastases is not present.

Newer techniques in fiberoptic bronchoscopy.

Flexible fiberoptic bronchoscopy has assumed a major role in the diagnosis and management of upper respiratory tract and pulmonary diseases. A new technique, utilizing a C-arm fluoroscopic control with an image intensification system, for the localization of peripheral lung lesions and subsegmental parenchymal infiltrates, is described. This method has proved useful in the early histologic and cytologic diagnosis of nonendoscopically visible bronchogenic carcinoma and in the drainage of lung abscesses. By employing a transendotracheal tube route with a ventilating, side-arm adaptor, continuous airway control and a selected inspired oxygen or anesthetic content is maintained. In addition, the problems of arterial hypoxemia, airway resistance, and ventilation-perfusion abnormalities are minimized. Several representative cases are discussed.