Charles N. Carney

Pathophysiology of acute acid injury in rabbit esophageal epithelium.

To increase our understanding of the pathophysiology of reflux esophagitis, we sought the early sequence of changes in mucosal structure and function in acutely acid-damage rabbit esophagus. Using a perfused catheter technique esophageal potential difference (PD) profiles were obtained in anesthetized rabbits before, during, and after perfusion of the lower one-half of the esophagus with phosphate-buffered saline or 80 mM NaCl. When acid perfusion reduced the lower esophageal PD by 40-50% or 80-100% of the initial values, the esophagus was removed, sectioned, and the mucosa studied with light microscopy, transmission electron microscopy, and Ussing chamber technique for evaluation of sodium and mannitol transport. The earlier stage of acid damage (PD 40-50%) was associated with reduced mucosal resistance fom 2,180 +/- 199 to 673 +/- 157 ohm cm2 and increased passive transport of sodium (0.10 +/- 0.06 to 1.82 +/- 0.48 microeq/h.cm2) and mannitol (0.008 +/- 0.003 to 0.051 +/- 0.012 microM/h.cm2) (p less than 0.05). There was no significant change in shirt circuit current (0.35 +/- 0.05 to 0.35 +/- 0.04) or net sodium transport (0.32 +/- 0.06 to 0.37 +/- 0.12) at this stage, and the only morphologic finding was dilated intercellular spaces on electron microscopy. The later stage of acid damage (PD 80-100%) exhibited a further reduction in resistance to 299 +/- 65 ohm.cm2 (p less than 0.05), a finding now accompanied by a reduction in short circuit current (0.35 +/- 0.05 to 0.21 +/- 0.04 microeq/h.cm2) and complete inhibition of net sodium transport (0.32 +/- 0.06 to 0.01 +/- 0.13) (p less than 0.05). Morphologic studies at this time revealed cellular necrosis, edema, and vesicle formation in the stratum spinosum. Both gross mucosal changes and transmural necrosis were notably absent. When esophageal perfusion was performed with a combination of acid (80 mM HCl-80 mM NaCl) and pepsin (100 microgram/ml), the morphologic and physiologic findings were essentially the same as with acid alone; however, the time of perfusion to reach either the 50 or 100% reduction in PD was shortened. The findings in this model can be explained on an initial increase in cellular and/or paracellular permeability followed by inhibition of active sodium transport. The resulting loss of osmolar regulation leads to cell necrosis in the stratum spinosum.

Barrett's Esophagus: Clinical, Endoscopic, Histologic, Manometric, and Electrical Potential Difference Characteristics

The clinical, endoscopic, histologic, manometric, and esophageal potential difference characteristics of 20 patients with columnar epithelia lining the lower esophagus (Barretts esophagus) are presented. Endoscopically, two distinct types were identified: a circumferential-type and an island-type Barretts esophagus. Patients with these types exhibited similarities in mean age, duration of symptoms, mean lower esophageal sphincter pressure, and frequency of gross esophagitis. Only patients with the circumferential lesion, however, had esophageal strictures or esophageal ulcers. Manometric testing revealed a range of lower esophageal sphincter pressures from 3 to 33 mmHg and qualitative motor abnormalities (i.e., aperistalsis, repetitive waves, tertiary waves) in 3 patients. Histologically, the frequency of epithelial types was junctional greater than specialized columnar greater than atrophic fundic epithelium. More importantly, dysplasia was identified in 2 patients with the circumferential lesion and in 1 patient with the island lesion. Potential difference measurements demonstrated that a high potential difference (greater than -25 mV) was highly specific (92%), but only moderately sensitive (70%) for detecting Barretts esophagus. Based on these findings, we conclude (a) that there are at least two endoscopically distinct types of Barretts esophagus involving the lower esophagus--a circumferential type and an island type, (b) that both types are associated with chronic gastroesophageal reflux, with the island type being accompanied by less severe epithelial injury than the circumferential type, and (c) that the identification of dysplasia in the two types suggests that both are unstable lesions requiring continued surveillance with endoscopy and biopsy.

Monolayer culture of human endometrium: Methods of culture and identification of cell types

SummaryMonolayer cultures can be established from human endometrial tissue after enzymatic dispersal into isolated glands or single cells. Three cell types that have distinct morphology by light and electron microscopy are observed in the resulting primary cultures. One cell type, an elongated spindle cell, is similar in appearance to fibroblasts derived from other tissues. A second cell type forms colonies of tightly cohesive cells, ranging in shape from oval to polygonal. These cells have typical organelles and junctional complexes characteristic of epithelial cells from the endometrium. The third cell type assumes a pavement-like appearance composed of polygonal cells when viewed by phase contrast microscopy, but lacks distinctive ultrastructural features of epithelial cells. These cells in culture resemble the endometrial stromal cell, the predominant cell type of the human endometrium in vivo. The epithelial cell does not survive subculturing but the other two cell types can be passaged through several generations and can be stored in liquid nitrogen and subsequently returned to culture.

Esophageal Potential Difference Measurements in Esophageal Disease

To determine if esophageal transmural electrical potential difference measurements are of use for evaluating esophageal disease, we recorded potential difference in 129 patients with one or more of the following: heartburn, dysphagia, and chest pain. All potential difference studies were performed at the time of esophageal manometry using a Ringer-perfused catheter technique which yields accurate and reproducible results in healthy subjects. In 103 of the 129 patients, esophageal potential difference measurements could be correlated with findings at manometry, endoscopy, and biopsy. The remaining 26 patients had primary esophageal motor disease and were not biopsied. The results of this investigation showed: (a) that 94% of patients with gross endoscopic lesions have an abnormal esophageal potential difference, (b) that an abnormal esophageal potential difference (found in only 1 of 24 patients with normal mucosa) is highly specific for the presence of esophageal mucosal disease, (c) that the type of potential difference abnormality may suggest the nature of the mucosal abnormality, for example high potential difference with Barretts esophagus and low potential difference with esophagitis or invasive carcinoma, and (d) that while an abnormal esophageal potential difference is highly sensitive for detecting gross esophagitis (38 of 40 patients), it is less sensitive for diagnosing microscopic esophagitis (8 of 16 patients). Based on these findings we conclude that the measurement of esophageal potential difference at the time of manometry can provide additional valuable information about the state of the esophageal mucosa.

Clear‐cell carcinoma of the endometrium

The clinical data of 22 patients with clear cell adenocarcinoma of the endometrium treated at the University of North Carolina Memorial Hospital are reported. In addition, the data with particular reference to survival, site of recurrence, and treatment are combined with information from two previous reports of clear cell adenocarcinoma of the endometrium to better define survival. It is noted that the patients with clear cell adenocarcinoma of the endometrium were older and had an overall poorer survival than is reported for adenocarcinoma of the endometrium (nonclear cell). Patients with Stage I clear cell carcinoma of the endometrium, however, had a similar five‐year survival to Stage I adenocarcinoma of the endometrium. The paper also examines treatment methods and correlates these with site of recurrence as well as survival.

High‐dose methotrexate in small cell lung cancer: Lack of efficacy in preventing CNS relapse

Few studies have incorporated high‐dose methotrexate (MTX) with leucovorin rescue in the treatment of small cell lung cancer (SCLC). Potentially therapeutic levels of MTX can be achieved in the central nervous system (CNS) by systemic administration of high doses of this drug. Utilizing a combination chemotherapy program of Adriamycin, vincristine, cyclophosphamide, and methotrexate, 31 patients were sequentially assigned to receive either low‐dose MTX (40 mg/m2), or high‐dose MTX (500 mg/m2) with leucovorin rescue. Radiation therapy to the primary site was also administered. At these dosage levels there were no statistically significant differences in response rate or survival between the two groups. High‐dose MTX did not prevent the appearance of CNS disease; there being 2/15 and 3/15 CNS relapses in the HD MTX and LD MTX treated groups, respectively. The occurrence of CNS disease did not significantly affect overall survival as compared to patients not similarly affected.

Diphenylhydantoin-Induced Hepatic Necrosis: A Case Study

A patient with post-traumatic seizure disorder developed lymphadenopathy, exfoliative dermatitis, and hepatic failure while on diphenylhydantoin therapy and died in hepatic coma. Autopsy disclosed massive hepatic necrosis. The clinical and pathological pictures are similar to the six previously reported cases of diphenylhydantoin-induced hepatic necrosis, with the exception of the time of onset of hepatic failure, which is explained. The cause of such hepatotoxicity is unknown, although hypersensitivity is postulated. It appears that studies of liver function in patients receiving diphenylhydantion are indicated to assess the true indicence of hepatocellular injury.

Nylon brush improves collection of cervical cytologic specimens

A prospective, randomized study was performed to compare the efficacy of a combined endocervical and ectocervical nylon brush with the cotton-tipped swab and wooden spatula for obtaining cervical cytologic specimens. Strict objective criteria were used to determine the adequacy of Papanicolaou smears on the basis of the number of cells present. The two methods were equally effective in collecting ectocervical smears. However, 96% of endocervical smears obtained with the nylon brush contained greater than 50 cells, compared with 58% of swab and spatula smears. Only 1.4% of brush samples contained no endocervical cells, versus 19% of swab and spatula smears. The presence of endocervical cells confirms adequate sampling of the transitional zone. Use of the cytologic Papanicolaou brush may result in fewer false negative and inadequate Papanicolaou smears.

Chapter 1 Studies of Human Endometrium in Organ Culture

Publisher Summary The chapter focuses to gain a greater understanding of the process of chemical carcinogenesis in human endometrium by observing long-term toxic and carcinogenic effects of chemicals on this tissue. Such observations require that methods be developed for the long-term maintenance morphological and biochemical properties of the endometrium tissue in vitro as organ cultures. This chapter describes such an in vitro model designed for long-term maintenance of human endometrial explants in organ culture. One feature of the methods mentioned that contributed to the sustained vitality of our organ cultures is the use of L-glutamine at concentrations much higher than those used in earlier studies with endometrial tissue. The results of this study demonstrate that human endometrial tissue can be maintained as organ cultures in vitro for many months. The tissue in culture retains differentiated morphology, responsiveness to hormones, and capacity for macromolecular synthesis. These properties provide opportunities for a wide variety of experimental studies. Human endometrial organ cultures provide a promising system for attempting to transform human cells in organ culture.

Malignant histiocytosis. A cytochemical and electron microscopic study of an unusual case

A 25‐year‐old black female presented with lymphadenopathy, fever and anemia of two months duration. The diagnosis of malignant histiocytosis was made on the basis of histiocytic infiltrations in the sinuses of spleen, liver and lymph nodes and by the demonstration of erythrophagocytosis in bone marrow. Following splenectomy, the patient developed a leukemic phase with as many as 50 × 109 abnormal histiocytes/1 and bone marrow necrosis. This patient was also atypical because of multiple granulomas in liver, spleen and lymph nodes. Cytochemical and immunofluorescent stains confirmed that the abnormal cells were derived from the monocyte‐macrophage series. Electron microscopy was used to further characterize this abnormal cell population. The electron microscopic and cytochemical evidence confirms that the malignant cells in malignant histiocytosis are derived from monocytes.