Abnormalities of cilia in the middle ear in chronic otitis media.

We studied the fine structure of nasal and middle ear mucosa in 18 patients with chronic otitis media, comparing them with ten age-matched control patients. Electron microscopy revealed no single fundamental defect of cilia in the tissue samples; however, patients with chronic otitis media had a significantly higher incidence of abnormal cilia in the middle ear without correlating abnormalities of nasal cilia. These findings indicated that ciliary anomalies, including deletion of ciliary microtubules, presence of supernumerary tubules, and fusion of cilia, occur as a result of infection or inflammation. Such abnormalities would impair normal mucociliary clearance and exacerbate clinical complications.

Genetic aspects of immotile cilia syndrome.

The genetics of the immotile cilia syndrome has been analyzed in a series of 46 affected individuals from 38 families. Both sexes were equally affected: there were 20 males and 26 females in this series. All patients had upper and lower respiratory disease with chronic sinusitis, otitis, and chronic cough from early childhood. Bronchiectasis was common in older children and adults. Situs inversus occurred randomly, affecting 11 males and 15 females. Biopsies of nasal and bronchial mucosa from these subjects have been investigated by electron microscopy and identified as having specific ultrastructural defects of respiratory tract cilia including deficiencies in outer dynein arms (19), inner dynein arms (3), both inner and outer dynein arms (15), radial spoke defect (5); and microtubular transposition anomaly (4). Segregation analysis of proband sibships was consistent with autosomal recessive inheritance. However, the different ultrastructural defects that underly the immotile cilia syndrome involve presumably different genetic determinants, and the different types have not been analyzed separately. Examination of paternal age and birth order gave no evidence of new autosomal dominant mutation in the series.

Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative.

Antipsychotic drugs, while ameliorating symptoms in schizophrenia, evoke extrapyramidal effects which resemble parkinsonism. We studied the potential of 1- (4,4-bis(4-fluorophenyl)butyl)-4-(4-fluorophenoxy)-1,2,3,6-tetrahydropyr idine d-tartrate to induce extrapyramidal side effects in Rhesus monkeys. This agent shares neurochemical effects of known antipsychotic agents in its ability to antagonize cerebral dopamine action by competing for (3H)-Haloperidol binding of the dopamine receptors and inhibiting limbic and striatal adenylate cyclase in rat brain. The compound was administered orally to monkeys for 18 days, starting at 2 mg/kg and increasing to 20 mg/kg. Additional groups of monkeys received the drug for 29 consecutive days at 5 and 7.5 mg/kg/day. In both studies, extrapyramidal signs were associated with neuropathological changes in the brains of treated monkeys. The findings resemble those reported in Rhesus monkeys and in drug addicts after repeated intravenous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The findings also suggest a structure/activity relationship of tetrahydropyridine analogs with neurologic and associated neuropathologic manifestations produced in monkeys. The experimental model is useful to study the pathogenesis and possibly therapeutic approaches for Parkinson's disease.

Morphologic and immunohistochemical features of two spontaneous peripheral nerve tumors in Wistar rats.

Morphologic features and S-100 protein immunoreactivity of a benign and malignant peripheral nerve sheath tumor were studied in two Wistar rats. Neoplasms that developed in untreated control rats from tumor bioassays were S-100 protein positive and had similar histopathologic features. Each peripheral nerve sheath tumor was encapsulated and composed of spindle cells arranged around small thin-walled blood vessels. Palisaded tumor cells were in the benign peripheral nerve sheath tumor while cells of the malignant peripheral nerve sheath tumor had cellular atypia and moderate numbers of mitoses. Ultrastructural examination of the malignant peripheral nerve sheath tumor revealed cells with external lamina and interdigitation of cytoplasmic processes. Intracytoplasmic concentric lamellae were seen; they were regularly spaced with a periodicity of about 15 nm. Such structures, indistinguishable from myelin sheaths, have not been commonly associated with peripheral nerve sheath tumors in man. Electron microscopy and immunohistochemistry were useful in the diagnosis of these tumors as Schwannomas and in differentiation from other spindle cell tumors.

Leukocyte and bone marrow effects of a thiomorpholine quinazosin antihypertensive agent.

PD-88823, a thiomorpholine analog of prazosin, induced a consistent dose-related suppression of granulopoiesis with subsequent neutropenia and leukopenia in rats and dogs. Rats treated at 600 mg kg-1 day-1 had neutrophil counts reduced by 44% in males and 30% in females after 13 weeks. A 4-week observation period after drug treatment resulted in a rebound in neutrophil counts to 123 and 215% of control values in males and females, respectively. White blood cell count reductions were less evident in dogs, probably because of the lower doses. In both species, the extent of bone marrow suppression was related to duration of treatment. No other hematologic changes were manifest in either species. The mechanism for bone marrow depression and subsequent granulocytopenia was not established. The lack of reported bone marrow effects by quinazosin analogs suggests that the thiomorpholine group of PD-88823 is involved in toxicity. This correlation may be important to safety considerations for future drug design.

Cystic fibrosis in Ontario.

The incidence of cystic fibrosis in Ontario, Canada has been determined from clinical data, from the cystic fibrosis database of the Hospital for Sick Children, Toronto, and from population statistics in the Province of Ontario. The survey included 420 confirmed cases of cystic fibrosis born during the period 1966-1980. The mean incidence during this period was one in 2,927. In the last 5-year period, a decline was noted in incidence that may have reflected in part the effectiveness of early diagnosis and genetic counseling in affected families. During the period of the survey, over 60% of cases were diagnosed within the first year of life, 74% by age 2 years, and 90% by age 5 years. Clinical diagnosis in the first year of life was more common in males (65%) than in females (54%), a consistent finding during the period of the survey. The incidence of meconium ileus was 15.7% of ascertained cases of cystic fibrosis, with similar incidences in males (16.4%) and females (14.4%). Although survival has not been the subject of this survey, mortality in the neonatal period was significantly higher in males than in females with cystic fibrosis.

The immotile cilia syndrome: radiological manifestations.

The immotile cilia syndrome (ICS) is an uncommon disorder characterized by specific and genetically determined defects of cilia that cause upper and lower respiratory disease. We reviewed the radiographic patterns in 30 patients who had ICS (15 females, 15 males) and ranged in age from newborn to 26 years. Except for two neonates, sinusitis and otitis were present in all patients. Chest radiographic abnormalities, universally present, included bronchial wall thickening, hyper-inflation, segmental atelectasis or consolidation, and segmental bronchiectasis. Situs inversus, present in 50% (7 females, 8 males), was not an essential part of this disorder. Radiologically, the disease progresses from bronchial wall thickening with or without hyperinflation, to increasing hyperinflation plus parenchymal changes including segmental atelectasis, consolidation, and bronchiectasis. There is also a predilection for anatomic middle lobe abnormalities. The radiological appearance and clinical state have similarities to cystic fibrosis, although they are less severe and less progressive. ICS should be considered in the differential diagnosis of slowly progressive chronic lung disease, sinusitis, and otitis.

Morphofunctional investigations on spontaneous pituitary tumors in Wistar rats.

Adenoma of the pituitary gland represents one of the commonest spontaneous tumors in strains of laboratory rats. In a retrospective survey of pituitary glands from 2165 albino Wistar rats, the total number of pituitary adenomas was 501, representing an overall incidence of 23% with females showing a higher incidence (32%) than males (13%). Pituitary adenoma was rare from 6-52 weeks of age and accounted for only 0.2% of the total incidence. The first pituitary tumors in this series were observed at 32 weeks in 2 female rats and at 40 weeks in a male rat. From 52-85 weeks of age, incidence remained low, and then increased progressively in animals that died from 85-110 weeks of age. In a series of 200 Wistar rats, detailed evaluation was completed for neoplastic and hyperplastic lesions of the pituitary gland. The immunocytochemical characteristics of the pituitary adenoma were investigated using markers for prolactin, growth hormone, and thyrotropic hormone. Positive immunoperoxidase staining revealed an incidence of 59% prolactinomas in both male and female rats. Forty-one percent of pituitary adenomas did not stain for prolactin, thyrotropic, or growth hormone and showed no specific morphologic differences from prolactinomas. The application of immunoperoxidase-staining techniques offers a useful tool for characterizing secretory activity of pituitary adenomas and evaluating histopathologic changes of the pituitary gland.

Histiocytic sarcoma in Wistar rats. A light microscopic, immunohistochemical, and ultrastructural study.

Histiocytic sarcoma, a recently described tumor entity in rats, was studied by light microscopy in 20 male and female Wistar rats. The tumors originated from subcutaneous tissues; metastasis involved primarily the liver with sinusoidal spread and the lungs with peribronchiolar distribution. The characteristic features of this tumor were the uniform population of tumor cells, palisading necrosis, and abundant multinucleated giant cells. Immunocytochemical and ultrastructural findings confirmed the histiocytic nature of the tumor cells.

Structural and developmental abnormalities of the exocrine pancreas in cystic fibrosis.

Normal infants from 32 to 54 weeks post-conceptional age show a clear pathway of development in the exocrine pancreas, involving differentiation of acinar tissue, reflected by increased acinar to connective tissue volumes. In contrast, an abnormal pattern of development has been found in cystic fibrosis. Early signs of a deficiency in exocrine tissue at 32-38 weeks post-conceptional age suggest that there is a lack of normal maturation of pancreatic exocrine tissue that occurs in utero, with a degenerative process supervening after birth. The volumes of the acinar and duct lumen is markedly increased, up to 10 fold normal volume in cystic fibrosis subjects. However, the lumenal changes are not a function of age. Accumulation of secretory material in the duct is a characteristic feature in cystic fibrosis and may cause dilation of the duct and acinar lumen and degradation of acini. Alternatively, the greater volume and lack of direct relationship to exocrine acinar volume may reflect a persistence of the fetal pattern of pancreatic development in cystic fibrosis. The diagnosis of cystic fibrosis within the first few months of life is difficult when based on conventional or subjective histologic criteria. By quantitative microscopy of the pancreas, an objective approach is available that clearly distinguishes cystic fibrosis from control subjects. In this retrospective survey, 93% of cystic fibrosis infants were discriminated from normals; only 2 of 30 cases (70%) were not clearly differentiated from controls. As a genetic disorder, the manifestation of cystic fibrosis would be expected to result in pancreatic dysfunction in utero. Other predisposing factors, however, may be involved in the pancreatic lesions such as obstruction of the pancreatic duct, failure in the synthesis or secretion of pancreatic enzymes or abnormal mucus production in the intestine. Further ultrastructural and functional investigations will be important to understand the underlying defect in cystic fibrosis.

Morphologic features and incidence of spontaneous hyperplastic and neoplastic mammary gland lesions in Wistar rats.

A morphologic study of spontaneous proliferative lesions of the mammary gland was based on histologic examination of mammary glands from 1020 male and 1145 female albino Wistar rats aged 6 to 110 weeks. Three hundred and seventy-five mammary tumors representing an overall incidence of 33% were identified in the female groups, while the males had a total of five tumors which represented an incidence of 0.5%. Histologically, the most common types of tumors in females were: fibroadenoma (236), carcinoma (85), adenoma (40) and fibroma (8). Duct papilloma (1), lobular carcinoma (1), fibrosarcoma (1) and phyllodes tumor (1), were rare and constituted less than 2% of mammary neoplastic lesions. Mammary tumors were rare before one year of age, but increased with age thereafter. Nine percent of female rats studied also had proliferative non-neoplastic lesions that showed a mixture of benign ductular and/or lobular hyperplasia. One hundred and six of these lesions were identified, representing 22% of all grossly palpable nodules, thus stressing the importance of histologic examination of all gross mammary nodules for tumor evaluation.

Pathophysiology of the ciliary motility syndromes.

The ciliary motility syndromes are characterised by specific and genetically determined defects of cilia with resulting impairment of mucociliary defense mechanisms in the respiratory tract. The ciliary pathobiology, clinical observations, serial pulmonary function and chest radiographs are reviewed and correlated for a series of 33 patients with the ciliary motility syndromes, aged from 0.5 to 75 years. The clinical course and progressive nature of this disease emphasizes the importance of early and accurate diagnosis to prevent irreversible pulmonary damage.

Genetic heterogeneity of dynein-deficiency in cilia from patients with respiratory disease.

Impairment of mucociliary clearance as a result of genetic defects of cilia in the respiratory tract has been recognized as a cause of chronic or recurrent respiratory diseases. Respiratory cilia have been examined by high resolution electron microscopy of nasal and bronchial biopsies from children and young adults from 6 months to 24 yr of age. In this series, 17 children with immotile cilia syndrome have been shown to have deficiencies of dynein arms in the cilia. Ultrastructural analysis reveals a variability of dynein defects from the lack of inner arms, the lack of outer arms, to the complete lack of both inner and outer dynein arms. The spectrum of defects that contribute to dynein-deficient cilia presumably reflects separate genetic determinants, affording further evidence that the immotile cilia syndrome is genetically heterogeneous. Despite ultrastructural differences in cilia, no significant differences are evident in the clinical course of the respiratory disease in affected subjects or in the incidence of situs inversus that affects 50% of subjects.

Poxvirus infection in a colony of common marmosets (Callithrix jacchus).

An epizootic poxvirus infection occurred in a colony of 80 common marmosets (Callithrix jacchus) recently introduced to a laboratory facility. Over an 18-week period, 29 of the monkeys exhibited skin lesions that persisted for 4-6 weeks. Although eight marmosets died during the outbreak, their deaths were not attributed directly to the poxvirus infection. The skin lesions developed over the entire body surface including the soles and palms. Initially characterized as erythematous papules, they quickly changed to elevated coalescing lesions with extensive scab formation. Histopathologically, the lesions revealed moderate to marked acanthosis, and they progressed to full-thickness epidermal necrosis and ulceration. Intracytoplasmic inclusion bodies were observed occasionally within degenerate keratinocytes. These inclusions most probably constituted the intracytoplasmic aggregates of viral particles observed ultrastructurally and confirmed as members of the poxvirus group by negative staining of direct skin scrapings.