Ethionine: a new antileukaemic drug?

Ethionine: a new antileukaemic drug? In our hands, benzene proved to be a valuable drug for the treatment of chronic leukaemia. When correctly administered it did not provoke the harmful side effects reported by several authors in accord with the first description of von Koranyi in 1912. In many cases benzene induced complete remission persisting for over 18 months. This compound was found to be active even in patients who had not responded to busulphan, although the contrary was also observed for certain subjects. In accordance with previous investigations carried out in the rabbit, concomitant administration of cysteine-HCl blocked the leucopenic effect of benzene in 5 of 6 cases whereas ethionine, an antimetabolite of methionine and/or cysteine, appeared to enhance its therapeutic action. It is worthy of note that in at least one case ethionine administered alone led to complete clinical and haematological remission of the leukaemic state.


Clostridium perfringens septicemia during the course of leukemia. Clostridium perfringens (CP) is an infrequent cause of septicemia in neutropenic patients. We report the case of a 17 year old man treated for acute lymphoblastic leukaemia in whom a strain of CP was isolated from blood cultures. The clinical spectrum and evolution of CP septicemia in neutropenic patients are discussed.


Relapse as acute monocytic leukaemia of acute lymphoblastic leukaemia with t(4;11). A young adult suffering from acute lymphoblastic leukaemia with t(4;11) relapsed with features of monocytic leukaemia. This unusual evolution is discussed in relation with the pluripotent nature of t(4;11) leukaemic cells.


Breast cancer.

Breast cancer. Breast cancer will continue to be a major health problem for women as long as there is a lack of prevention strategies and underuse of early detection programs. The role of the nurse in health promotion must focus on educating women about the ambiguity surrounding risk factors and the importance of participating in early detection practices.


Ovarian cancer. The most lethal gynecologic malignancy. The need for the early detection of ovarian cancer continues to be one of the most important issues in women's health care. The overall 5-year survival rate for epithelial ovarian cancer remains approximately 30% and has not improved over the last three decades. The failure to improve the prognosis for women with ovarian cancer is directly attributable to the lack of an effective screening test for early-stage disease. It is hoped that with the study of those women at high risk, an appropriate screening method will be discovered. Nurses should become knowledgeable about the nature of ovarian cancer, should be able to identify the woman at familial risk, and should look at a symptomatic woman with a high degree of suspicion. As health educators, nurses can provide up-to-date information about Ca 125 serum tests and vaginal ultrasonography used to screen high-risk populations. Nurses must educate women about the importance of the pelvic examination. Historically, nurses are trained to view the patient holistically. Such a viewpoint will help to put together all of the pieces of a difficult puzzle.


Holistic care of the patient with cervical cancer. Participation by women in screening programs for cervical cancer is far from optimal, and many lives are lost because of this. Cervical cancer is common, and is easily detected and treated. It has a good prognosis for cure if detected early in its course. Effective screening has been shown to have a major role in decreasing the morbidity and mortality associated with cervical cancer. Therefore, there is a need for increased public health education and availability of screening programs for women. It is particularly important that public health efforts reach women in the lower socioeconomic groups who are less apt to exhibit health promotive behaviors. Women of Latin American heritage are at particularly high risk because of cultural barriers to the discussion of sexual practices. Until public health interventions are more successful, cervical cancer will continue to pose a major threat to women who are either too embarrassed or too misinformed to understand that prevention is an integral part of women's health care. Nurses view patients in a holistic way. It is this philosophy of care that offers women who are diagnosed with cervical cancer a means to adapt successfully to the psychologic and physiologic stresses associated with the diagnosis. Nurses need to recognize this strength and to offer holistic approaches to women in crisis. No two patients deal with a diagnosis of cancer in the same manner. A major challenge to nurses across a hospital community continuum is to provide comprehensive psychologic and physiologic assessment of a women's response to a diagnosis of cervical cancer and to provide effective and holistic intervention when necessary.


Lung cancer in women. Rising epidemic, preventable disease. Lung cancer is a preventable disease. Like acquired immunodeficiency syndrome, lung cancer is reaching epidemic proportions in women. This article overviews selected epidemiology of lung cancer and discusses public health issues that are gender-specific to women. Community nursing approaches are advocated that address risk behaviors in women and girls.


Domestic violence. The pregnant battered women. Nurses need to understand the theoretic debates that attempt to explain why men batter women. Nurses can participate more effectively in preventing and reducing the incidence of physical violence directed against women in intimate relationships. A raised feminist consciousness will expand the nurse's repertoire of interventions to assist in the identification and treatment of victims.


Homeless women. The context of an urban shelter. The role of the nurse in a shelter has just begun to emerge. The prevalence of homeless women is escalating, and nurses are playing primary roles in teaching, health care, social support, and case finding for women in shelters. This article describes some of the health, social, and psychologic issues facing women in a large urban shelter from the perspective of a senior nurse psychologist at Boston's Long Island Shelter.


Addicted women. Profiles from the inner city. This article has focused on addicted women and the contexts in which they present to the community nurse. An effort has been made to broaden the clinical applications to include the societal problems underlying addiction and the policy issues that must be addressed to solve them. Addicted women can be described from a societal dimension, in which the health care system reflects disarray and fiscal chaos, and from a community dimension. The two dimensions link the public and the private spheres. To evaluate addicted women and the options for their recovery more effectively, it is helpful to integrate the societal and personal milieu--public issues and the private lives that illustrate them. This is how policy is best formulated. The numbers of addicted women in the health care system reflect only the tip of the iceberg. Health care providers must strive to reach women who are outside of the health care system who have not been connected to a hospital, shelter, or home care agency. Researchers need to differentiate sample patient populations, and the patient selection bias needs to be addressed early on. A model of a community support for recovery located within a housing project was a viable option for reaching addicted women. The role of nurses is becoming increasingly unique. Nurses are skilled as caregivers and clinicians. They can open doors of opportunity for inner-city women and children by developing health-promotive programs in hospital settings for substance abusing women and by continuing to work with their colleagues in the community context. On both dimensions, nurses have front-line accessibility to women and children who are vulnerable. Often, commonality of gender strengthens the nurse/patient relationship and facilitates trust as well as empathy between female addicts and their nurse advocate counterparts. Never has the call to inner-city nurses been more compelling. The problems related to drug abuse and parenting are multidimensional. They resist easy definition and solution. Nurses have the education and the clinical expertise to provide front-line interventions for inner-city women who are addicted to drugs. Nurses are educated holistically as caregivers and teachers. Ideally, nurses can exert their strongest impact on health promotion in the neighborhoods of communities. In reality, this has not worked, and nurses remain part of a health care system that has failed inner-city poor women and their children. Nurses in hospitals and in community setting spend most of their time applying "bandages" to the psychologic and physical wounds that emerge from the addiction to drugs.(ABSTRACT TRUNCATED AT 400 WORDS)


Identifying the woman with alcohol problems. The nurse's role as gatekeeper. Alcoholism among women, although frequently undetected, is on the rise, posing a significant social health problem. Nurses acting as gatekeepers are in an excellent position to identify alcohol problems and refer the individual to the appropriate health care provider. Concern about a lack of knowledge of signs of this problem and ingrained moralistic attitudes often interfere with this process. This article reviews some of the historical antecedents contributing to our present view of alcoholism, explores some of the known differences between male and female alcoholics, defines the tasks and limits of the nurse's role as gatekeeper, and identifies helpful qualities of the nurse.


HIV infection in women. Implications for nursing practice. Much remains to be explained regarding women with HIV infection or AIDS. Interest in determining whether the natural history of the disease or the clinical manifestations are gender specific is leading to more research focused on women. The female roles of childbearer and caretaker evoke ethical issues that are unique to this epidemic and that can impact on the development and delivery of health care services. Women at the greatest risk for HIV disease are not likely to form coalitions to advocate for services, research dollars, and education. They need advocates and assistance in becoming united to advocate for themselves. Nurses have a critical role in the provision of services to women with HIV disease. As educators, direct service providers, and administrators, nurses contribute to the development of services that are holistic and family centered. As advocates, nurses can ensure that women are accurately and well informed about the disease and the resources available to them. Because AIDS no longer affects only those persons living in large metropolitan areas, it is imperative that all nurses become experts in the care of women with AIDS and advocates for a better outcome.


Older women. Sexually transmitted diseases and acquired immunodeficiency syndrome. Increasingly, American women aged 50 and over are afflicted with sexually transmitted diseases (STDs) and acquired immunodeficiency syndrome (AIDS). In order to meet the US Public Health Services' Health Objective for the Year 2000, health care workers must address the issues that impact on the older woman's ability to protect herself and others from these highly stigmatized diseases. Nurses must be aware of the potential for STDs and AIDS in this population and appropriately refer individuals for screening and follow-up care. Older women must be empowered economically, legally, and politically so they can assume an assertive role in their own health promotion. Cultural and societal barriers need to be overcome to change stereotypic attitudes about older women's sexuality. Only then can access to health information, health care, and research be assured.


Women at midlife. The transition to menopause. The advantage over men that women experience in life expectancy does not extend to morbidity. Although women live on average approximately 7 years longer than men, their later years are often filled with medical problems. Much is currently known that could influence and effect improved health for women. Menopause is not a dramatic event that signals an abrupt change in the health and well-being of women. Rather, it is a transitional time of perhaps a 25-year span when estrogen production gradually declines and results in a variety of bodily changes. Concurrent with the hormone changes are other effects of the normal cycle of aging. Comprehensive multidisciplinary health care clinics for adult women have the potential to provide health services that women seek.


Women at midlife. Hormone replacement therapy. As women approach the climacteric period, many changes are occurring in their bodies. Many of the physiologic changes are related to a decrease in estrogen production by ovaries. Hormone replacement therapy has been proposed to help relieve many of the manifestations associated with menopause. Before they begin hormone replacement therapy, women need to be informed about the advantages and disadvantages of this treatment. Decreasing the risk of cardiovascular disease and preventing further development of osteoporosis are primary reasons for administering hormone supplementation to postmenopausal women. The risk of breast cancer is not increased with low-dose estrogen, and by adding progesterone, the risk of endometrial cancer is virtually eliminated. Not every woman is a potential candidate for hormone replacement therapy. Contraindications exist, and some women experience discomforting side effects. Withdrawal bleeding with combination therapy is the main reason women do not comply with treatment protocols. Although supplementation may prove helpful for the postmenopausal woman, each individual needs to evaluate her own personal situation carefully. Accurate knowledge about normal changes due to decreased estrogen production, the pros and cons of therapy, and personal health status assists in the decision as to whether hormone replacement therapy is appropriate for a particular postmenopausal woman.


Nutrition in women across the life span. Recent recommendations on nutrition, such as the Surgeon General's Report on Nutrition and Health, have emphasized the relationship between diet and disease. In the Surgeon General's report, Americans have been advised to limit their consumption of fat, cholesterol, sodium, and alcoholic beverages, and to increase their consumption of complex carbohydrates and fiber. Two of the recommendations in this report related to the consumption of iron and calcium are particularly important to women's health. Women are advised to increase their consumption of food high in calcium and to include foods containing iron, such as lean meats, fish, certain beans, iron-enriched cereals, and whole grain products. Iron is essential as a constituent of hemoglobin, myoglobin, and certain enzymes. Iron losses during menstruation and the increased need for iron during pregnancy place women at risk for iron deficiency. Bone mass continues to increase until the late twenties, and one method to prevent osteoporosis may be adequate calcium intake during these years of early adulthood. Food guides that list amounts and types of foods to be eaten are helpful for the individual or as an educational tool for the nurse or educator. A Daily Food Guide was recently designed to meet the nutritional needs of women throughout the life cycle, and the government has very recently released a Food Guide Pyramid. Although it is important for women to learn how to control certain dietary components, they should also be aware of the protective nature of certain nutrients, such as iron and calcium.


Predictors of depression in women.

Predictors of depression in women. The identification of depression in women is a challenge for nurses. Case finding for health promotion can be performed when risk factors are identified, when a determination of symptoms using DSM III-R2 criteria is made, and when the clients are referred for appropriate interventions. The referring nurse can be a support system while the client is in the initial phases of intervention. Nurses can have a major role in the identification of and planning of treatment for women who are depressed or at risk for depression.


Using Kryofix as alternative for formalin results in more optimal and standardized immunostaining of paraffin sections. Although used for over one century formalin has several disadvantages which Kryofix, an alternative fixative for paraffin blocks used in Leiden for 6 years, does not have. In this study the effects of Kryofix on tissue regarding immunohistochemistry are compared with those of buffered formalin. All markers studied showed enhanced staining in the Kryofix blocks after 4 hours of fixation, whilst in some cases the immunostaining of the formalin blocks was even negative. For all markers, the sera could be further diluted for the Kryofix sections, for some with as much as a factor 20, enhancing the cost-effectiveness of the method. We established that for formalin, the fixation time strongly influenced the results. For Kryofix there was no time factor: the immunostaining results of 1 hour fixation were identical to those after 3 months of fixation. This study shows that by this method of fixation, in which there is no cross-linking of proteins, immunostaining of paraffin sections is optimized and standardized.


Tumour-like lesions of the salivary glands. The new WHO classification. Tumour-like lesions must be distinguished from true tumours of the salivary glands. In the new WHO classification of salivary gland tumours seven entities were considered: sialadenosis, oncocytosis (diffuse oncocytosis and focal adenomatous oncocytic hyperplasia), necrotizing sialometaplasia (salivary gland infarction), benign lymphoepithelial lesion (chronic myoepithelial sialadenitis), salivary duct cysts (mucoceles of the minor salivary glands of extravasation or retention type, cysts of the major salivary glands, ranula and dysgenetic polycystic disease of the parotid gland), chronic sclerosing sialadenitis of the submandibular gland (Küttner tumour), and cystic lymphoid hyperplasia in AIDS. The main topics of clinical data and pathohistology were described and documented by the results of the Salivary Gland Register in Hamburg (1965-1989).


Morphometric distinction of sclerosing adenosis from tubular carcinoma of the breast. Objective features have been identified that assist in distinguishing sclerosing adenosis from tubular carcinoma of the breast. Hematoxylin and eosin stained paraffin sections of 18 sclerosing adenoses and 18 tubular carcinomas were studied using a TAS Plus image analysis system. Histological measurements from lumens and glands included stereologic features of architecture and morphometry of size and shape (the latter by Fourier coefficients). Cytological measurements included nuclear area, perimeter, diameter and formfactor. Initial analysis suggested utility for several individual features. However, after a modified Bonferroni procedure only two of the features were statistically significant, i.e. the coefficient of variation of luminal form factor and the surface density of glands. Multivariate discriminant analysis using these two variables correctly classified 86% of the cases, with three adenoses and two carcinomas misclassified. Validity of the discriminant rules was supported by classification using measurements from a separate, independent set of cases (ten sclerosing adenoses and nine tubular carcinomas). The classification function computed from the first set misclassified only one case from the second set, a tubular carcinoma, leaving 95% of the cases successfully categorized. Chi square test for 2 x 2 contingency tables gave a p-value < 0.001 for both sets of cases. The results suggest that morphometric features are helpful in distinguishing tubular carcinoma from sclerosing adenosis and point out the need for conservative analysis of high-dimensional data sets.


Nucleolar silver staining patterns and HLA-DR antigen expression in bronchial epithelial cells in chronic bronchitis. Bronchial epithelial cells obtained by brush biopsy during fiberoptic bronchoscopy performed in 12 patients with chronic bronchitis and 12 healthy control subjects, were investigated for HLA-DR antigen expression and nucleolar silver staining patterns. In all patients with chronic bronchitis the number of bronchial epithelial cells positive to HLA-DR antigen was highly increased (> 90%), whereas in the controls only a few epithelial cells (< 10%) showed a weak HLA-DR antigen expression. Patients with chronic bronchitis showed an increased lymphocytic reaction compared to the control subjects. Both in the patients with chronic bronchitis and in the healthy controls the number of nucleoli was the same. The number of silver stained dots per nucleus was significantly higher in patients with chronic bronchitis than in the control subjects (7.70 +/- 0.87 as against 5.11 +/- 0.52; p < 0.0001). The intensity of the lymphocytic reaction correlated with the HLA-DR antigen expression and the increase in silver staining (Spearman's r = 0.543; p < 0.01). This indicates the influence of inflammation on the activation of epithelial cells derived from the respiratory tract.


Assessment of the risk on endometrial cancer in hyperplasia, by means of morphological and morphometrical features. The value of two "cancer risk" assessment rules (one consisting of qualitative microscopical features and one consisting of morphometric characteristics) has been evaluated in 39 patients with hyperplasia of the endometrium. Of these, in seven (7139 = 18%) cancer was detected in the follow-up and 32 remained stable or became less abnormal. The results of the qualitative analysis were well in agreement with those published earlier. In none of the eight patients with simple hyperplasia cancer was detected, in contrast to five of the 11 patients (45%) with cytologic atypia and glandular complexity. Twenty patients showed cytologic atypicality in the absence of glandular complexity, or no atypicality but glandular complexity; in two (10%) of these patients cancer was detected later in the follow-up. The morphometric rule (consisting of volume percentage of stroma, log-normally transformed standard deviation of the shortest nuclear axis and outer surface density of the glands) results in a multivariate score. Nineteen patients had a score value above 0.6 and in none of them cancer was found. In contrast, in seven of the 20 patients (35%) with a score value below 0.6, cancer was detected. Regarding the question which of the techniques is more powerful, the specificity is better with the qualitative evaluations; the sensitivity is higher with the morphometric rule. An advantage of the morphometric rule is that only two groups (very low/very high risk) are discerned.


Morphometric discrimination of colonic tubular adenoma from adenocarcinoma by vector and tensor analyses. Four parameters were considered in this study to discriminate between tubular adenoma and adenocarcinoma of the colon. The deformation of the tubular profile (TD) and the average sector resultant (AR) were used as supracellular parameters, the vector resultant strain (VS) which represented the cellular crowding as a cellular parameter, and the deformation of the nucleus (ND) as a nuclear parameter. Statistical comparison between the two groups showed that all the parameters had high levels of significance. Direct discriminant analysis was applied to discriminate between the two diseases and all parameters showed large F-ratios; however, the evaluation by the stepwise discriminant method indicated that ND had a sufficient power of discrimination between the two diseases. Biplot with confidence interval ellipses (95%) was plotted for ND versus TD to demonstrate the graphical separation of the groups.


Differentiation of human thyroid follicle cells from normal subjects and Basedow's disease in three-dimensional collagen gel culture. Thyroid follicles, an essential functional unit of the thyroid, exist in the extracellular matrix of the tissue in vivo. Therefore, in any monolayer culture system, the follicles cannot be reconstructed. Our previous study adopting three-dimensional collagen gel culture showed that isolated porcine follicle cells reconstructed thyroid follicles specific for the thyroid gland in vivo. To elucidate whether this culture system is also applicable to human follicle cells, and furthermore to provide a culture system for investigations of the pathogenesis of human thyroid diseases, we tried to culture isolated human follicle cells of normal thyroid tissue and of Basedow's disease in three-dimensional collagen gel. In this culture system, they apparently reconstructed thyroid follicles. The component cells of the reconstructed follicles exhibited structural polarity specific for human thyroid follicle cells and produced thyroid hormones. In addition, the cells responded to a TSH-stimulation in terms of morphological and functional differentiation, and they presented HLA-DR antigen with an interferon-gamma-stimulation. This report is a first instance of reconstruction of human thyroid follicles and HLA-DR antigen induction in three-dimensional follicle structures in vitro. This culture system provides a more physiological environment in vitro for biological and pathogenetic investigations of human thyroid follicle cells than the monolayer culture system. Further experiments using this method will probably provide new clues to the pathogenetic mechanisms of human thyroid diseases.


Small adrenocortical tumors without apparent clinical endocrine abnormalities. Immunolocalization of steroidogenic enzymes. Immunohistochemical analysis of steroidogenic enzymes (P-450 side-chain cleavage, 3 beta-hydroxysteroid dehydrogenase, P-450 C21-hydroxylase, P-450 17 alpha-hydroxylase and P-450 11 beta-hydroxylase) was performed on fifteen cases of small adrenocortical adenomas, which were detected incidentally in hormonally asymptomatic patients (non-functioning adrenocortical tumor), in order to study steroidogenesis in these tumors. Immunolocalization revealed that all cases examined expressed all the enzymes in the adrenocortical steroidogenic pathway to various degrees, and in twelve cases abnormalities of precursor hormones and steroid metabolites were clinically observed. Attached non-neoplastic adrenals were present in twelve cases. Among these twelve cases, eight showed cortical atrophy, especially in the zona fasciculata. These atrophied adrenals expressed little immunoreactivity of the enzymes examined. These results strongly indicate that most of small non-functioning adrenocortical tumors have the capacity to produce biologically active steroids including cortisol, although not necessarily associated with hypercorticism. Especially in the cases with cortical atrophy in attached non-neoplastic adrenals, it is considered that autonomous neoplastic production and secretion of cortisol may be insufficient to cause clinical and routine laboratory abnormalities but sufficient to subtly alter the hypothalamic-pituitary-adrenal axis by suppressing ACTH and/or CRF secretion and to result in adrenocortical atrophy. It should be recognized that corticosteroidogenesis does take place in the majority of clinically small non-functioning adrenocortical tumors incidentally detected in hormonally asymptomatic patients when managing these patients.


Meningothelial meningioma with "amianthoid" fibers. Case report with ultrastructural study. The case of a meningothelial meningioma with 'amianthoid' fibers in a 48-year-old woman is presented. By light microscopy the tumor showed the typical features of meningothelial meningioma and rounded, deeply eosinophilic, and fibrillary areas, especially around and/or in the vicinity of blood vessels. These fibers are also called 'amianthoid' fibers. Ultrastructurally, these foci were made up of disorderly arranged and interwaving mature collagen fibrils with a variable width between 40 and 190 nm. No evidence of intracellular collagen synthesis by the tumor cells was found. The presence of 'amianthoid' fibers does not seem to carry any prognostic significance.


Cell-matrix patterns in the cutaneous lesion of chromomycosis. Chromomycosis is a chronic fungal infection characterized by dermal fibrosis with persisting fungi in situ, generally leading to a verrucous skin lesion. The absence of good clinical results under specific treatment suggests irreversibility of the fibrotic lesion. Frozen and paraffin-embedded skin biopsies of eleven patients with chromomycosis due to Phialophora pedrosoi were studied by immunohistochemistry and electron microscopy. Distinct cell-matrix patterns were found in different tissue localizations: neutrophilic abscesses with oedema and necrotic keratinocytes in the epidermis; dense connective matrix around inflammatory infiltrates, mainly composed of macrophages and giant cells, and organized granuloma in the dermis. Active fibroblasts and mast cells were constantly observed. The inability of fibrotic tissue to be remodelled seems correlated to the nature and the organization of the matrix components but, the factors triggering the initial fibrogenic events remain to be characterized.


The long-term prognosis of the primary glomerulonephritides. A morphological and clinical analysis of 1747 cases. Long-term studies of all types of primary glomerulonephritis (GN) taking into consideration the major morphological and clinical findings revealed the following: 1) Endocapillary GN, post-streptococcal type has a very good prognosis when only glomerulitis is present. The prognosis is significantly worse if either interstitial inflammation with fibrosis or nephrotic syndrome (NS) is present at the time of the biopsy. 2) The prognosis of the various types of mesangioproliferative GN (IgA nephritis, non-IgA nephritis, and immunohistologically negative GN) is very good if there is only glomerulitis. The prognosis is worse for all three types when the renal cortical interstitium exhibits inflammation with fibrosis at the time of the biopsy, and is worst of all when both interstitial fibrosis (IF) and the signs of acute renal failure (ARF) are present. Of this group, the type in which there are negative immunohistological findings exhibits the best prognosis. No difference in prognosis is found between IgA nephritis and non-IgA nephritis. 3) Minimal changes GN with NS has a very good prognosis when the interstitium is not involved. The presence of interstitial inflammation and fibrosis worsens the prognosis significantly. 4) Focal sclerosing GN has a much poorer prognosis than minimal changes GN with NS, even when there is glomerulitis only (5- and 10-year renal survival rates (RSRs) of 90% and 67%, respectively). If interstitial inflammation and fibrosis are present, the prognosis is significantly worse (5- and 10-year RSRs of 84% and 55%, respectively). The prognosis is worst when both ARF and IF are present at the time of the biopsy (5- and 10-year RSRs of 56% and 46%, respectively). From the clinical side, the prognosis is significantly worse if, at the time of the biopsy, NS is present or the serum creatinine concentration is elevated to more than 1.3 mg%. 5) Chronic membranous GN has a better prognosis than focal sclerosing GN if glomerulitis only is present (5-year RSR, 88%; 10-year RSR, 77%). If the renal cortical interstitium is also involved (in the form of IF), the prognosis is significantly worse (5-year RSR, 65%; 10-year RSR, 38%). The prognosis in this disease, too, is worst when both ARF and IF are present at the time of the biopsy (5-year RSR, 38%; 10-year RSR, 25%). 6) Membranoproliferative GN has a worse prognosis than any of the types of GN so far mentioned (5-year RSR, 51%; 10-year RSR, 32%).(ABSTRACT TRUNCATED AT 400 WORDS)


Cellular autofluorescent pigment and interstitial fibrosis in smoker's lung. The mechanisms by which cigarette smoking lead to bronchopulmonary diseases are incompletely understood. The most characteristic lesion is a chronic macrophage-alveolitis accompanied by slight fibrosis and emphysema. The macrophages contain a ceroid-like granular autofluorescent pigment in their lysosomes. Using immunohistochemical methods, open lung-, transbronchial biopsies and cells obtained by broncho-alveolar lavage from cigarette smokers were studied: anti-human macrophage serum and anti-human elastase, immune sera against type I, type III collagens and fibronectin were used in the demonstration of the cellular components of alveolitis and the connective tissue constituents of fibrosis. The characteristic red-brown autofluorescent pigment of the macrophages was also found in an extra-alveolar location mainly in peribronchial, septal and pleural scars. Similar emission colour occurred focally in the elastic laminae of fibrotic alveoli and sclerotic arteries. Granular fluorescent pigment was found in many bronchial epithelial cells. The epithelial pigmentation was associated with increased transcription of nucleic acid proteins, revealed by colloid silver (AgNOR) reaction. The results suggest that the autofluorescent pigment substances in macrophages may indicate or also play a role in the development of pathological connective tissue and epithelial changes of smoker's lung, in addition to the known mediators and enzymes.


Mobilization of iron and iron-related proteins in rat spleen after intravenous injection of lipopolysaccharides (LPS). We used lipopolysaccharide (LPS) to provoke immune responses and observed the changes in the localization of iron and iron-related proteins, such as transferrin receptor, ferritin and hemosiderin in the rat spleen. After intravenous injection of 250 micrograms LPS (salmonella minnesota R595), spleen weight and serum IgM levels increased, cells incorporating 5-bromo-2'-deoxyuridine (BrdU), and transferrin receptor positive cells increased in the peripheral portion of the periarterial lymphoid sheath (PALS), the marginal zone (MZ) and the follicles. Ferritin positive cells increased markedly in the white pulp and stainable iron increased in the marginal metallophils (MM) and in the macrophages in the MZ and the outer PALS. Even in iron deficient rats, a similar change was observed for the localization of iron and iron-related proteins after injection of LPS. After injection of 0.4 mg keyhole limpet hemocyanin (KLH), changes similar to but less pronounced than that in the LPS injected rats were observed for serum IgM levels and for the localization of iron and iron-related proteins. These results showed that the iron in the MM and the macrophages in the white pulp have a dynamic response to immunological challenges and suggested that they play some role in immune responses.


Zinc concentrations in human tissues. Liver zinc in carcinoma and severe liver disease. In 58 unselected necropsies, zinc (Zn) in specimens of liver (mean +/- s = 280 +/- 178 micrograms/g d.w./4.28 +/- 2.72 mumol/g d.w.), kidney (170 +/- 57 micrograms/g d.w./2.60 +/- 0.87 mumol/g d.w.), spleen (69 +/- 13 micrograms/g d.w./1.05 +/- 0.20 mumol/g d.w.), and lung (64 +/- 16 micrograms/g d.w./0.98 +/- 0.24 mumol/g d.w.) were analysed by means of flameless atomic absorption spectrometry. In the examined range from 25 to 92 years of age, the Zn concentrations in all tissues measured did not show age or sex-dependency. There was a high correlation between the tissue concentration of Zn and Mg in lung, liver, and spleen, between Zn, Mg, and Pb in liver as well as between Zn and Pb and Zn and Cd in kidney. All hepatic cirrhosis cases had very low Zn conc. in liver tissue, the tumor cases generally increasing Zn conc. in liver tissue with progressive stage of regional invasion and distant metastasis.


Endometrial cancer associated with polycystic ovaries in young women. Two women (17 and 36 years old) are presented, who complained about abnormal vaginal bleeding. The rare diagnosis of an adenocarcinoma of the corpus uteri with concomitant polycystic ovaries (Stein-Leventhal-Syndrome) was made.


Patterns of measles pneumonitis.

Patterns of measles pneumonitis. As a result of the enlarging pool of unvaccinated children and young adults, there has been an increase in serious measles pneumonitis in our areas. We recently examined autopsy and/or lung biopsy material from five children with fatal measles pneumonitis. Two patients were immunocompromised because of either prematurity or acute leukemia and died 13-16 days following onset of symptoms. Both had classic giant cell pneumonitis, with readily demonstrable intranuclear inclusions. Three other children without known immunocompromise had a more prolonged course. The lungs of these patients lacked the classic pattern and displayed instead a spectrum of less specific findings ranging from organizing diffuse alveolar damage to interstitial pneumonia with giant cells, but without viral inclusions. An accompanying necrotizing bronchiolitis was also present. Electron microscopy and/or detection of elevated measles-specific immunoglobulin M was necessary to confirm the diagnosis in these apparently immunocompetent patients. We conclude that the histologic features of fatal or serious measles pneumonitis are variable and depend to some extent on the immunocompetence of the host as well as the duration and tempo of the disease. Ancillary studies may be necessary to establish the diagnosis in cases lacking classic histopathologic features.


Rectal myopathy in chronically constipated children. We examined full-thickness rectal biopsies from 30 children who had chronic constipation, including 5 children with constipation associated with clinical symptoms of intestinal pseudo-obstruction. Biopsies from 9 patients who required colonic interposition and from 7 with Hirschsprung's disease were used as controls. Tissues were evaluated for muscularis mucosae thickness (in mm), for absolute circular and longitudinal muscle layer thicknesses and their ratio, and for the intensity of neural vasoactive intestinal peptide (VIP) immunohistochemical staining. Atrophy of the rectal musculature with focal muscle fiber vacuolation or muscle fiber disappearance was found in all children with chronic constipation. Muscularis mucosae thickness was increased (P < .01) and the circular-to-longitudinal muscle ratio was decreased in the constipation group, with the greatest degree of atrophy being demonstrated in the circular layer. Two of the patients had additional biopsies up to 9 years after the first that illustrate progressive myopathic changes over time. This study demonstrates muscular atrophy in the rectum of children with chronic constipation. Besides primary idiopathic disease, potential etiologies include chronic distention, denervation, functional obstruction from obstipation, alteration in gut hormones, and toxic, ischemic, or neural injury.


Glomic cells and their peptides in the carotid body of the human fetus. Carotid bodies from 15 human fetuses of gestational ages 13-19 weeks were examined by light and electron microscopy. They were also labeled with antisera to methionine- and leucine-enkephalins, substance P, and bombesin. At 13 weeks of gestation most fetal glomic cells formed a homogeneous population but a few could be distinguished by light microscopy as rounded, pale fetal chief cells or elongated, darker fetal sustentacular cells, a distinction that became more certain with increasing gestational age. Electron microscopy confirmed this distinction, in which fetal chief cells contained dense-core vesicles and were partially enfolded by cytoplasmic extensions of fetal sustentacular cells. Immunoreactivity to methionine- and leucine-enkephalins was found at all gestational ages and was confined largely to fetal chief cells. Immunoreactivity to substance P was less specific, and there was no reaction for bombesin. Thus, by as early as the 13th week of gestation the two principal types of cell of the mature human carotid body begin to become recognizable on paraffin-embedded sections stained with hematoxylin and eosin. Furthermore, fetal chief cells can synthesize the peptides found in the adult.


An overview of survival studies in patients with heart failure. Heart failure is associated with poor prognosis, but recent large-scale investigations have generated valuable and practical information to help improve clinical management and patient survival. This review presents an overview of the findings of recent heart failure survival studies and how these may affect therapeutic strategy for patients with this condition.


Chronic granulomatous disease: an ultrastructural study of the pigment laden histiocytes. We have studied the ultrastructural characteristics of the pigments in the macrophages of liver and lymph nodes from three children with chronic granulomatous disease (CGD). The pigments represent lipofuscin bodies and appear to be formed from lysosomes. Characteristic structures are believed to represent transitional stages between lysosomes and mature pigment granules. It is thought that the residual lipids undergo progressive oxidation secondary to deficient lipolytic activity, overloading the lysosomes. It was also noted that liver biopsy can be a valuable tool in confirming the diagnosis of CGD, particularly when the disease is clinically suspected but the results of the nitroblue tetrazolium test are equivocal.


Use of fluorescent in situ hybridization to detect trisomy 13 in archival tissues for cytogenetic diagnosis. The present report describes the use of molecular probes to investigate the chromosomal constitution of interphase nuclei of formalin-fixed, paraffin-embedded tissue from three infants with multiple congenital malformations and a provisional diagnosis of trisomy 13 in two. Fluorescent in situ hybridization with the probe for the 13 and 21 centromeric regions revealed five nuclear signals in two of the cases, indicating the presence of an extra chromosome, and only four nuclear signals in the other case. Only the two positive cases had phenotypic features consistent with trisomy 13. Routine cytogenetic analysis was performed on one child and confirmed an additional chromosome 13. The child without an extra chromosome had features consistent with Ivemark syndrome. This study demonstrates the utility of fluorescent DNA probes for the retrospective diagnosis of aneuploidies in archival material.


Oral congenital cystic choristomas: a case report. Solitary choristomas containing gastrointestinal mucosa occur rarely in the tongue and the oral mucosa and usually present as an asymptomatic mass. This report documents the occurrence of two congenital intraoral cystic choristomas in a 5-month-old male infant. The cysts were located on the dorsum of the base of the tongue and left floor of mouth anterior to the lingual cyst. Both cysts were lined by nonkeratinizing squamous epithelium and gastric, intestinal, and respiratory epithelium. The cysts were excised by an oral approach.


The law and medical fitness to drive--a study of doctors' knowledge. We assessed doctors' knowledge on laws and recommendations regarding fitness to drive in certain medical conditions by a questionnaire survey. A total of 646 doctors consisting of 400 general practitioners and 246 hospital doctors of all grades were circulated with the questionnaire. The survey was anonymous so non-responders could not be re-circulated. The response rate was 26% general practitioners and 32% (hospital doctors). The results show the poor knowledge of doctors on several aspects of fitness to drive. It is necessary for all doctors to have a basic knowledge on the laws and recommendations on fitness to drive so that they can advise their patients correctly. Our survey clearly shows that doctors' knowledge is poor. Many drivers may therefore be placing themselves and others at risk. It is mandatory that this subject receives more attention in undergraduate and postgraduate education and that doctors should be regularly updated on new recommendations from the Driver and Vehicle Licensing Agency.


Cardiovascular complications of parenteral nutrition. During a 3 year period, 1987-1989, we encountered three major complications associated with parenteral nutrition leading to congestive cardiac failure--acute beriberi, right atrial and superior vena caval thrombosis, and fungal endocarditis. Unrecognized, these are invariably fatal. Persistent vomiting from intestinal obstruction led to the development of thiamine deficiency in the patient with beriberi. Recurrent catheter tip sepsis probably accounted for thrombosis and endocarditis in the second and third cases, respectively. These conditions are preventable with careful attention to nutritional replenishment and aseptic technique. In patients with catheter-related sepsis early, repeated blood culture is of diagnostic value. Patients with Staphylococcus aureus catheter-associated bacteraemia require at least 4 weeks of appropriate antibiotic therapy. Recurrent sepsis, especially when associated with pulmonary embolic phenomena, is an indication for echocardiography.


Concentrations of vitamins A, C and E in elderly patients with Parkinson's disease. Concentrations of the naturally occurring antioxidant vitamins A, C and E were measured in 27 patients with Parkinson's disease and 16 age-matched control subjects, from a similarly disabled patient group. There was no significant difference in the serum concentrations of vitamins A and E in the two groups. Vitamin C was significantly higher (P < 0.05) in the Parkinson's disease group, however, the mean leucocyte vitamin C concentration in the control group was low (101 nmol/10(8) WBCS) compared to established data in healthy young individuals (119-301 nmol/10(8) WBCS). There was no correlation between the severity or duration of Parkinson's disease and concentrations of vitamins A, C and E. There is therefore no evidence from this study that a deficiency of these antioxidants contributes to the onset or progress of Parkinson's disease.


Microalbuminuria in non-insulin-dependent (type 2) Nigerian diabetics: relation to glycaemic control, blood pressure and retinopathy. Twenty-four hour urinary albumin concentrations were measured in 113 (mean age 51.1 years) non-insulin-dependent (NIDDM) Nigerian diabetics (50 males, 63 females). A high prevalence of microalbuminuria (> or = 30 mg/24 hour) was observed in male (54%) as well as female diabetics (59%). Microalbuminuria was also observed in a high proportion of diabetics (52%) with a short duration (< 5 years) of disease. Elevated blood pressure and retinopathy were present in 41% and 16% of patients respectively. Among the 49 patients with normoalbuminuria (< 30 mg/24 hour), six (12%) had retinopathy compared with 12 (18%) in the microalbuminuria group. Diastolic blood pressure levels were significantly higher (P < 0.01) in male diabetics with retinopathy but this was not associated with higher albuminuria. Urinary albumin concentrations were not influenced by elevated blood pressure. There were no significant differences in age, duration of diabetes, blood pressure or serum creatinine between diabetics with and without microalbuminuria. These results suggest that though there is a high prevalence of microalbuminuria amongst NIDDM Nigerian diabetics it may not predict retinopathy and occurs independently of either glycaemic control or elevated blood pressure levels.


Magnetic resonance imaging for the assessment of residual masses after treatment of non-Hodgkin's lymphomas. Eight patients with non-Hodgkin's lymphoma who were in clinical remission but showed residual masses after therapy were examined with magnetic resonance imaging at 1.5 T at the end of therapy, with the sequences TR/TE:500/35,500/70,2000/35 and 2000/70. Residual masses were found in lymphoid areas (7), spleen (3) and kidney (1). In three patients, T2 showed high signal intensity. Disease progressed in the following 1-3 months and active lymphoma was histologically identified. In the other five patients, T2 showed a very low signal intensity. One of them had a distant relapse in lymphoid areas but the remaining four patients are asymptomatic after a mean follow-up time of 13 months, suggesting that the lymphoma is cured and the mass inactive. We conclude that magnetic resonance imaging seems to distinguish active from non-active residual masses after treatment of non-Hodgkin's lymphoma patients otherwise in clinical remission.


The value of urinary red cell shape in the diagnosis of glomerular and post-glomerular haematuria. A meta-analysis. The proportion of dysmorphic red cells (DRC) in the urinary sediment and their mean corpuscular volume (MCV) have been claimed to discriminate between glomerular and postglomerular sources of haematuria. To determine the diagnostic value of urinary DRC and MCV, we searched the literature and critically reviewed 21 published studies using a predetermined set of criteria for evaluation. All studies originated from referral centres. Interobserver variability in identifying urinary DRC was reported in four studies and found to be unacceptably large in one. Although reproducible over different samples of the same individual, urinary MCV was unreliable in cases of low-grade haematuria because of interfering debris. Weighted averages and 95% confidence limits of the sensitivity and specificity of the DRC proportion for glomerular disease were 0.88 (0.86-0.90) and 0.95 (0.93-0.97), respectively; those of a low MCV were 1.00 (0.98-1.00) for sensitivity and 0.87 (0.80-0.91) for specificity. Sensitivity and specificity values derived from in-patients were slightly higher than those in referred outpatients. No studies of urinary DRC or MCV in patients with incidentally detected microhaematuria in the primary care setting were found. We conclude that at present the diagnostic value of urinary DRC and MCV is limited. In referral centres, that is, in patients with a high probability of postglomerular haematuria, the test cannot rule out urological lesions, because its specificity for glomerular disease may be as low as 0.80. In the primary care setting, that is, in unselected patients with incidentally detected low-grade haematuria, the accuracy of the test has not been studied but may be even lower. The use of urinary DRC or MCV as an indicator of the source of haematuria is in need of further experimental development and confirmation.


Costovertebral joint dysfunction: another misdiagnosed cause of atypical chest pain. The diagnostic work-up of atypical chest pain frequently leads to invasive procedures. However, this painful symptomatology can sometimes be of benign origin and respond to simple therapeutic manoeuvres. A number of musculoskeletal conditions such as costovertebral joint dysfunctions should be carefully considered. We report five cases in which patient discomfort and high costs could have been avoided if awareness of these conditions had led to a correct diagnosis upon initial physical examination.


Acute renal failure in a case of paraquat poisoning with relative absence of pulmonary toxicity. A 37 year old male presented after the ingestion of paraquat ('Gramoxone', 20% w/v). Plasma paraquat concentrations indicated that he had a greater than 50% probability of death. The patient survived following a period of acute oliguric renal failure and with only mild pulmonary toxicity.


'Pseudo-Alzheimer's' and primary brain tumour. Primary brain tumour may present in the elderly purely as a dementing illness before the onset or detection of sensorimotor neurological symptoms or signs. Although neurological examination may indicate no definite signs, close attention to accepted DSM-IIIR and NINCDS-ADRDA diagnostic criteria for primary degenerative dementia and 'probable' Alzheimer's disease respectively will suggest a process other than a degenerative one. This was the case in two patients with primary brain tumour presenting clinically with dementing illness similar to but distinct from Alzheimer's disease.


Miliary tuberculosis presenting with thyrotoxicosis. A male patient is described who presented with thyrotoxicosis, and a large painful neck mass. From the excised mass and stomach aspiration Mycobacterium tuberculosis was cultured and a diagnosis of miliary tuberculosis was made. The thyrotoxicosis was attributed to tuberculous thyroiditis.


Ménétrier's disease in a child.

Ménétrier's disease in a child. A case of Ménétrier's disease in a 3 year old child presenting with subtotal pyloric stenosis and fatal outcome due to postoperative complications is reported. It is emphasized that although radiographic and gastroscopic studies are helpful, a full-thickness mucosal biopsy is essential for the diagnosis of Ménétrièr's disease.


Primary renal renin secretion responding to angiotensin converting enzyme inhibition. A case of primary renal renin secretion of probable neoplastic origin is reported. Investigation demonstrated renin secretion to be incompletely autonomous with suboptimal suppression to posture and hypervolaemia. Easy control of the hypertension and hypokalaemia was achieved with an angiotensin converting enzyme inhibitor. Such treatment may prove to be a preferable option to surgery.


Delivery of plasmid DNA into mammalian cell lines using pH-sensitive liposomes: comparison with cationic liposomes. We compare the transfection efficiency of plasmid DNA encoding either luciferase or beta-galactosidase encapsulated in pH-sensitive liposomes or non-pH-sensitive liposomes or DNA complexed with cationic liposomes composed of dioleoyloxypropyl-trimethylammonium:dioleoylphosphatidyl-eth anolamine (1:1, w/w) (Lipofectin) and delivered into various mammalian cell lines. Cationic liposomes mediate the highest transient transfection level in all cell-lines examined. pH-sensitive liposomes, composed of cholestryl hemisuccinate and dioleoylphosphatidylethanolamine at a 2:1 molar ratio, mediate gene transfer with efficiencies that are 1 to 30% of that obtained with cationic liposomes, while non-pH-sensitive liposome compositions do not induce any detectable transfection. Cationic liposomes mediate a more rapid uptake of plasmid DNA, to about an eightfold greater level than that obtained with pH-sensitive liposomes. The higher uptake of DNA mediated by Lipofectin accounts for part of its high transfection efficiency. Treatment of cells with chloroquine, ammonium chloride, or monensin decreases (threefold) transfection using pH-sensitive liposomes and either has no effect on or enhances cationic liposome-mediated transfection. Therefore plasma membrane fusion is not the only mechanism available to cationic liposomes; in certain cell lines DNA delivery via endocytosis is a possible parallel pathway and could augment the superior transfection efficiency observed with cationic liposomes.


Regional jejunal perfusion, a new in vivo approach to study oral drug absorption in man. Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)


Suppression of inflammation by cyclosporin A is mediated via a T lymphocyte-independent process. An athymic mutant rat strain was used to examine the hypothesis that modification of diseases with an inflammatory component by cyclosporin A (CsA) results from the suppression of nonspecific inflammatory mechanisms, rather than T-lymphocyte function, as is commonly inferred. Confirmation that the animal host was grossly depleted of T cells was obtained from anatomic and morphologic examination and functional tests of T-lymphocyte responsiveness. The experimental approach was to determine the effect of CsA on the course of experimentally induced infection with Escherichia coli, and extracellular pathogen. Host protection against this microorganism is dependent on an effective nonspecific inflammatory response. CsA administration prior to bacterial challenge resulted in a highly significant increase in bacterial numbers in the kidneys of both euthymic and athymic hosts. The data have provided a direct demonstration that modulation of the nonspecific inflammatory response by CsA can occur via a T lymphocyte-independent process.


Microdialysis sampling for the investigation of dermal drug transport. Microdialysis perfusion in vivo has the potential to be a powerful sampling technique in dermal and transdermal drug delivery studies. Characterization of a commercially available microdialysis probe in vitro considering relevant physiological parameters is a vital first step in the evaluation of microdialysis as a dermal sampling technique. In previous microdialysis studies, analyte concentration and neutrality have been implicated in altering microdialysis recovery. The recovery of a model compound 5-fluorouracil (5-FU) was investigated at several pH values and donor concentrations. The relative recovery of 5-FU by the microdialysis probe was affected by pH but not by donor concentration. To confirm further that the changing concentration and pH profile presented by the flux of 5-FU was not significantly altering microdialysis recovery, an experiment comparing direct and microdialysis sampling of a Franz diffusion cell receptor compartment was performed. Although the 5-FU concentration (0-686 ng/ml) and pH (7.40-7.24) changed substantially, the recovery of 5-FU was not adversely affected. To demonstrate the feasibility of dermal microdialysis, the flux of a commercial preparation of 5-fluorouracil was monitored utilizing a microdialysis probe implanted in excised rat skin in vitro. The results from the dermally implanted probe demonstrate the potential of the technique while establishing the limitations of the current microdialysis system.


Acyclovir permeation enhancement across intestinal and nasal mucosae by bile salt-acylcarnitine mixed micelles. The purpose of this study was to investigate the absorption enhancement of acyclovir, an antiviral agent, by means of bile salt-acylcarnitine mixed micelles. The specificity, site dependence, palmitoyl-DL-carnitine chloride (PCC) concentration dependence, and effects of absorption promoters on acyclovir absorption via the nasal cavity (N) and four different intestinal segments of the rat, i.e., duodenum (D), upper jejunum (UJ), combined lower jejunum and ileum (LJ), and colon (C) were evaluated. The present study employed the rat in situ nasal and intestinal perfusion techniques and utilized sodium glycocholate (NaGC), three acylcarnitines, and their mixed micelles as potential nasal and intestinal absorption promoters. Acylcarnitines used were DL-octanoylcarnitine chloride (OCC), palmitoyl-DL-carnitine chloride (PCC), and DL-stearoylcarnitine chloride (SCC). All acylcarnitines and NaGC by themselves produced negligible enhancement of acyclovir absorption in the rat intestine, while OCC and SCC were totally ineffective in the nasal cavity. However, the mixed micellar solutions of NaGC with PCC or SCC could significantly increase the mucosal membrane permeability of acyclovir in the colon and nasal cavity. On the other hand, NaGC-OCC mixed micelles slightly increased the absorption of acyclovir by both routes. When a mixed micellar solution of NaGC with PCC was used, the rank order of apparent acyclovir permeability (Papp; cm/sec), corrected for surface area of absorption, was N (10.54 +/- 0.62 x 10(-5)) > D (6.82 +/- 0.30 x 10(-5)) > LJ (2.90 +/- 0.08 x 10(-5)) > C (2.54 +/- 0.14 x 10(-5)) > UJ (2.30 +/- 0.22 x 10(-5)).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of loading on swelling-controlled drug release from hydrophobic polyelectrolyte gel beads. The effect of oxprenolol HCl loading on the kinetics of polymer swelling and drug release from suspension-polymerized poly(methyl methacrylate-co-methacrylic acid) (PMMA/MAA) beads has been studied in detail. Within the range of variables studied, the polymer swelling rate increases with buffer pH and concentration. And an ionization-controlled swelling mechanism (analogous to the relaxation-controlled mechanism) mechanism) seems to become more rate-limiting at higher buffer concentrations. At oxprenolol HCL loading levels below 17.8%, the drug release and associated dimensional changes (in pH 7.4) exhibit an extended quasi-linear region despite the inherent limitation of spherical geometry. At higher loading levels, the drug release becomes faster and first-order in nature. This is apparently a result of the transition from a dissolved to a dispersed system above a percolation threshold (15-18% loading in the present study). As a result of competition from processes such as the reduction of bead dimension due to drug release and the dimensional increase due to polymer swelling and osmotic contributions from the drug, the transient bead diameter increases monotonically during drug release at loading levels up to 25.6%, whereas upon further increasing the drug loading, the bead diameter goes through a maximum during the early drug release, which eventually increases again as a result of the slow but continuous increase in polymer swelling due to further ionization. In all cases, both the drug release and the dimensional changes approach completion as the penetrating ionization fronts meet at the center, indicating a true swelling-controlled behavior.


Metabolism, distribution, and transdermal permeation of a soft corticosteroid, loteprednol etabonate. The soft corticosteroid, loteprednol etabonate (chloromethyl 17 alpha-ethoxycarbonyloxy-11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carboxylate), I, was designed based on the "inactive metabolite approach." Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related "hard" steroids, without significant metabolism taking place in the skin.


Molecular weight changes in polymer erosion. We report a study of the effects of polymer molecular weight on the erosion of polyanhydride copolymer matrices composed of 1,3-bis(p-carboxyphenoxy)-propane (CPP) and sebacic acid (SA) in aqueous solution. The erosion profile characteristically displays an induction period during which the erosion rate is relatively slow. The length of this period depends on the initial molecular weight of the polymer. The induction period may be characterized as a time during which a rapid decrease in polymer molecular weight occurs, the end of this period correlating with the time required for the polymer molecular weight to decrease to below a value of approximately 5000 (MW).


Dose proportionality of transdermal nitroglycerin. The FDA Cooperative Efficacy Study of transdermal nitroglycerin utilized a combination of marketed products over a wide dose range. Unfortunately, plasma nitroglycerin concentrations were not determined. The current study was conducted to assess plasma nitrate concentrations after transdermal doses of 15, 30, 60, and 105 mg/24 hr employing the FDA Cooperative Study design. Plasma concentrations of nitroglycerin, 1,3-glyceryl dinitrate, and 1,2-glyceryl dinitrate were determined during the 24 hr of application and for 1 hr after transdermal system removal. Dose proportionality was assessed after normalizing the data by theoretical dose. For nitroglycerin, dose-normalized AUC(0-infinity) and Cmax were higher for the 105 mg/24 hr dose than for the other doses. For the metabolites, 1,3-glyceryl dinitrate and 1,2-glyceryl dinitrate, there were no differences in dose-normalized AUC(0-infinity) and dose-normalized Cmax between the dose levels. No differences were seen in Tmax between the dose levels for all three species. Based on the dinitrate metabolites, dose proportionality was seen over the 15 to 105 mg/24 hr dose range. Nitroglycerin, however, was found to be linear only between 15 and 60 mg/24 hr.


Metabolism of testosterone during in vitro transport across CACO-2 cell monolayers: evidence for beta-hydroxysteroid dehydrogenase activity in differentiated CACO-2 cells. Testosterone has previously been used as a model compound for the determination of unstirred water layer thickness in the CACO-2 transport model. We have found, however, that testosterone is metabolized during in vitro transport across the CACO-2 cell monolayers. This suggests that testosterone is not an ideal model substance. Testosterone is metabolized to androstenedione, indicating the formation of 17-beta-hydroxysteroid dehydrogenase by differentiated CACO-2 cells. No reverse metabolism is observed, thus androstenedione is considered superior to testosterone for determination of unstirred water layer thickness in the CACO-2 system. Permeability coefficients for testosterone and androstenedione obtained under identical transport conditions were 66 (+/- 7) * 10(-6) (n = 26) and 84 (+/- 7) * 10(-6) (n = 9) cm/sec, respectively. The unstirred water layer thicknesses at different agitation rates are determined for the CACO-2 transport model used in our laboratory utilizing androstenedione as a model compound. The system is capable of controlling the water layer thickness from about 200 to 1000 microns.


High-dose methotrexate does not affect the pharmacodynamics of phenobarbital hypnotic action but decreases the central nervous system (CNS) sensitivity to pentylenetetrazol-induced maximal seizures in rats. Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.


Studies on the excretion of diazepam and nordazepam into milk for the prediction of milk-to-plasma drug concentration ratios. The influence of varying protein and fat content in milk of New Zealand White rabbits on the milk-to-plasma drug concentration (M/P) ratio of diazepam was studied. At various time points after littering, a bolus dose (1.5 mg/kg) followed by a 26-hr infusion (1.8 mg/h) of diazepam was administered to freely moving rabbits via a jugular vein catheter. Milk and blood samples were collected to allow characterization of milk composition and quantitative determination of diazepam and nordazepam in milk and plasma. At steady state diazepam showed M/P ratios between 3.7 and 9.5, whereas nordazepam showed ratios between 2.1 and 4.3, respectively. The relative importance of milk protein binding and milk-fat partitioning for the excretion of a drug into milk depended on the drug's affinity to milk fat. A stepwise multiple regression analysis suggested that observed M/P ratios of diazepam could be explained by considering the fat content of milk alone. Nordazepam with a lower solubility in milk fat showed M/P ratios which could be best explained by considering protein and fat concentrations together. Using the data from the infusion studies, two recently published diffusional models to predict M/P ratios were evaluated. Neither model could accurately predict the M/P ratios of diazepam and nordazepam observed in rabbits. However, after extending the model described by Atkinson and Begg to take the actually measured partitioning between skim milk and milk fat into account, a great improvement in the predictive power for observed M/P ratios occurred.(ABSTRACT TRUNCATED AT 250 WORDS)


General treatment of the enterohepatic recirculation of drugs and its influence on the area under the plasma level curves, bioavailability, and clearance. A general treatment of enterohepatic recirculation of drugs has been developed based on the fraction of drug in systemic circulation that is excreted in the bile and the fraction of drug reabsorbed from the gut that reaches systemic circulation in each enterohepatic cycle. The deduced equations make it possible to establish mathematical relationships between the areas under the blood level curves (AUC) of a drug when administered to normal and bile duct-cannulated animals and to predict the effect of enterohepatic recycling on bioavailability and clearance. The results were compared with those obtained by other authors using different approaches to enterohepatic recirculation, and some discrepancies were found in the equations describing the effect of enterohepatic recycling on AUC and bioavailability of drugs. The cause of such discrepancies and the problems associated with the prediction of hepatic extraction ratio from in vitro studies are discussed.


A quantitative structure-activity relationship (QSAR) study of alkylpyrazine odor modalities. The odor strength of a series of alkylpyrazines has been quantitatively investigated applying molecular connectivity, molecular shape, and the recently developed electrotopological state indices. The successful use of the latter parameters indicates that both electronic and topological features contribute to the odor strength of the compounds under study, while the specific role of the two nitrogen atoms is revealed.


The effects of N(4-methylphenyl)diphenimide on lipid metabolism of Sprague Dawley rats. N(4-Methylphenyl)diphenimide proved to be an effective hypolipidemic agent in rats at 10 and 20 mg/kg/day. Both serum cholesterol and triglyceride levels were reduced significantly. Decreases in tissue lipids as well as VLDL cholesterol levels were observed. HDL-cholesterol was elevated even at 10 mg/kg/day. The agent was equally effective in hyperlipidemic diet-induced rats, lowering serum lipids and VLDL- and LDL-cholesterol while elevating HDL-cholesterol levels. The drug interfered with the incorporation of 3H-cholesterol and 3H-palmitic acid into chylomicrons, VLDL, and LDL. The two precursors were incorporated at a higher rate into HDL. 3H-Leucine was incorporated into chylomicrons, VLDL, and LDL at a higher rate, but not into HDL. Reduced uptake of the precursor for lipid synthesis was noted in tissues after treatment with the drug.


Microparticles of polyvinyl alcohol for nasal delivery. I. Generation by spray-drying and spray-desolvation. Spray-drying and spray-desolvation are described for the generation of polyvinyl alcohol microparticles intended for nasal administration. The spray-dried microparticles of polyvinyl alcohol were of an appropriate size distribution but consisted of hollow spheres, which made them unsuitable for nasal delivery, as rapid clearance and a varied deposition pattern would be expected. Microparticles were also produced by spraying polyvinyl alcohol (average molecular weight of 14,000) solution (12.5%, w/v) at 0.332 ml/min onto the surface of acetone (spray-desolvation). These microparticles were solid collapsed spheres with the desired size for nasal deposition (10-200 microns). This method can be applied to encapsulation of drugs that are heat labile such as peptides and proteins.


Participation of Macrogolstearate 400 lamellar phases in hydrophilic creams and vesicles. In binary Macrogolstearate 400 (MS 400)/water systems, lamellar surfactant arrangements can be detected by polarized light and transmission electron microscopy. As demonstrated by X-ray diffraction and differential scanning calorimetry, the alkyl chains of the emulsifier are in the crystalline state. Ternary systems with liquid paraffin represent optically isotropic, homogeneous o/w creams for a wide composition range. Incorporation of up to 50 mol% cholesterol into the MS 400 lamellar structures leads to a gel-liquid crystalline phase separation within the bilayer, thus enabling the formation of spherical nonionic vesicles. The transition enthalpy of the samples decreases linearly with increasing cholesterol concentrations. The Macrogolstearate 400/cholesterol vesicles proved to be stable in hydrophilic cream systems. Cationic vesicles can be prepared using cetyltrimethylammonium bromide (CTAB) as a charge inducer. Low-CTAB portions are inhomogeneously distributed within the bilayer, as detected by DSC. The results also indicate a perturbation of the alkyl chains packing for the positively charged vesicles.


Benzoyl peroxide solubility and stability in hydric solvents. Saturated solubility and reaction rate constants for the decomposition of benzoyl peroxide in solution and suspension were determined for use in formulation development. The solvents studied included ethanol, propylene glycol, and cosolvent mixtures of PEG 400 and water. The solubility of benzoyl peroxide was inversely related to the solvent polarity, with greater solubility occurring with semipolar solvents. The stability of benzoyl peroxide in solution was dependent on the solvent, concentration of benzoyl peroxide, and temperature. The compound was least stable in PEG 400. Stability was improved when water was added to PEG 400. Similar solvent effects were observed in suspension. In benzoyl peroxide suspensions of PEG 400 and PEG 400/water blends, benzoyl peroxide stability was dependent on solubility, with improved stability occurring in blends where the benzoyl peroxide was least soluble. Thus, solution formulations of benzoyl peroxide in pharmaceutically acceptable solvents are unlikely to show good stability; however, suspension formulations should be reasonably stable if the vehicle is selected to provide low benzoyl peroxide solubility.


Predicting the effect of nonionic surfactants on dispersed droplet radii in submicron oil-in-water emulsions. A novel theoretical model which describes the mass mean radius of oil droplets in an oil-in-water emulsion is described. A modified form of the Langmuir adsorption isotherm is used to account for nonlinear adsorption of surfactant to an oil-water film and its effect on interfacial tension and oil droplet radius. On the basis of this model, the mass mean oil droplet radius may be related to bulk surfactant concentration for a nonionic surfactant. An analysis of the mineral oil-Triton X405-water system shows that aqueous solutions of Triton X405 against mineral oil behaved in accord with the proposed model. gamma m, the maximum interfacial tension lowering by Triton X405, was estimated to be 20.9 dyne/cm. A surfactant specific apparent constant (B) which relates the rate constant for adsorption to the interface to the rate constant for desorption from the interface into the aqueous bulk was estimated as 5.44E4 cm3/g. The pressure across the curved interface, delta P, was estimated as 1.05E6 dyne/cm2. The theoretical model appears to be consistent with experimentally observed oil droplet radii and is considered to be an accurate representation of the mechanics of dispersed droplet radii under conditions of moderate load of nonionic surfactant.


Powdered solution technology: principles and mechanism. The concept of powdered solutions can be used to formulate liquid medications in dry, nonadherent, free-flowing, and readily compressible powders. The technique is based on simple admixture of drug solution or liquid drug with selected carrier and coating materials. Improved drug release profiles are exhibited by such delivery systems even for poorly water-soluble drugs. Previous work using this method has rendered its industrial application impractical because of the unsatisfactory flow properties of the powder admixtures. This article presents a theoretical model based on the principles and mechanism of powdered solutions and introduces a new physical property of powders termed the flowable liquid-retention potential (phi value). Mathematical expressions are derived that can be used to calculate the optimum amount of excipients required to yield powder admixtures with acceptable flowability. The validity and applicability of these expressions have been verified experimentally using clofibrate and prednisolone as test materials. The proposed model is shown to be superior to previously reported studies in optimizing the amount of excipients needed to prepare powdered solutions with acceptable flow properties.


Excessive accumulation of hepatic copper in LEC rats aged 80 days without hepatitis and 130 days with hepatitis. The Cu concentration was about 40 and 60 times higher in the liver in Long-Evans with a cinnamon-like coat color (LEC) rats aged 80 days (without hepatitis) and 130 days (with hepatitis), respectively than in the liver in Fischer rats. Most hepatic Cu was recovered in the cytosol fraction. Furthermore, about 96% and 84% of the cytosolic Cu was found in the metallothionein region on a Sephadex G-75 column in LEC rats aged 80 and 130 days, respectively. The hepatic metallothionein concentration was about 130 to 140 times higher in LEC rats than in Fischer rats when the concentration was expressed as metallothionein-bound Cu. Three forms of Cu-metallothionein were isolated by DEAE-cartridge. Although the concentration of hepatic Cu-metallothionein and its composition of polymorphic form were not changed greatly in hepatitis phase (in the 130-day-old LEC rats), activities of serum enzymes, aspartate aminotransferase (GOT) and alanine aminotransferase (GPT) were increased significantly. The LEC rat showed a significantly low concentration of biliary Cu and markedly low activity of ceruloplasmin (as ferroxidase). Serum Cu showed a low concentration in the 80-day-old LEC rats, but recovered to the control level in the 130-day-old LEC rats. The abnormal accumulation of Cu may be due to the inherent reduction of excretion of Cu into the bile and blood. Such deposition may be a trigger for the onset of the spontaneous hepatitis occurring at 90-120 days after birth and for the onset of hepatoma later.


Experimental evaluation of the effects of pravastatin on electrophysiological parameters of rat skeletal muscle. The effects of daily chronic treatment for 6 months with pravastatin was evaluated on the performance of the skeletal muscle system of different rat groups. At all doses (0.1 mg/kg-20 mg/kg) the righting reflex and the electromyographic signals observed in vivo did not show any abnormality. At the end of the treatment the Extensor digitorum longus muscles were dissected from treated and control rats and their passive and active electrical parameters were analyzed in vitro by standard microelectrodes technique. Pravastatin did not modify the chloride conductance nor the excitability characteristics of the fibers. Chronic treatment with pravastatin does not produce any alteration of skeletal muscle function.


Mechanical effects of some prostanoids on isolated human oesophageal submucosal veins. The effects of prostaglandins E1, E2, F2 alpha, prostacyclin, and the thromboxane A2-mimic U46619 were investigated on isolated human oesophageal submucosal veins from the oesophageal body and the oesophagogastric junction. U46619 most potently, but also PGF2 alpha produced venocontraction without differences between preparations from the oesophageal body and the oesophagogastric junction. PGE1 and prostacyclin caused relaxation of vessels precontracted with U46619 (10(-9) M). PGE2 induced either contraction or relaxation, but biphasic effects in the same vessel segment were not seen. Indomethacin 10(-6) M inhibited the contractile responses to both noradrenaline and K+ (124 mM), suggesting that the agonists induced synthesis or release of vasoconstrictor prostanoids. Prostanoids exert potent mechanical effects in submucosal oesophageal veins and may be of physiological importance.


Bioactivation of halogenated hydrocarbons by rabbit pulmonary cells. 1,1-Dichloro-2,2-bis (4'-chlorophenyl)ethane (DDD), 1,2-dibromoethane (DBE) and trichloroethylene are three halogenated hydrocarbons that selectively bind to pulmonary epithelial cells and that may be pneumotoxic. The susceptibility of pulmonary cells and the mechanisms of cytotoxicity of these compounds were evaluated using enriched subpopulations of isolated rabbit lung cells incubated with DDD, DBE, and trichloroethylene. These chlorinated and brominated hydrocarbons were studied to evaluate their ability to induce selective pneumotoxicity by their bioactivation in three cell types, i.e. Clara cells, alveolar type II cells, and alveolar macrophages. Evidence of cytochrome P-450 bioactivation was assessed by utilizing the suicide inhibitor, 1-aminobenzotriazole (ABT) to ameliorate cytotoxicity. DDD, DBE and trichloroethylene were cytotoxic to Clara cells, type II cells and alveolar macrophages and the order of cell susceptibility to DDD was Clara > type II > macrophages. DBE and trichloroethylene were nonselectively cytotoxic. ABT reduced the cytotoxic effects of DDD and DBE in Clara cells. These studies indicated that all three compounds were toxic to isolated lung cells and that bioactivation of DDD and DBE in rabbit Clara cells to a cytotoxic intermediate was mediated, at least in part, by cytochrome P-450 oxidation.


Pharmacokinetics of the oxime HI-6 from a mixture with atropine sulphate in dogs. The pharmacokinetics of the oxime HI-6 from an aqueous solution and from a mixture containing HI-6 and atropine (in doses similar as proposed for their combination in an automatic injector) was studied in German shepherd dogs. A standard manual injection of mixed drugs was followed by enhanced resorption of HI-6 while the elimination curves were quite similar. A comparison of the parameters describing relative bioavailability at the 80% probability level did not reveal any significant differences between the formulations of HI-6. The increase in HI-6 level in blood of animals receiving a mixture is more likely to be attributed to the local vasodilatation than to the systemic cardiovascular effects of atropine.


Effects of toluene and n-hexane on rat synaptosomal membrane fluidity and integral enzyme activities. The effects of toluene and n-hexane on rat synaptosomal membrane fluidity and the integral enzymes acetylcholinesterase (AChE) and ATPase were studied in vitro. The synaptosome membranes were isolated in Percoll and sucrose gradients. After adding toluene and n-hexane to the incubation mixture (37 degrees) in 2,4,6 and 8 mM concentrations, the fluidity changes were measured by the lateral pyrene diffusion method from Percoll-isolated membranes, and the ATPase and acetylcholinesterase activities were determined from both synaptosome isolations. Addition of toluene caused a linearly correlated increase of the synaptosomal membrane fluidity and a linear decrease of the AChE activity. The ATPase activity did not decrease linearly but dose-dependently. In contrast to the effects of toluene in vitro, addition of n-hexane in the same concentration range had no comparable influence on membrane fluidity nor on the activities of both integral enzymes despite its even higher lipid/water partition coefficient. Toluene increases synaptosomal membrane fluidity and at the same time inhibits the integral enzymes, probably by disturbing the lipid/protein interaction.


Interaction between ciprofloxacin and thiopental in the central nervous system of the male rat. The effect of intravenous ciprofloxacin (CPX) pretreatment on the kinetics and brain sensitivity for thiopental was studied in male rats using a previously developed electroencephalographic (EEG) threshold method. Thiopental was administered intravenously with constant infusion rate. Immediately after the appearance of the first burst suppression of 1 sec. or more (the "silent-second") in the EEG the infusion was stopped and the rats were killed by decapitation. The dose of thiopental needed to reach the criterion of silent-second was slightly reduced in ciprofloxacin pretreated rats when compared with saline pretreated controls. One rat that developed seizures after CPX pretreatment needed a considerably reduced dose of thiopental to induce the silent-second. The serum concentrations of thiopental were markedly reduced in the experimental group while no significant differences were found in the concentrations of thiopental in the different parts of the central nervous system (CNS), fat or muscle tissue. The kinetics of CPX were also affected. The experimental group (CPX + thiopental treated) had significant higher brain concentrations of CPX than the corresponding only CPX treated control group while no differences were found in the serum concentrations of CPX between the groups. As previously suggested, the distribution of thiopental in the CNS is not only dependent on its lipid solubility, but also as a weak organic acid, on the transport system for organic acids out of the CNS which both thiopental and ciprofloxacin seem to use and mutually compete for it.


Effects of felodipine on utero-placental blood flow in normotensive rabbits. The utero-placental blood flow was investigated in anaesthetized normotensive pregnant rabbits after repeated administration of a high dose of the antihypertensive calcium antagonist felodipine and in untreated controls. By means of the microsphere technique blood flow was also determined in the lungs, skin, intestine, skeletal muscle and kidneys during chloralose anaesthesia. Felodipine reduced mean arterial blood pressure, which was associated with a marked reduction in vascular resistance in the skeletal muscle vascular bed, where blood flow was increased seven-fold. In contrast, blood flow to placentae and kidneys were reduced. The pronounced reduction in placental blood flow may limit foetal nutrition and hence explain reported foetal digital defects after administration of high doses of felodipine to pregnant normotensive rabbits.


On the pharmacological and physiological role of glibenclamide-sensitive potassium channels in colonic smooth muscle. Actions of activators of glibenclamide sensitive K+ channels on canine colonic circular muscle were investigated. Cromakalim as well as its (-) enantiomer lemakalim caused inhibition of spontaneous phasic contractile activity (EC50's 4.4 +/- 0.1 x 10(-7) M and 2.3 +/- 0.4 x 10(-7) M, respectively) and of carbachol induced activity (EC50's: 9.4 +/- 5.1 x 10(-7) M and 4.3 +/- 1.4 x 10(-7) M, respectively). Cromakalim and lemakalim effects were completely inhibited by glibenclamide. Additive effects between K+ channel activators and other drugs relaxing colonic muscle (the L-type calcium channel blocker D600 and forskolin) were seen. A physiological role for specific glibenclamide sensitive K+ channels, if existing, remains unresolved. The present study indicates that the non-adrenergic inhibitory nerves do not act through these channels, neither does stimulation of muscarinic or beta-adrenergic receptors.


The effect of high calcium intake on intracellular free [Ca2+] and Na(+)-H+ exchange in DOC-NaCl-hypertensive rats. The effects of calcium supplementation on blood pressure, intracellular free calcium concentration ([Ca2+]i) and rate of Na(+)-H+ exchange were studied in DOC-NaCl-hypertensive rats. All the animals were uninephrectomized and divided into two main groups: the first group received deoxycorticosterone (DOC) (25 mg/kg, s.c.) once a week and had 0.7% NaCl as drinking fluid while the other received equal volumes of saline and tap water to drink. The animals were further divided according to dietary calcium intake: in the Control and DOC groups the chow contained 1.1% calcium, in the Calcium and DOC+Calcium groups, 2.5%. After 6 and 8 weeks, blood pressure in the DOC group was higher than in the Control group; on the other hand, the development of hypertension was attenuated in the DOC+Calcium compared with the DOC group. The Control and Calcium groups did not differ from each other. Platelets and lymphocytes were used as experimental models to study changes in the regulation of [Ca2+]i, evaluated by fluorescent indicators indo-1 and quin-2. In lymphocytes, basal [Ca2+]i was highest in the DOC group, but similar in DOC+Calcium and Control groups. In platelets, both basal and thrombin-stimulated [Ca2+]i were higher in the DOC and DOC+Calcium groups than in the Control group. In both cell types [Ca2+]i was similar in Control and Calcium groups. In addition, platelets were used to study the ability of the cells to recover from intracellular acidification by first blocking the Na(+)-H+ exchange in a Na(+)-free medium and then restarting the exchange mechanism by increasing the extracellular Na+ concentration at constant speed.(ABSTRACT TRUNCATED AT 250 WORDS)


Bioavailability of two Soviet sustained-release theophylline formulations in comparison with TheoDur. The pharmacokinetic parameters of two theophylline preparations of Soviet origin (Theobiolongas and Theopaek) were compared with the reference preparation TheoDur. The three sustained-release preparations were administered in a single oral dose (400 mg) to healthy volunteers. Blood samples were drawn over 36 hr and plasma concentrations of theophylline were measured by HPLC. Significant differences in the pharmacokinetic parameters were observed between the drugs. Compared to TheoDur, the two Soviet drugs, Theobiolongas and Theopaek, had lower bioavailability (86% and 82%, respectively), and higher rate of absorption. An 8-hr dosing interval should be preferred for Theobiolongas and Theopaek while twice-daily administration appears to be appropriate for these preparations only in exceptional cases.


Characterization of cultured human nesidioblasts and their associated macromolecules: cross-reactivity with a cloned rat pancreatic beta-cell line. Near-total pancreatectomy in a neonate presenting with persistent hypoglycemia offered an unusual opportunity to grow preparations enriched in beta-cells. Morphology, chromosomal analysis, and immunohistochemistry were used to characterize a subculture (Nesi B) that remained stable through passage 11. Insulin secretion of Nesi B was constitutive at 38-74 nU/microliters of medium/24 h, increasing modestly in the presence of isobutylmethylxanthine, an inhibitor of cyclic AMP phosphodiesterase. Endocrine cells, exclusive of those in islet regions, were widely distributed throughout the original tissue section, and immunostaining of the Nesi B subculture demonstrated well-differentiated heavily granulated insulin-positive cells, each with a normal modal number of chromosomes (46). Nesi B cell-associated macromolecules were isolated in 3 x 10(-3) ethylenedinitrilotetraacetate/phosphate-buffered saline and were found to be reactive with a heterologous immune serum elicited to a cloned rat pancreatic beta-cell line (RIN-5F). Western (immuno) blotting showed this immunoreactivity to reside primarily in a 95-kDa fraction of Nesi B-derived components. These results indicate that human nesidioblasts can be cultured for a sufficient number of passages to allow isolation and immunochemical characterization of pancreatic beta-cell macromolecules shared between rat and human and that may serve as organ-specific antigens for inflammatory disorders of the pancreas.


Heterotopic autotransplantation of the distal pancreas segment after total pancreatectomy for cancer of the head of the pancreas. Autotransplantation of the distal pancreas segment with pancreaticojejunostomy was performed in four patients with cancer of the head of the pancreas to preserve endocrine pancreatic function after extended total pancreatectomy. All patients had tumor involvement of both the celiac axis and the portal vein. The pancreatic graft was determined to be cancer-free by frozen section histologic and pancreatic juice cytologic examinations. The distal pancreas segment was autotransplanted to the iliac vessels heterotopically and placed in the extraperitoneal pocket to avoid untoward effects of any local recurrence or pancreatic leakage. This procedure, in the form of reconstruction, might be called modified subtotal pancreatoduodenectomy. Postoperatively, all patients remained normoglycemic without exogenous insulin administration, and their quality of life was considered satisfactory.


A stereological investigation of rat endocrine pancreas after a long-term low-protein diet. Stereological analysis of rat endocrine pancreas was carried out after 4 months of low-protein intake. Thirty make Wistar rats, aged 2 months at the beginning of the experiment, were divided into three groups. The control group (NP) received a standard laboratory diet. The experimental group (LP) received a low-protein diet, and the pair-fed animals also received a standard laboratory diet, as the NP rats did, but restricted to the amounts consumed by the LP group. All groups were offered drinking water ad lib. Weibel's multipurpose lattice was used to determine the volume fraction of cells and numerical density of islets in the endocrine pancreas. The results showed that the long-term low-protein diet decreased the volume fraction of B-cells and increased that of A-cells. Numerical density of islets was significantly increased, whereas the absolute number was decreased. The mean number of B-cells per islet was found to be decreased and that of D-cells increased. The mean radius of the islets was decreased, as was the mean surface area.


Element distribution in organelles of pancreatic acinar cells of rat, mouse, and pig investigated by energy-dispersive X-ray microanalysis. The exocrine pancreas was long thought to be composed of identical subunits, the acinar cells that store the inactive forms of the digestive enzymes in zymogen granules (ZGs). These were generally seen as a homogeneous population of vesicles. This homogeneity was recently questioned: Digestive demands are answered by the release of specific enzymes and immunocytochemical labeling showed distinctive nonidentical populations of ZGs. We have aimed at finding concomitant differences in element contents. We analyzed by energy-dispersive x-ray microanalysis (EDX) the subcellular distribution of elements in acinar cells of resting and stimulated rat, resting mouse, and resting pig pancreas and compared the results with values from the literature. We found large variances in the concentrations of Na, Mg, P, S, Cl, K, and Ca in cytoplasm rich in endoplasmic reticulum (C/E), whereas the concentrations of P, Cl, K, and Ca in mitochondria and ZGs had surprisingly small variations. Na and Mg were detected in measurable amounts only in C/E and mitochondria and Ca was detectable only in ZGs. We could not find any other elements. We have not found clearly distinguishable populations of ZGs. We critically discuss our findings in comparison with the literature. Many discrepancies can be explained by the different preparation procedures. We show that it is questionable to present absolute values of concentration in biological specimens on the basis of EDX. The technique should, in our opinion, be used only for the study of relative concentrations.


Contribution of postprandial amino acid levels to stimulation of insulin, glucagon, and pancreatic polypeptide in humans. The present study was designed to examine the contribution of the postprandial increase of plasma amino acids after ingestion of a protein-rich meal to the rise of the three pancreatic hormones insulin, glucagon, and pancreatic polypeptide (PP). A mixed amino acid solution was designed, which permitted a fairly close imitation of the arterial plasma pattern of the 21 amino acids that rise after ingestion of a 200-g porcine steak meal. In 10 healthy subjects the intravenous infusion of this mixed amino acid solution at a rate of 10 g/h elicited a rise of the 21 amino acids examined that correlated well with the postprandial increase (r = 0.89, p < 0.001). The maximal rise of plasma insulin (64 +/- 5 pmol/L) and glucagon (630 +/- 21 ng/L) was not significantly different from the postprandial increase of these two hormones (49 +/- 4 pmol/L and 780 +/- 28 ng/L, respectively). PP levels rose by 316 +/- 33 ng/L postprandially, which was clearly above the increase of 112 +/- 13 ng/L during intravenous amino acids (p < 0.01). In conclusion, the present data demonstrate that the postprandial rise of amino acid levels in arterialized venous plasma can account for most if not all of the postprandial increase of insulin and glucagon during the ingestion of a protein-rich meal. In contrast, only 35% of postprandial PP levels can be ascribed to the rise of plasma amino acids. In contrast to the effect of carbohydrate-rich meals, an enteric augmentation of insulin release seems to be of minor and possibly of no importance during ingestion of protein-rich meals.