Effects of combined treatment with enalapril and losartan on myocardial function in heart failure.
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Aged↗
Biomedical subjects
S Kohn
Publications and source records attributed to S Kohn.
Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections.
OBJECTIVE: To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). METHODS: An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). RESULTS: There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were > or = 2 mg/l, whereas in the TD group only 0.7% were > or = 2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. CONCLUSIONS: With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.
Anti-Bacterial Agents↗
Rod-shaped bodies resembling birbeck granule-like structures in endothelial cells of dermal capillaries in generalized granuloma annulare.
A previous study demonstrated that, in generalized granuloma annulare in the epidermis, the Langerhans' cell section area and the number of Langerhans' cell granules or Birbeck granules per cell section were increased, suggesting an active state of these Langerhans' cells. Reexamination by transmission electron microscopy of the same tissue, but in samples also containing dermal tissue, from the same subjects revealed endothelial cells with rod-shaped bodies resembling Birbeck granules or Birbeck granule-like structures. This finding has not been previously described in blood vessels of human skin and is described here.
Capillaries↗
[Birbeck granules in epidermal Langerhans cells of elderly patients with decubital ulcers].
UNLABELLED: Birbeck granules (Bg), known also as Langerhans cell (L) granules are special organelles found in the L cells' cytoplasm, which serve as a marker for their identification. These organelles have been studied in epidermal L cells in elderly patients with pressure sores and were compared to those found in epidermal L cells of healthy volunteers who served as controls. RESULTS: There was an increase of about 47% in the number of B granules in patients' L cells from sacral epidermis near lesion (p < 0.01) and an increase of about 68% of the number of B granules in patients' L cells from normal epidermis (p < 0.005) was found as compared to healthy control L cells. Part of the B granules in patients' L cells were of similar morphology to those of controls. They were found throughout the cytoplasm as simple rods or rackets. In addition, in patients' epidermis some irregularly shaped granules were observed, such as: racket structure common to two or more rod structures; rod shaped granules in direct continuity with mitochondria, and others with lysosomes. Moreover, B granules in continuity with the cell plasma membrane and groups of closely opposed rod shaped granules were observed. These two last shaped structures apparently reflected formative stages of B granules. It is suggested that an increase of the number of B granules indicated an active state of L cells in the epidermis of patients studied. It is not clear whether the morphologic alterations of B granules influence the L cell functions in antigen presentation. It is possible that they may be partly involved in infections which occur frequently in patients with decubital ulcers. It is also possible that the increase in the number of B granules and the altered structures found among them in patients' epidermis express a reaction of L cells to inflammation.
Aged↗
Effect of zinc supplementation on epidermal Langerhans' cells of elderly patients with decubital ulcers.
In the present study, Langerhans' cells (LCs) in the sacral epidermis, 8-10 cm from lesions of patients (mean age 71 years) with decubital ulcers, were compared ultrastructurally and morphometrically with those in the patients' own normal epidermis from the upper leg, before and after supplementation with 50 mg/day elementary zinc (in the form of a 220-mg tablet of Avazinc, administered once daily) for four months. Zinc intake resulted in from 80% to full healing of the decubital ulcers in the patients studied. The percentages of LCs were low in both perilesional sacral epidermis (2.07 +/- 0.71%) and in control leg epidermis (2.71 +/- 1.38%) before zinc supplementation and also afterward (2.12 +/- 0.16% and 2.59 +/- 0.88%, respectively). LCs demonstrated a more dendritic morphology after zinc supplementation: 68.15 +/- 9.28% and 77.0 +/- 3.45% of sacral and of control leg epidermal LCs, respectively, had dendrites before, and 91.52 +/- 3.43% and 84.15 +/- 3.64% of sacral and of control leg epidermal LCs, respectively, had dendrites after zinc supplementation. The LC section area in the sacral epidermis near the lesion as well as in the control leg epidermis and the number of LC granules in LC sections were not affected by zinc supplementation. The higher percentage of LCs having dendrites in the epidermis of patients with decubital ulcers after zinc supplementation may indicate that these LCs are in a more motile state, which might affect the healing process of the lesions.
Administration, Oral↗
An encyclopedia of mouse genes.
The laboratory mouse is the premier model system for studies of mammalian development due to the powerful classical genetic analysis possible (see also the Jackson Laboratory web site, http://www.jax.org/) and the ever-expanding collection of molecular tools. To enhance the utility of the mouse system, we initiated a program to generate a large database of expressed sequence tags (ESTs) that can provide rapid access to genes. Of particular significance was the possibility that cDNA libraries could be prepared from very early stages of development, a situation unrealized in human EST projects. We report here the development of a comprehensive database of ESTs for the mouse. The project, initiated in March 1996, has focused on 5' end sequences from directionally cloned, oligo-dT primed cDNA libraries. As of 23 October 1998, 352,040 sequences had been generated, annotated and deposited in dbEST, where they comprised 93% of the total ESTs available for mouse. EST data are versatile and have been applied to gene identification, comparative sequence analysis, comparative gene mapping and candidate disease gene identification, genome sequence annotation, microarray development and the development of gene-based map resources.
Animals↗
Ototoxicity resulting from combined administration of cisplatin and gentamicin.
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Animals↗
Effect of artificial stimulants on cryopreserved spermatozoa from cancer patients.
PURPOSE: We determined whether cryopreserved sperm samples obtained from cancer patients before treatment respond to artificial motility stimulants and if this response is related to the extent of disease. MATERIALS AND METHODS: Pre-freeze distribution of disease stage in the different types of cancer and the percentage of the population with or without oligospermia before cryopreservation were examined. Cryopreserved semen samples from 17 cancer patients (10 with testicular cancer, 5 with Hodgkin's disease and 2 with other metastatic disease) were examined for a relationship between post-thaw sperm motion characteristics and patient age or status (survived versus died) and type of disease. Motion characteristics (curvilinear velocity, straight line velocity, average path velocity, linearity and amplitude of lateral head displacement) were analyzed on a computer assisted semen analyzer before (time 0), and 30 and 60 minutes after addition of a 2.5 mM. concentration of pentoxifylline and 2-deoxyadenosine. RESULTS: Post-thaw sperm motion characteristics were not correlated with patient age or status, whether they did or did not have oligospermia, or type of cancer. Compared to baseline values, sperm motion characteristics increased significantly after stimulation at time 0 (p < 0.02) and at 60 minutes (p < 0.05). Oligospermic or nonoligospermic specimens responded to the same extent with pentoxifylline and 2-deoxyadenosine. A negative correlation was noted between overall stage, and type of disease and motion characteristics. CONCLUSIONS: Sperm banking should be encouraged at cancer diagnosis regardless of semen quality. Artificial stimulation of sperm motility results in significant improvement in sperm motion characteristics.
Adult↗
The vesiculo-vacuolar organelle (VVO): a distinct endothelial cell structure that provides a transcellular pathway for macromolecular extravasation.
The vesiculo-vacuolar organelle (VVO) is a recently described organelle found in the cytoplasm of endothelial cells that line tumor microvessels and normal venules. VVOs are grape-like clusters of interconnecting uncoated vesicles and vacuoles, bounded by trilaminar unit membranes, that span the entire thickness of vascular endothelium, thereby providing a potential trans-endothelial connection between the vascular lumen and the extravascular space. Macromolecular tracers preferentially cross hyperpermeable tumor microvessels through VVOs. The present investigation was undertaken to elucidate further the ultrastructure and function of VVOs in a murine ovarian carcinoma (MOT) and in normal venules. Morphometry revealed that VVOs were enormous cytoplasmic structures (median area, 0.12-0.14 microns2 in single electron micrographs). Moreover, the individual vesicles and vacuoles that comprised VVOs were on average substantially larger than capillary caveolae and followed a non-normal distribution that was skewed to the right. Specimen tilting provided conclusive evidence that individual VVO vesicles and vacuoles communicated with each other and with the endothelial cells' plasma membranes by stomata, some of which were closed by diaphragms composed of a single membrane. Studies with two tracers, ferritin (FE, diameter approximately 11 nm) and horseradish peroxidase (HRP, diameter approximately 5 nm), revealed that passage of macromolecules through VVOs was regulated at the level of stomatal diaphragms, thereby demonstrating a mechanism for controlling the passage of macromolecules across endothelial cells. Thus, compared with tumor microvessels, little circulating FE and HRP entered the VVOs of normal venular endothelium because stomata joining vesicles and vacuoles to each other and to the lumen and ablumen were closed. VVOs and their component vesicles/vacuoles were readily distinguished from endosomal organelles such as coated vesicles and multivesicular bodies, which also accumulated FE and HRP. Our findings indicate that VVOs provide a major pathway for the extravasation of circulating macromolecules across endothelia taller than capillary endothelium and suggest that upregulated VVO function accounts for the well-known hyperpermeability of tumor blood vessels.
Animals↗
[The stria vascularis of the inner ear and its normal structural variations].
The ultrastructural effects of gentamicin on the stria vascularis of the inner ear of guinea pigs were studied by transmission electron microscopy. In a single specimen of an isolated, inner ear we found an unexpected variation in the structure of the stria vascularis in a normal, pigmented, guinea pig not treated with ototoxic drugs. There were prominent, wide protrusions from the apical surfaces of marginal cells into the endolymphatic space. This finding has not been previously reported and was seen in only 1 of 7 animals studied. It may be considered a normal structural variation, and is not pathological change in the stria vascularis due to ototoxic drugs.
Animals↗
The mast cell and mast cell disease.
Mast cell disease or mastocytosis is a heterogeneous group of clinical disorders characterized by the proliferation and accumulation of mast cells in a variety of tissues, most often the skin. The signs and symptoms of mast cell disease are varied, dependent on the localization of mast cells in different organs and the local and systemic effects of mediators released from these cells. Although mast cell disease is most commonly identified in the skin, involvement of the skeletal, hematopoietic, gastrointestinal, cardiopulmonary, and central nervous systems may be seen. Clinical management of mastocytosis depends most heavily on knowledge of the diverse effects of mast cell mediators on various tissues and organs, the stimuli that can cause their release, and the different methods available for blocking the effects of these mediators.
Bone Diseases↗
Langerhans' cells of elderly patients with decubital ulcers.
An ultrastructural and morphometric study compared Langerhans' cells in sacral epidermis, 8-10 cm from the lesion of patients (mean age 70) with decubital ulcers, with those in the patients' own normal epidermis from the upper leg and with those in the epidermis from the upper leg of normal age-matched volunteers. The Langerhans' cell section area was significantly lower in patients' control leg epidermis (25.86 +/- 2.29 microns2) than in that from normal controls (35.74 +/- 3.76 microns2) or that from patients' sacral epidermis near the lesion (41.26 +/- 3.45). The number of Langerhans' cell granules was higher in control leg epidermis of patients (10.22 +/- 1.26) and was significantly higher in lesioned sacral epidermis (12.94 +/- 1.90) than in normal controls (6.97 +/- 1.47). In Langerhans' cells in patients' epidermis, formative stages of Langerhans' cell granules were observed. The findings may indicate that Langerhans' cells in patients' epidermis are in an active state.
Aged↗
Persistent cerebrospinal fluid neutrophilia in delayed-onset neonatal encephalitis caused by herpes simplex virus type 2.
We describe an infant with three unusual features of perinatally acquired herpes simplex virus type 2 encephalitis: onset of illness at 34 days of age, absolute cerebrospinal fluid neutrophilia, and systemic viral dissemination after central nervous system disease. To provide early, effective antiviral therapy, clinicians should be aware of atypical presentations of serious herpes simplex virus infections.
Encephalitis↗
Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels.
BACKGROUND: Blood vessels supplying tumors are hyperpermeable to macromolecules, but the mechanisms responsible are poorly understood. EXPERIMENTAL DESIGN: To investigate the structural basis for the leakiness of tumor blood vessels, we performed a transmission electron microscopic study of three syngeneic transplantable carcinomas (mouse ovarian carcinoma and the line 1 and line 10 bile duct guinea pig carcinomas) at early intervals after intravenous injection of several macromolecular tracers. Tracers with widely differing physical properties were studied: horseradish peroxidase, ferritin, 150 kilodalton fluorescein isothiocyanate-dextran and gold-bovine serum albumin. RESULTS: All tracers leaked primarily from venules and small veins at the tumor-host interface, for the most part vessels lined by a continuous endothelium. The predominant pathway by which all four tracers exited venules in all three tumors was by way of a system of smooth membrane-bound, interconnecting vesicles and vacuoles; these tended to cluster together at irregular intervals in the endothelial cell cytoplasm to form organelle-like structures, vesiculo-vacuolar organelles (VVO). In favorable sections, VVO interfaced with both the luminal and abluminal surfaces of endothelial cells. HRP alone crossed venules and small veins through apposed inter-endothelial cell junctions. Tracers also exited vessels by way of endothelial fenestrae where these occurred (rarely) in mouse ovarian tumor-associated venules. VVO occurred with similar frequency and complexity in the continuous endothelium-lined venules and small veins that supplied the normal subcutis of either tumor-bearing or control animals. As in tumor-associated vessels, VVO provided the predominant pathway by which all four tracers exited normal vessels, but VVO labeling and extravasation were both much greater in tumor than in control vessels (p < 0.001 for ferritin). CONCLUSIONS: VVO are prominent structures in both tumor-supplying and control vessel endothelial cells and provide the primary pathway for macromolecular extravasation. The large increase in permeability characteristic of tumor vessels is likely attributable to upregulation of VVO function.
Animals↗
Toxic effects of cisplatin alone and in combination with gentamicin in stria vascularis of guinea pigs.
The toxic effects on the stria vascularis of treatment with cisplatin alone and combined with the aminoglycoside antibiotic, gentamicin, were studied in guinea pigs. The toxicity induced in albino and pigmented guinea pigs was investigated morphologically with light and transmission electron microscopy, and functionally by brainstem-evoked response audiometry. The results of hearing thresholds were variable, ranging from no change in one ear in some of the animals to a hearing loss of 20 dB in one or both ears when treated with low-dose cisplatin alone or in combination with gentamicin. Bilateral deafness resulted from high-dose cisplatin combined with gentamicin. The combined treatment produced prominent structural damage in the stria vascularis. The results should be considered when aminoglycoside therapy is required in conjunction with cisplatin.
Animals↗
Epidermal Langerhans' cells in elderly patients with decubital ulcers.
Langerhans' cells in the sacral epidermis 8-10 cm from the lesion of elderly patients (mean age 74 years) with decubital ulcers were studied ultrastructurally and compared with the patients' own normal epidermis from the upper leg, with age-matched normal controls, and with young normal controls (mean age 43 years). High percentages of Langerhans' cells (ranging between 30 and 50%) without dendrites were found in patient epidermis from the sacral region near the lesion and similar percentages in normal skin from the patients' upper leg. In both elderly and young controls, Langerhans' cells without dendrites found in the epidermis of the upper leg were fewer, ranging between 13 and 33%. The density of Langerhans' cells in adjacent sites of the same epidermis was non-homogeneous, being in the range of 0.56-1.19% in patient sacral epidermis, 0.69-1.31% in patient normal leg epidermis, 0.63-4.17% in leg epidermis of the elderly controls, and 0.63-3.94% in leg epidermis of the young controls. The majority of the Langerhans' cells in both patients and controls were located near the basal cell layer and in the mid-epidermis. The percentage of Langerhans' cells found in patient sacral epidermis (0.84 +/- 0.08%) and in their leg epidermis (0.87 +/- 0.15%) was significantly lower than in the elderly controls (1.91 +/- 0.30%) and young controls (1.84 +/- 0.24%). The low percentage of Langerhans' cells in the epidermis of patients with decubital ulcers may affect the healing process of the lesions.
Adult↗
Blood-brain barrier permeability of human gliomas as determined by quantitation of cytoplasmic vesicles of the capillary endothelium and scintigraphic findings.
The number of cytoplasmic vesicles in the capillary endothelium was determined by ultrastructural morphometry and correlated with the uptake of technetium-99m pertechnetate used in brain scintigraphy. Ten gliomas were studied for uptake rates of 99mTc pertechnetate. Three gliomas from the different groups of uptake rates were quantitatively analyzed for cytoplasmic vesicle content. Capillaries of tumors without uptake had a low content of cytoplasmic vesicles, which was similar to that obtained in normal brain control. In tumors with low and moderate uptake rates, the cytoplasmic vesicles content increased significantly (p less than 0.05) by about 300% and 400%, respectively, as compared with that found in impermeable tumor and in normal brain. The correlation found between the cytoplasmic vesiculation of the endothelial cells in gliomas' capillaries and the uptake of 99mTc pertechnetate suggests that pinocytosis might be a factor in the uptake of the radionuclide. The present findings might be applicable to treatment with hydrophilic chemotherapeutic agents in moderate and highly permeable tumors.
Blood-Brain Barrier↗