Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

Chiari pelvic osteotomy for osteoarthritis. The influence of the torn and detached acetabular labrum

We assessed the results of Chiari pelvic osteotomy in 64 hips with early osteoarthritis in terms of acetabular labral detachment detected pre-operatively by arthrography. At an average follow-up of four years, assessment by the Merle d'Aubigńe score showed 83% excellent or good results. These satisfactory results were achieved in only half the cases with a detached labrum, but in nearly all cases with normal or torn acetabular labra. Other factors such as the acetabular index, the level and angle of osteotomy, and the displacement following osteotomy did not affect the results. Chiari pelvic osteotomy is a worthwhile procedure for early osteoarthritis in selected cases, but a detached acetabular labrum increases the risk of clinical failure.     

Effects of ultraviolet B irradiation on lenticular riboflavin metabolism and high-molecular-weight-protein aggregation

We investigated the effects of ultraviolet B (UVB) irradiation on the formation of ester forms of riboflavin and of high-molecular-weight (HMW) protein aggregates and on lenticular riboflavin-binding capacity (LRBC). Esterification of riboflavin decreased as the duration of UV irradiation increased, suggesting the irradiation-induced denaturation of the apoenzyme of synthetases of ester forms of riboflavin. UVB irradiation of lens homogenate supplemented with riboflavin increased LRBC and the formation of HMW protein aggregates, while gamma-crystallin was decreased. These results are consistent with those of our earlier studies in which we obtained data suggesting that, upon exposure of rat lens homogenate to fluorescent light, photosensitized riboflavin may bring about cross-linking of lens protein. Our data demonstrate that the photosensitivity of lenticular riboflavin is increased by longer periods of UV irradiation.     

Collagen abnormalities in the spinal cord from patients with amyotrophic lateral sclerosis

During the last 10 years, we have demonstrated morphological and biochemical abnormalities of skin extracellular matrices in amyotrophic lateral sclerosis (ALS). However, currently little is known concerning collagen of the spinal cord in ALS. We measured the amount of collagen and characterized collagen at light and electron microscopic levels in posterior funiculus, posterior half of lateral funiculus and anterior horn of cervical enlargement of the spinal cord obtained from ten patients with ALS, 11 patients with other neurologic diseases (control group A), and ten patients without neurologic ones (control group B). In posterior half of lateral funiculus and anterior horn, (1) by light microscopy, there was no significant difference in vessel wall area between ALS patients and control groups A and B; (2) ultrastructurally, collagen bundles were more fragmented and widely separated, and the fibrils were randomly oriented in the perivascular space of capillaries in ALS patients, which were not observed in any areas of control groups or in posterior funiculus of ALS patients; and (3) the collagen contents in ALS were significantly lower (P<0.001 and P<0.001, respectively) than those in control groups A and B. Fragmented and widely separated collagen bundles in the interstitial tissue surrounding capillaries and markedly decreased amount of collagen in posterior half of lateral funiculus and in anterior horn of ALS could be related to the degeneration of the upper and lower motor neurons in the spinal cord in ALS, that is, selective neuronal vulnerability in ALS.     

Clinical pathology of primitive gliomas in the cerebrum

Summary To clarify the biological features of primitive gliomas in the cerebrum and clearly distinguish them from malignant or anaplastic gliomas and glioblastomas, we studied eight cases clinically and pathologically. Our evaluations included immunohistochemical and electron microscopic observations. We divided the patients into two groups, children and young adults. Most tumours appeared as ring-like, enhanced masses on computed tomography and avascular or ring-like, vascular masses on angiography. Macroscopically, the tumours were well demarcated and contained cysts. Ocassionally we found tumour dissemination. Microscopically, the tumours were composed of small, round cells without remarkable structural features. Ependymal, astroglial, and oligodendroglial differentiation was evident, in varying proportions; tumours in which the differentiated areas constituted more than half of the mass were classified as poorly differentiated gliomas. By these criteria, this series comprised four undifferentiated and four poorly differentiated gliomas. Cell anaplasia and polymorphism were rare in both undifferentiated and differentiated areas of the tumours. Immunohistochemical and electron microscopic examinations also revealed glial differentiation. These primitive gliomas appear to be biologically similar, but not identical, to cerebellar medulloblastomas. In this series, five patients died because of recurrence or dissemination. Whole brain and spinal irradiation should be considered after total or subtotal surgical removal.     

Activity-dependent survival and enhanced turnover of calcium in cultured rat cerebellar granule neurons

Neurons survive when their activity is maintained. An influential hypothesis on the cellular mechanism underlying this phenomenon is that there is an appropriate range of intracellular Ca²⁺ concentration ([Ca²⁺]i) for survival. The rat cerebellar granule neuron in culture serves as the most often used model system for the analysis of activity-dependent survival, since it does not survive unless an excitant (KCl or glutamate) is added to the culture medium. Against the above-mentioned hypothesis, we found in our previous examination no difference between steady-state [Ca²⁺]i in granule neurons cultured under high KCl (i.e., survival) and low KCl (i.e., death) conditions. In this report, we present the quantitative background of unchanged [Ca²⁺]i between the two culture conditions. Influx of Ca²⁺ due predominantly to L-type voltage-dependent calcium channels was higher in high KCl cultures than in low KCl cultures. At the same time, efflux of Ca²⁺ due to the activity of Ca²⁺/Na⁺ antiport was also higher in high KCl cultures. Additionally, we found that the endocytotic activity was greater in high KCl cultures than in low KCl cultures, as monitored by the rate of uptake of horseradish peroxidase added to medium. Since the uptake was blocked by an internal Ca²⁺ chelator, the increased endocytotic activity in high KCl cultures might be a consequence of the enhanced Ca²⁺ turnover.     

Regional cerebral blood flow in the persistent vegetative state

Regional cerebral blood flow (CBF) in eight patients in a persistent vegetative state was measured and compared with that in five healthy volunteers. The patients were classified into three groups: Group 1 (locked-in syndrome) consisted of a single patient, Group 2 (typical vegetative state) of five patients, and Group 3 (prolonged coma) of two patients. CBF was measured early after onset by single photon emission computed tomography with 123I-N-isopropyl-p-iodo-amphetamine and/or 99mTc-hexamethyl-propyleneamine oxime. The regions of interest (ROIs) were the bilateral frontal, temporal, parietal, occipital, and cerebellar areas and basal ganglia. The values obtained in these areas were averaged, and the ratio for each ROI [(the value in the ROI/the mean value) x 100] was calculated. "Hyperfrontal distribution" of CBF was found to be rare in both the normal condition and the vegetative state. Higher CBF values were noted in the left than in the right frontal area in four of the five volunteers but in only four of the eight patients. CBF distribution in the frontal lobe was characteristic for each group: Group 1 showed high CBF bilaterally, although the elevation was statistically significant only on the right side, and Group 3 exhibited significantly low values. In Group 2, CBF was variable but, for the most part, within normal limits. Awareness was closely correlated with frontal lobe function and alteration of CBF in the frontal region.     

A case of adenocarcinoma of the nasal cavity associated with syndrome of inappropriate secretion of antidiuretic hormone(SIADH)

An inappropriate antidiuretic hormone secretion (SIADH) has been recognized as the cause of hypotonic hyponatremia, and the occurrence of this syndrome, accompanied by an ADH-producing adenocarcinoma in the nasal cavity, is reported. In February, 1987, a 50-year-old male, showing sights of delirium, disorientation, and irritability was admitted to the hospital. The patient was observed to be healthy, except for a neck lymphnode metastasis that was present up to the time of his hospitalization. The hyponatremia was incidentally found, although dehydration or intravascular volume depletion were not noted. These neuropsychiatric symptoms were considered to be associated with hyponatremia due to SIADH. He had had a partial maxillectomy, a neck dissection, and irradiation to the nose and nasal cavity 32 months earlier, and then underwent a surgical resection of the neck metastasis; he had a total of 10 other operations before the onset of the symptoms. Upon initial inspection, since neither an intracranial invasion nor a brain metastasis was found, we diagnosed that his symptoms were due to an autonomic disturbance caused by surgical and mental "stress". When he died of cardiac failure due to a mediastinal invasion 8 months after the onset of SIADH, tumor tissues was extirpated in an autopsy and was then cultured. In this manner, it was proved that the tumor cells had been producing ADH. This procedure clarified that the syndrome had resulted from an ADH-producing tumor of the nasal cavity.     

Lipopolysaccharide Induces CD25-Positive, IL-10-Producing Lymphocytes Without Secretion of Proinflammatory Cytokines in the Human Colon: Low MD-2 mRNA Expression in Colonic Macrophages

Despite the huge number of colonized Gram-negative bacteria in the colon, the normal colon maintains its homeostasis without any excessive immune response. To investigate the potential mechanisms involved, human colonic lamina propria mononuclear cells (LPMCs) obtained from uninflamed mucosa were cultured with lipopolysaccharide (LPS) prepared from Bacteroides vulgatus (BV-LPS) or Bacteroides fragilis (BF-LPS), as representatives of indigenous flora, or pathogenic Salmonella minnesota (SM-LPS). Colonic LPMCs failed to produce inflammatory cytokines in response to any type of LPS. Colonic macrophages barely expressed mRNA for MD-2, an essential association molecule for LPS signaling via Toll-like receptor 4. Further, BV-LPS induced CD25 and Foxp3 expression in lymphocytes and CD4(+)CD25(+) cells expressed IL-10 mRNA. Thus, the low expression of functioning LPS receptor molecules and induction of IL-10-producing CD4(+)CD25(+) lymphocytes by indigenous LPS may play a central role in the maintenance of colonic immunological homeostasis.     

Development of the articular cavity in the rat temporomandibular joint with special reference to the behavior of endothelial cells and macrophages

Previous developmental studies on the temporomandibular joint (TMJ) have proposed several hypotheses on the formation of its articular cavity. However, detailed information is meager. The present study examined the formation process of the articular cavity in the rat TMJ by immunocytochemistry for CD31, RECA-1, and ED1, which are useful cellular markers for endothelial cells and monocyte/macrophage lineages, respectively. The upper articular cavity formation had begun by embryonic day 21 (E21) and was completed at postnatal day 1 (P1) in advance of the lower cavitation; the latter took place from P1 to P3. The occurrence and distribution pattern of the CD31-, RECA-1-, and ED1-positive cells differed between the upper and lower articular cavity-forming areas: the ED1-positive cells exclusively occurred in the area of the prospective upper articular cavity prior to its formation, while no ED1-positive cell appeared in the lower cavity-forming area. In contrast, the CD31- and RECA-1-positive endothelial cells were restricted to the lower cavity-forming area (never the prospective upper cavity) at E19 and diminished thereafter. Throughout the cavity formation, we failed to find any apoptotic cells in the cavity formation area, indicating no involvement of apoptosis in the cavity formation in TMJ. The present findings on the behaviors of endothelial cells and ED1-positive cells show a possibility of different mechanism in the cavity formation between the upper and lower articular cavities in the rat TMJ. The appearance of ED1-reactive cells and temporal vascularization may play crucial roles in the upper and lower articular cavity formation, respectively.