A pitfall in analyses of relevant factors concerning phenomena in the process of initiating dialysis: alterations in the characteristics of subjects diminish the significance of age

In our previous studies, relevant factors concerning the main phenomena related to the process of initiating dialysis were examined in elderly patients with chronic renal failure. Examined phenomena were as follows: (1) the acceptance of dialysis; (2) the urgency of initiating dialysis; (3) short-term outcome; (4) returning home. Multivariate logistic regression analysis was used to determine relevant factors. Although we speculated that age should be a relevant factor for each phenomenon, the phenomenon on which age had some impact was only the first. We suspected the existence of a pitfall, through which the relation of age was lost in the second, the third, or the fourth phenomenon. The fact that every phenomenon had its own relevant factors was thought to be an important clue to the discovery of pitfalls. Relevant factors were derived from both the number of dropout-patients and their demographic and clinical status. From the viewpoint of nondropout-patients, the progression of the process of initiating dialysis might alter the characteristics of subjects for successive phenomena In this study, we set out to investigate whether alterations in the characteristics of subjects were pitfalls. Alterations were regarded as a fall of the mean age, an increment of the rate of the patients with ability to walk, and an increment of the rate of the patients with normal cognitive function. In addition, the old-old patients tended to have limited numbers of those who had the ability to walk and normal cognitive function. In other words, aging changes in ambulatory and cognitive function were not brought to subjects. These alterations may cause the loss of the relation of age to each phenomenon. Thus, we presumed these alterations to be pitfalls. We must clarify whether aging changes are brought to subjects beforehand in analyses that include the old-old patients as subjects.     

Transient liver injury caused by gefitinib]

Gefitinib blocks epidermal growth factor receptor autophosphorylation and subsequently the signal transduction pathways implicated in proliferation, metastasis, invasion, and angiogenesis. Reported adverse reactions to gefitinib include liver injury that is not fully understood. Liver injury was observed in 5 (12.2%) of 41 patients with non-small cell lung cancer who received gefinitib monotherapy. Onset of liver injury was seen between 28 and 56 days after initiation of administration. Two patients had Grade 2 liver injury and 3 patients, Grade 3. In 4 patients, liver injury was temporary, lasting during a period of continuous gefitinib administration. In another patient, gefitinib was discontinued because of the onset of liver injury, which improved when gefitinib administration was restarted. Gefitinib is necessary in most patients whose lung cancer is refractory to cytotoxic chemotherapy, because no other treatment regimens are available at present. The rate of liver injury in cases treated with gefitinib is high, and so it is necessary to observe liver function carefully, but the liver injury due to this drug is often transient. However, the use of gefitinib in many cases appears to be a necessity.     

The 5th report on long-term chemotherapy using erythromycin (EM) for chronic lower airway infection--cases followed over 7 years]

Clinical studies were made over 7 years on 9 cases to whom long-term chemotherapy with EM was administered for chronic airway infection. 1) Clinical effectiveness: Highly effective in 8 cases; Improvement in QOL was observed in 8 cases. Bacteriological effect: In 7 cases, pathogenic bacteria disappeared. 2) No side effects were observed. 3) Changes in PaO2 levels with the passage of time: In most cases, PaO2 reached a plateau within 1 year. Although in some cases, there was subsequent elevation. 4) The frequency of catching cold over the 7 years period was low with an average of 1.2 times/year per subject. In only 2 cases were subject hospitalized due to acute exacerbation triggered by a cold. 5) Mucociliary transport improved in 7 out of 8 cases examined. However, only 4 of these recovered normal transport. The effect of EM in the other cases in which clinical improvement was not demonstrated was deemed slightly effective. On the basis of the above findings, it was suggested that long-term chemotherapy using EM was clinically efficacious. This is based on the fact that its efficacy, including amelioration of QOL appeared within one year of the initiation of therapy, and continued without decline for over 7 years.     

Effect of oral glucose administration on plasma growth hormone-releasing hormone (GHRH)-like immunoreactivity levels in normal subjects and patients with idiopathic GH deficiency: evidence that GHRH is released not only from the hypothalamus but also from extrahypothalamic tissue

Using a specific and sensitive RIA for GH-releasing hormone (GHRH), we examined the effect of oral administration of 75 g glucose on peripheral plasma GHRH-like immunoreactivity (GHRH-LI) in normal subjects (n = 12) and patients with idiopathic GH deficiency (IGHD) (n = 6). The normal subjects had two peaks of plasma GHRH-LI after oral glucose administration. The initial peak GHRH-LI levels occurred 30-150 min after glucose ingestion and corresponded to an increase in blood glucose. The increment in plasma GHRH-LI levels 30 min after glucose ingestion [7.4 +/- 2.4 (+/- SEM) pg/ml] was significantly higher (P less than 0.05) than that during a control study. Second peaks in plasma GHRH-LI occurred 3.5-6 h after glucose ingestion, and the mean increment 5 h after glucose ingestion was 9.4 +/- 2.4 pg/ml. This second rise of plasma GHRH-LI coincided with a significant increase in plasma GH after reactive hypoglycemia. This second GHRH-LI peak and the rise of plasma GH after hypoglycemia were absent in patients with IGHD, whereas the first peak of plasma GHRH-LI appeared shortly after glucose ingestion in these patients as well as in normal subjects. In addition, hypoglycemia produced by iv injection of regular insulin (0.1 U/kg) was not accompanied by increases in plasma GHRH-LI and GH levels in patients with IGHD, whereas insulin-induced hypoglycemia resulted in significant elevations of both plasma GHRH-LI and GH levels in normal subjects. These findings suggest that peripheral plasma GHRH-LI is derived from the hypothalamus as well as from an extrahypothalamic source(s); extrahypothalamic GHRH is released shortly after glucose ingestion; and secretion of GHRH from the hypothalamus is stimulated by hypoglycemia.     

Effect of passive immunization with antisera to vasoactive intestinal polypeptide and peptide histidine isoleucine amide on 5-hydroxy-L-tryptophan-induced prolactin release in rats

The present study was aimed to clarify, by use of the passive immunization method, the involvement of endogenous vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine amide (PHI)-like peptides in the stimulation of PRL-like immunoreactive material release induced by 5-hydroxy-L-tryptophan (5HTP), a serotonin precursor. We used conscious, freely moving male rats of the Wistar strain (BW, 250-300 g) chronically cannulated with atrial catheters. Anti-VIP serum (AVS) and anti-PHI serum (APS), each generated in rabbits against synthetic porcine VIP and natural porcine PHI, respectively, were highly potent [maximum binding capacity (Bmax): AVS, 55.5 nmol/ml; APS, 5.53 nmol/ml] and specific. Bolus injection of 5HTP (10 mg/kg BW) through the catheter caused a significant increase in plasma PRL (nanograms per ml) in rats pretreated with normal rabbit serum (NRS) [14.3 +/- (SE) 3.8----56.3 +/- 11.2], with AVS (12.3 +/- 3.5----48.5 +/- 6.2), with APS (10.5 +/- 3.9----43.5 +/- 8.8), and with AVS plus APS (9.0 +/- 1.4----28.5 +/- 2.7). The basal PRL concentrations did not differ significantly among these groups, whereas the PRL responses to 5HTP were significantly blunted in AVS plus APS-pretreated rats (P less than 0.05 vs. NRS). To eliminate the modification by dopaminergic control of 5HTP-induced PRL release, the next experiment was performed in rats repeatedly injected with sulpiride, a dopamine receptor antagonist (5 mg/kg BW), every 30 min. The first injection of sulpiride caused a prompt and marked increase in plasma PRL, followed by decreasing but still high levels of plasma PRL upon the subsequent injections of sulpiride every 30 min. The cumulative release area of PRL after pretreatment with AVS plus APS or APS alone was significantly lower than that after NRS (P less than 0.05). The same dose of 5HTP resulted in a significant further increase in plasma PRL exceeding the levels elevated by sulpiride injections in NRS-treated rats. Prior simultaneous administration of AVS and APS resulted in a complete suppression of 5HTP-induced PRL release, whereas pretreatment with either AVS or APS showed only a minimal effect. These results suggest that endogenous VIP and PHI-like peptides are PRL-releasing factors, involved at least in the mechanism of 5HTP-induced PRL release, in which the dopaminergic control may be also involved.     

Enteroscopy

Wireless capsule endoscopy and double-balloon endoscopy are new methods of enteroscopy that have been introduced in recent years. Wireless capsule endoscopy is an epoch-making examination method that makes possible an endoscopic imaging examination of the entire small intestine without discomfort and without confining patients to a medical facility. Although it is expected to be useful as an initial examination for finding diseases of the small intestine, it cannot be used for biopsy or treatment. One risk associated with the capsule endoscopy technique is entrapment by strictures. Double-balloon endoscopy is based on a new insertion technique in which two balloons, one at the distal end of the endoscope and the other at the distal end of an overtube, are operated in combination, and the endoscope is inserted while simultaneously shortening the intestine. It can be inserted through either the mouth or the anus, allowing the observation of the entire gastrointestinal tract. It features excellent maneuverability even in the distal small intestine, and enables back-and-forth observation, biopsy, and endoscopic treatment at any given site. These two new enteroscopy techniques are expected to lead to innovations in how diseases of the small intestine are approached.     

Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia

The homozygous WHHL (Watanabe heritable hyperlipidemic) rabbit displays either no or only minimal low density lipoprotein (LDL) receptor activity on cultured fibroblasts and liver membranes and has therefore been proposed as an animal model for human familial hypercholesterolemia. To assess the impact of this mutation on LDL metabolism in vivo, we performed lipoprotein turnover studies in normal and WHHL rabbits using both native rabbit LDL and chemically modified LDL (i.e., methyl-LDL) that does not bind to LDL receptors. The total fractional catabolic rate (FCR) for LDL in the normal rabbit was 3.5-fold greater than in the WHHL rabbit. Sixty-seven percent of the total FCR for LDL in the normal rabbit was due to LDL receptor-mediated clearance and 33% was attributable to receptor-independent processes; in the WHHL rabbit, essentially all of the LDL was catabolized via receptor-independent processes. Despite a 17.5-fold elevated plasma pool size of LDL apoprotein (apo-LDL) in WHHL as compared to normal rabbits, the receptor-independent FCR-as judged by the turnover of methyl-LDL-was similar in the two strains. Thus, the receptor-independent catabolic processes are not influenced by the mutation affecting the LDL receptor. The WHHL rabbits also exhibited a 5.6-fold increase in the absolute rate of apo-LDL synthesis and catabolism. In absolute terms, the WHHL rabbit cleared 19-fold more apo-LDL via receptor-independent processes than did the normal rabbit and cleared virtually none by the receptor-dependent pathway. These results indicate that the homozygous WHHL rabbit shares a number of metabolic features in common with human familial hypercholesterolemia and should serve as a useful model for the study of altered lipoprotein metabolism associated with receptor abnormalities. We also noted that the in vivo metabolic behavior of human and rabbit LDL in the normal rabbit differed such that the mean total FCR for human LDL was only 64% of the mean total FCR for rabbit LDL, whereas human and rabbit methyl-LDL were cleared at identical rates. Thus, if human LDL and methyl-LDL had been used in these studies, the magnitude of both the total and receptor-dependent FCR would have been underestimated.     

Attenuated Apoptosis in H. pylori-Colonized Gastric Mucosa of Mongolian Gerbils in Comparison with Mice

Although gastric cancer formation with H. pylori in Mongolian gerbils was recently reported, the same inoculation procedure did not result in cancer formation in other animals such as mice. Disturbed regulation of apoptosis and cell proliferation are known to link the multistep process of carcinogenesis. The present study is designed to examine the level of gastric epithelial cell apoptosis in Mongolian gerbils colonized with the H. pylori (Sydney strain: SS1) in comparison with that in mice. Mice (C57BL/6) and Mongolian gerbils were orally inoculated with SS1 and the stomachs were examined 9 and 18 months later. MPO activity increased persistently in gerbils, but increased transiently in mice. While the levels of DNA fragmentation, caspase-3 activity, and the number of TUNEL-positive cells increased significantly in mice, such parameters were attenuated in gerbils. On the other hand, the number of PCNA-positive cells increased after SS1 inoculation only in Mongolian gerbils, suggesting the enhancement of cell turnover in H. pylori-colonized gerbils. In conclusion, the SS1-induced increase in gastric mucosal apoptosis observed in mice was attenuated significantly in Mongolian gerbils, suggesting the causative role for the higher incidence of gastric carcinogenesis in this animal.