Inhibition by a novel azole antifungal agent with a geranyl group on lanosterol 14 alpha-demethylase of yeast.

AFK-108 (1-[2-(2,4-dichlorophenyl)-2-((2E)-3,7-dimethylocta-2,6- dienyloxy)ethyl]-1H-imidazole) is a new imidazole derivative characterized by a geranyl substituent showing strong antifungal activity. Azole antifungal agents are known to be potent inhibitors of lanosterol 14 alpha-demethylase (P450(14)DM) of fungi. The role of the geranyl group of AFK-108 on interaction of AFK-108 with the target was studied by using Saccharomyces cerevisiae P450(14)DM as the model enzyme. AFK-108 and some of its derivatives bound to oxidized P450(14)DM with one-to-one stoichiometry and inhibited the demethylase activity. AFK-108 derivatives having the longer farnesyl or the shorter prenyl group showed lower affinity than AFK-108 for the enzyme. AFK-108 caused 100% inhibition at the equivalent concentration to P450(14)DM in the reaction mixture (0.07 microM), while the farnesyl derivative inhibited the activity by 60% at the same concentration. AFK-108 interfered with the binding of CO to the ferrous P450(14)DM. However, the interfering effect of the prenyl derivative was lower than that of AFK-108. Another AFK-108 derivative having the saturated 3,7-dimethyloctyl group was also a weaker inhibitor than AFK-108. These experiments suggest that the geranyl group of AFK-108 interacts with the substrate binding site of P450(14)DM that recognises the side chain of the substrate. AFK-108 is the first example of an azole derivative interacting with the side chain recognising region of the substrate binding site of P450(14)DM.     

Significance of prenatal diagnosis in a patient with a huge neck tumor.

Due to the great advancements in fetal ultrasonography, the number of prenatal diagnoses are increasing, greatly contributing to improved neonatal surgery. It is now relatively easy to detect huge fetal cystic masses, and we have experienced three cases with a huge neck tumor detected in utero, one case with teratoma and two cases with cystic hygroma. Each case was complicated by neonatal asphyxia, and the neonate needed resuscitation by means of endotracheal intubation. The infant with teratoma unfortunately died of respiratory distress due to compression of the trachea before a perinatal team could be organized. Although the remaining cases with cystic hygroma were treated by a perinatal team, one died 19 hours after birth and the other has survived with the aid of endotracheal intubation in the hospital for three years. In addition, all four cases of cystic hygroma detected antenatally in our institute, which were not delivered, also had fetal hydrops which suggested a general lymphatic derangement. Cystic hygroma detected in utero is considered to be different from that detected after birth, since the former is associated with genetic lymphatic derangement. Prenatal diagnosis enables such patients to survive the perinatal period, but may not improve the prognosis of fetal cystic hygroma so much.     

Plasminogen activators and plasminogen activator inhibitor 1 before and after venous occlusion of the upper limb in thromboangiitis obliterans (Buerger's disease).

Plasma levels of plasminogen activators (t-PA, u-PA) and their inhibitor (PAI-1) were studied in patients suffering from Buerger's disease and healthy volunteers before and after 15 minutes of venous occlusion test. The baseline levels of t-PA in group of patients did not differ from those of controls. On the contrary patients with Burger's disease showed a marked increase in u-PA antigen concentrations with concomitant decrease in PAI-1 antigen levels. During venous stasis t-PA antigen concentrations increased in all subjects, however it was much pronounced in controls. Venous occlusion resulted in significant decrease in free PAI-1 levels in the group of patients only. In conclusion, Buerger's disease is associated with the endothelial derangement with increased u-PA release and decreased PAI-1 release, which does not influence the function of fibrinolytic system. The fact that the reduced response of the endothelium to release t-PA after venous stasis goes in parallel with marked decrease in PAI-1 antigen levels seems to suggest that patients suffering from Buerger's disease are not at high risk of intravascular fibrin deposition.     

Mouse monoclonal antibodies which recognize a human (beta 1-4)galactosyl-transferase associated with tumor in body fluids.

Mouse monoclonal antibodies against human (beta 1-4)galactosyl-transferase (GalT) purified from human ovarian tumor effusion fluids were prepared and characterized. GalT purified from normal human plasma showed a single diffused band in nondenaturing polyacrylamide gel electrophoresis, but GalT purified from human ovarian tumor effusion fluids showed several oligomeric bands and a monomeric band in nondenaturing polyacrylamide gel electrophoresis. These oligomeric bands were dissociated into monomer by urea treatment and polymerized by a 2-mercaptoethanol treatment. Nine monoclonal antibodies (MAb) were prepared by immunization of purified GalT from human ovarian tumor effusion fluids and classified into three groups. Type I MAbs (MAb8611, MAb8913, and MAb8919) reacted only to the GalT monomer. Type II MAbs (MAb4880, MAb8507, and MAb8628) reacted to both the GalT monomer and the GalT polymer. Type III MAbs (MAb7907, MAb8513, and MAb8677) reacted only to the GalT polymer. These MAbs except MAb7907 could recover GalT enzyme activity from effusion fluids by immunoprecipitation. A fraction passed through MAb8513 affinity chromatography still showed reactivity to MAb8919, demonstrating that an epitope of MAb8513 resides on a minor part of GalT. A sandwich immunoassay (MAb8513-MAb8628HRP) was developed, and serum samples from ovarian cancer patients and benign ovarian patients were tested. The levels of sandwich immunoassay of serum samples from cancer were elevated significantly compared to those from benign and did not necessarily correlate to total GalT enzyme activity in serum samples. These results suggested that MAb8513 (Type III) might recognize a unique GalT associated with tumor (GAT).     

Changes in water intake following hepatic vagotomy in young rats

Changes in water intake after hepatic vagotomy were examined in the body weights of 3 different rats (about 100, 200 and 280 g). The vagotomy reduced water intake only in the 100-g rats.     

Delayed sternal closure following cardiac operations

In 13 patients, sternal closure was delayed at the end of open heart procedures. Seven patients underwent coronary artery bypass surgery (CAB), 5 valve replacements, and one left ventricular aneurysmectomy and closure of post myocardial infarction VSD. In all, primary closure of the sternum was considered impossible or inadvisable. The major indications for delaying sternal closure were: cardiac dilatation with tamponade-like behaviour upon attempted sternal closure (8 patients); intractable bleeding (2); intractable arrhythmia (1); insertion of mediastinal assist devices (3) and intraoperative non-cardiogenic pulmonary edema (1). In all, only the skin was closed. Delayed sternal closure (DSC) was performed 36-120 hours later on 10 of the patients, when their condition had stabilized. Nine patients are long term survivors. None of these patients has developed mediastinitis, wound infection, osteomyelitis or instability of the sternum. The judicious use of DSC in selected situations has several advantages: hemodynamic deterioration from pressure upon the heart may be prevented; a quick access to the heart in case of tamponade or intractable arrhythmia is obtained; insertion of mediastinal assist devices is facilitated. With careful technique the risk of infection is low.     

Comparison of positive allergy skin tests among asthmatic children from rural and urban areas living within small geographic area.

BACKGROUND: Evidence of increased asthma and allergic response among urban versus rural residents has been reported. OBJECTIVE: To evaluate the prevalence of allergic response among asthmatic children from urban and rural areas living within close proximity. METHODS: In all, 448 asthmatic children from urban (363) and rural (85) areas were studied. The study group consisted of 234 9-year-olds and 214 12-year-olds. A health questionnaire was completed on each child who subsequently underwent allergic skin prick tests (SPTs). RESULTS: There was significantly more positive SPT response to house-dust mite, mold, cat, and cypress among asthmatic children from urban areas compared with children living in rural areas: 58.3% versus 37.6%, 46.1% versus 31.8%, 17.45 versus 5.9%, and 26.2% versus 15.3%, respectively. Positive SPT for indoor allergens were significantly greater among asthmatic urban residents than asthmatic rural residents: 63.3% versus 45.5%, respectively (P < 0.02). Positive SPT response to all the allergens checked was higher among the 12-year-old age group when compared with the 9-year-olds, 34.6% versus 22.7%, respectively (P = 0.05). CONCLUSIONS: Allergic response measured by SPT is significantly more common among asthmatic children from urban areas as opposed to rural, even though both areas are within small distance of one another. Further, asthmatic children living in urban areas demonstrated more allergic response to both indoor and outdoor allergens. The allergic response tends to increase with increased age in both urban and rural asthmatic children.     

Morphological study of renal changes with age: the possibility of kidney donations by the elderly

Samples from seventy autopsy cases ranging from 27 to 79 years of age who had shown no evidence of renal or malignant diseases were examined histologically to clarify renal changes with age. We evaluated scores for renal histological change and referred the scores to clinical laboratory data; blood pressure, complete blood counts (RBC count, hematocrit, hemoglobin), serum chemistry values (creatinine, urea nitrogen, total cholesterol, total protein, sodium, potassium, chloride) and urinalysis (protein, sediment). We found the score to be related to serum creatinine level, blood urea nitrogen level and the degree of hematuria but not related to the other factors. The progression of arteriosclerosis, tubulo-interstitial change and global sclerosis were found to be severe with ageing. Also renal weight decreased with increasing age. However there were great differences among individuals in the extent of changes. We could not assume histological changes were generally severe in those of more than 55-65 years of age. It was impossible to clarify renal states only with clinical findings. Some kidneys had severe histological changes though less than 2.0 mg/dl of serum creatinine level. It suggests that living relatives and cadavers over 60 years old can be donors for renal transplantation when there are no significant findings of abnormality in preoperative evaluations of their physical state. If insufficient examinations are done, we cannot determine which of them will be good donors. Therefore preoperative biopsy is the best way to evaluate donor suitability. To evaluate only clinical data, it is necessary that serum creatinine level be less than 1.2 mg/dl, blood urea nitrogen level be less than 23 mg/dl and there be no hematuria.     

A case of Vibrio cholerae non-O1 septicemia with liver cirrhosis]

A case of Vibrio cholerae non-O1 septicemia is described in this paper. A 45-year-old male with a three year history of liver cirrhosis, was admitted to our division with hematemesis, abdominal pain, high fever and a loss of consciousness. Three days before onset of symptoms, he traveled to Ishigaki Island and ate a raw lobster. Two days after, his temperature rose to 39.7 degrees C and the blood pressure dropped to 36/- mmHg. By endoscopic examination, an ulcer was found in the stomach, and the bleeding was stopped by electrical coagulation. Blood culture showed growth of V. cholerae non-O1. The organism was found to be sensitive to OFLX, CZX, MINO, LMOX and CP. Although DIC, infections of fungus and MRSA occurred as complications, he recovered by adequate procedures. Subsequently, he left this division after eight weeks. There are various reports related to V. cholerae non-O1 septicemia in foreign countries, but few cases have been reported in Japan. And these cases had severe underlying diseases such as leukemia and liver cirrhosis.     

Positive clinical impressions: II. Participants' evaluations

Nine months after the residential stage of Koach, participants were asked to evaluate the program's effectiveness. Most of the veterans reported improvement in the areas queried, and especially in social relations, and nearly all of them stated that they would recommend the program to other veterans. The commander-therapists became the major source of help for these veterans following the Koach project, and about half reported that they participated regularly in self-help groups. Most of the participants acquired coping techniques that continued to serve them 9 months after the end of the residential stage of Koach. One of the more important measures of Koach was thought to be the veterans' own evaluations of the project, their assessment of the project's success in achieving its aims, and their satisfaction with it. In this article we will present the subjects' evaluations of treatment effectiveness as expressed in behavioral and emotional changes that they attributed to the treatment.