Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100.

Bicyclams, in which the cyclam (1,4,8,11-tetraazacyclotetradecane) moieties are tethered via an aliphatic bridge (i.e., propylene, as in JM2763) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) (E. De Clercq, N. Yamamoto, R. Pauwels, M. Baba, D. Schols, H. Nakashima, J. Balzarini, Z. Debyser, B. A. Murrer, D. Schwartz, D. Thornton, G. Bridger, S. Fricker, G. Henson, M. Abrams, and D. Picker, Proc. Natl. Acad. Sci. USA 89:5286-5290, 1992). We have now found that the bicyclam JM3100, in which the cyclam moieties are tethered by an aromatic bridge [i.e., phenylenebis(methylene)], inhibits the replication of various HIV-1 and HIV-2 strains in various cell lines at a 50% effective concentration (EC50) of 1 to 10 ng/ml, which is about 100-fold lower than the concentration required for JM2763 to inhibit HIV replication and at least 100,000-fold lower than the cytotoxic concentration (> 500 micrograms/ml). In primary T4 lymphocytes or primary monocytes, JM3100 proved inhibitory to HIV-1(IIIB) and several clinical HIV-1 isolates at an EC50 of less than 1 ng/ml. On the basis of time-of-addition experiments, JM3100 appeared to interact with a viral uncoating event, and this was further corroborated by an uncoating assay in which RNase sensitivity of [5-3H]uridine-labeled virions was monitored. In addition, but possibly mechanistically related, JM3100 blocks formation of infectious particles. JM3100 was also found to interfere directly with virus-induced syncytium formation, albeit at a higher concentration (1 to 2 microgram/ml) than that required for inhibition of viral replication. Following subcutaneous injection of 10 mg of JM3100 per kg of body weight to rabbits, anti-HIV activity was detected in serum corresponding to serum drug levels exceeding for at least 6 h by >100-fold the EC(50) required to inhibit HIV replication in vitro. When combined with either 3'-azido-2',3' -dideoxythymidine or 2',3' -dideoxyinosine, JM3100 achieved a additive inhibition of HIV replication, and when repeatedly subcultivated in the presence of JM3100, the virus remained sensitive to the compound for at least 30 passages (120 days) in cell culture.     

Macrolide–lincosamide–streptogramin B resistance phenotypes and genotypes among Staphylococcus aureus clinical isolates in Japan

In total, 269 methicillin-resistant Staphylococcus aureus (MRSA) and 434 methicillin-susceptible S. aureus (MSSA) isolates were investigated to determine their macrolide-lincosamide-streptogramin B (MLS(B)) resistance phenotypes and genotypes. The constitutive phenotype (61.3% in MRSA, 1.3% in MSSA) and erm(A) gene predominated among the 261 erythromycin-resistant MRSA isolates, while the inducible phenotype (38.7% in MRSA, 94.0% in MSSA) and erm(C) gene were more prevalent among the 150 erythromycin-resistant MSSA isolates. There was a higher incidence of the MLS(B) inducible phenotype compared with other countries, perhaps because MLS(B) antibiotics are not recommended as first-line agents against S. aureus in Japan.     

Changes in pulmonary circulation during the early postoperative period following single lung transplantation

This study examines the pulmonary hemodynamics during reimplantation and rejection following unilateral lung transplantation in dogs. Nineteen mongrel dogs were divided into three groups according to the method of treatment used: group 1 (n = 6) underwent modified autotransplantation of the left lung; group 2 (n = 6), allotransplantation without immunosuppression; and group 3 (n = 7), allotransplantation with immunosuppression. The pulmonary arterial blood flow and ventilation scores, assessed by chest X-rays, were measured for 2 weeks postoperatively. Pulmonary blood flow to the transplanted lung decreased slightly in group 1, whereas in group 2, it decreased sharply from the 3rd postoperative day (POD) and was almost completely absent by the 14th POD. In group 3, it decreased by 28% on the 1st POD but recovered gradually to 37% by the 14th POD. Ventilation scores were the same among the three groups on the 1st POD but in group 2, they decreased rapidly from the 3rd POD. This change correlated well with that of the pulmonary arterial (PA) flow, although the ventilation score changed after the PA flow did. In conclusion, rejection was reflected earlier and more distinctly by the changes in PA flow than by chest X-rays.     

A rare case of allergic granulomatous angitis (Churg Strauss syndrome) with positive anti-glomerular basement membrane (GBM) antibody in serum]

A 33-year-old man with a 6-month history of rhinitis and bronchial asthma was referred to our hospital with polyarthralgia, severe anemia, hypoxemia, mononeuropathy multiplex, and renal insufficiency with hematuria. Marked eosinophilia was observed in his sputum, peripheral blood, and bronchoalveolar lavage fluid (BALF). In addition, his sputum contained many hemosiderin-laden macrophages, indicative of pulmonary hemorrhage. His chest roentgenogram on admission showed diffuse ground grass appearance. High resolution computed tomography (HRCT) demonstrated diffuse high density areas throughout the lung fields and characteristic irregularity and enlargement of the peripheral pulmonary arteries. His general condition rapidly deteriorated, but dramatically improved with oral steroid administration, and his major symptoms disappeared within a few days. Examination of the biopsied lung tissue revealed unequivocal evidence of pulmonary angitis with marked eosinophilic infiltration and perivascular granulomas. Bone marrow biopsy showed hyperplasia of eosinophilic leukocytes in contrast to the low cellularity. Suppression of erythroid hemopoiesis was thought to be the primary cause for his rapidly progressive anemia. Serum anti-GBM antibody titer returned to within the normal range soon after the initiation of steroid therapy.     

A New Instrument for Immobilization and Hemostasis During Minimally Invasive Direct Coronary Artery Bypass ("MIDCAB doughnut"): Experimental Study

A bstract A new instrument for the immobilization and hemostasis of an anastomotic site is described for use during minimally invasive off-pump direct coronary artery bypass (MID-CAB). The mechanism is based on air suction of the heart surface. The instrument is unique in that it can avoid direct temporary of the distal end of the coronary artery to control bleeding. With this instrument, anastomosis of left intemal thoracic artery to left anterior descending artery (LAD) was successfully performed on three pigs. Additionally, in six patients the LAD could be stably and securely immobilized in the beating heart by the present instrument. The instrument is hereinafter referred as "MIDCAB doughnut," which can make an operative field motionless and bloodless without distal snaring.     

Differential anatomical and cellular patterns of connexin43 expression during postnatal development of rat brain.

We have shown previously that connexin43 in the adult rat central nervous system (CNS) is predominantly localized at astrocytic gap junctions. Here we document immunohistochemically the emergence of connexin43-immunoreactive (connexin43-IR) structures and the regional patterns of connexin43 expression during postnatal maturation of the rat brain. On Western blots, connexin43 was detected in brain samples at postnatal day (P) 5, the earliest age studied. Immunohistochemically, most brain regions displayed a characteristic sequence of transient immunoreactive profiles that ultimately gave rise to the uneven distribution of the protein seen in adults. Generally, brains at P1-P5 exhibited long, fibrous connexin43-IR elements which were identified as radial glial cells. This fibrous immunostaining was considerably diminished at P5 and was replaced by short immunoreactive processes which predominated up to P10. These processes had a stellate appearance, emanated from partially stained astrocytic cell bodies and were heterogeneously distributed throughout the developing brain. By P15, there occurred only punctate immunolabelling similar to that seen in adult brain. Some brain regions including the amygdaloid complex, septohypothalamic nucleus, preoptic hypothalamus, zona incerta, ependyma and subfornical organ were exceptional in that they displayed adult immunostaining patterns at early postnatal ages suggesting a precocious maturation of gap junctions in these areas. We conclude that the highly heterogeneous distribution of connexin43-immunoreactivity among defined nuclear structures in adult brain does not reflect an antecedent requirement for connexin43 in early brain morphogenesis, but rather is related to the development of neuronal activity, the establishment of functional circuitry and the contribution of astrocytic gap junctions to glial metabolic coupling and potassium spatial buffering in the mature CNS.     

A one-year series of pediatric emergency department wheezing visits: the Hawaii EMS-C project.

During a 12-month period ending on November 30, 1988, data were collected on 2468 pediatric patients with wheezing who visited a pediatric ED. Cohort characteristics included: sex (64% male, 36% female), history of prematurity (12%), evidence of concurrent infection (82%), taking theophylline (35%), taking beta adrenergics (60%), taking cromolyn (6%), and taking corticosteroids (4%). The hospitalization rate was 10.5%. Seasonal variations, weather, air quality, and infections appeared to have significant effects on the daily variation of wheezing exacerbations. Initial oxygen saturation (OSAT) correlated with disease severity as measured by hospitalization risk and the number of bronchodilator treatments required in the ED. A suggestion for categorizing the treatment of asthma based on past history is proposed. Using this system in conjunction with pulse oximetry, wheezing severity and appropriate therapy can be more objectively determined.     

Evaluation of the measurement of plasma fructosamine concentration in aged subjects

Recently, plasma fructosamine concentration has been used as an indication of mean plasma glucose level preceding at last 1 to 2 weeks. In the present study, to characterize the clinical significance and problems of plasma fructosamine concentration in aged subjects (greater than or equal to 65 yrs), we determined plasma fructosamine concentration as well as serum albumin, total protein, HbA1, AbA1c and fasting plasma glucose concentrations in 81 (less than 65 yrs) non-diabetic subjects (group A), 161 aged (greater than or equal to 65 yrs) non-diabetic subjects and 26 aged diabetics (group D). Aged non-diabetic subjects were further classified into 75 subjects with good ADL (group B) and 86 with poor ADL (group C). The normal limit of plasma fructosamine concentration (mean +/- 2SD) in group A was 24% higher (3.1 mmol/l) than that in group B (2.5 mmol/l) but the plasma fructosamine/serum albumin ratio (F/ALB) was similar in these two groups. Plasma fructosamine correlated negatively (p less than 0.01) with age. This aging effect was explained by the reduced serum albumin in aged subjects. However, in group C, reduced plasma albumin was not associated with reduced plasma fructosamine. Plasma fructosamine corrected by albumin (F/ALB) is a useful parameter of blood glucose control in aged subjects. In aged subjects with poor ADL, HbA1, HbA1c and plasma glucose should be determined with fructosamine.     

Clinicopathologic Study of Angiogenesis in Japanese Patients with Breast Cancer

p = 0.0007) and tumor necrosis (TN) (HMC: p = 0.0050). Univariate analysis showed that AMC or HMC was a statistically significant predictor of overall survival in all patients ( p = 0.0086 and p = 0.0307, respectively). Multivariate analysis showed that AMC was an independent predictor of node status when we fitted a model with node status, BVI, and either AMC or HMC; but HMC was not independent. However, when we fitted a model including all 11 of the other indicators and AMC or HMC, the node status, HG, and LI were independent predictors, but AMC and HMC were not. Although AMC was a better method than HMC for evaluating angiogenesis, we cannot confirm angiogenesis as a significant independent prognostic factor associated with long-term survival in Japanese breast cancer patients.