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Leri-Weill dyschondrosteosis (LWD) (MIM 127300) is a dominantly inherited skeletal dysplasia characterized phenotypically by Madelung wrist deformity, mesomelia, and short stature. LWD can now be defined genetically by haploinsufficiency of the SHOX (short stature homeobox-containing) gene. We have studied 21 LWD families (43 affected LWD subjects, including 32 females and 11 males, ages 3-56 yr) with confirmed SHOX abnormalities. We investigated the relationship between SHOX mutations, height deficit, and Madelung deformity to determine the contribution of SHOX haploinsufficiency to the LWD and Turner syndrome (TS) phenotypes. Also, we examined the effects of age, gender, and female puberty (estrogen) on the LWD phenotype. SHOX deletions were present in affected individuals from 17 families (81%), and point mutations were detected in 4 families (19%). In the LWD subjects, height deficits ranged from -4.6 to +0.6 SD (mean +/- SD = -2.2 +/- 1.0). There were no statistically significant effects of age, gender, pubertal status, or parental origin of SHOX mutations on height z-score. The height deficit in LWD is approximately two thirds that of TS. Madelung deformity was present in 74% of LWD children and adults and was more frequent and severe in females than males. The prevalence of the Madelung deformity was higher in the LWD vs. a TS population. The prevalence of increased carrying angle, high arched palate, and scoliosis was similar in the two populations. In conclusion, SHOX deletions or mutations accounted for all of our LWD cases. SHOX haploinsufficiency accounts for most, but not all, of the TS height deficit. The LWD phenotype shows some gender- and age-related differences.

A new method of measuring digital range of motion (the Littler line method) is presented. When a Gaussian curve is centered over the Littler line and the appropriate area under the curve is computed, this area can provide a measure of the functional range of motion regained by an injured digit. Seventeen children (24 digits) with flexor tendon injuries were evaluated at an average follow-up period of 58 months (range, 12-121 months). The Littler line/Gaussian curve method was found to be more reproducible than total active motion, particularly in zone I and II injuries. This method can serve as a more meaningful functional assessment tool than a linear measurement such as total active motion, because it emphasizes digital motion in the mid-ranges of digital motion. (J Hand Surg 2001;26A:23-30., (Copyright 2001 by the American Society for Surgery of the Hand.))

A resurgence of interest in Madelung's deformity has developed recently because of improved operations for correction of the deformity, identification of the genetic loci for the condition in certain syndromal variants, identification of an anterior ligamentous structure tethering the carpus, and preventive treatments in growing children. The process is reviewed in this article and a new surgical technique is presented. The procedure is performed by way of an anterior incision that is more cosmetically appealing. The release of an anterior ligamentous structure described by Vickers is performed simultaneously with a dome shaped osteotomy of the radius. The fragments, once alignment is corrected, are stablized with temporary pin fixation and a long arm cast until the bone has healed.

There are good options to maximize upper limb function for the child with arthrogryposis. Preservation of available elbow and wrist motion is essential. A comprehensive plan for upper limb treatment includes operative and nonoperative care.

At the Texas Scottish Rite Hospital for Children, 239 trigger digits in 176 children were seen and treated surgically over a 10-year period. Trigger fingers accounted for 33 (14%) of these digits in 18 (10%) of the patients. In 8 of 18 patients (44%) the fingers continued to trigger after A-1 pulley release. In children, trigger fingers are different from trigger thumbs. Trigger fingers in children are uncommon and have variable causes, and an A-1 pulley release alone will not always correct the triggering. Additional treatments, such as resection of one or both limbs of the sublimis tendon or an A-3 pulley release, may be required. An awareness of other contributing factors and readiness to explore the entire flexor mechanism should help prevent failure of surgical treatment.

In this study, the correlations of factors with Epstein-Barr virus (EBV)-association were investigated in 50 patients with nasopharyngeal carcinoma (NPC), 61 with oropharyngeal carcinoma (OPC), and 55 with hypopharyngeal carcinoma (HPC) in Okinawa and Osaka prefectures in Japan. The incidence of pharyngeal carcinoma in Okinawa was previously found to be higher than that in Osaka; the incidence of OPC was approximately 6 times higher and that of HPC was two times higher. The EBV genome was detected in the tumor cells of the present patients; 83% of the Okinawa and 92% of the Osaka NPC patients. The EBV genome was not detected in OPC or HPC. A univariate analysis showed that sex, the location of the tumor, histology, and the degree of lymphocytic infiltration correlated with the EBV-positive rate. A multivariate analysis revealed that only the location of the tumor was independently correlated with the EBV-positive rate. Histology and tumor size were factors affecting the prognosis of the patients with NPC. The NPC of poorly differentiated type frequently showed the EBV genome, and NPC with lymphocytic infiltration showed a more favorable prognosis compared to the other NPC types. These findings suggest that latent genes of EBV expressed in cancer cells might trigger a cytotoxic T cell reaction against the cancer.

Oxidative modification of LDL plays an important role in early atherogenesis but the mechanisms, nonenzymatic and/or enzymatic, by which LDL is oxidized in vivo remain to be established. Several lines of evidence suggest that cellular 15-lipoxygenase (arachidonate 15-oxidoreductase, EC.1.13.11.13) (15-LO) may contribute to oxidative modification of LDL, including recent studies demonstrating that murine fibroblasts overexpressing 15-LO have an enhanced capacity to oxidize LDL in the medium. The present studies were undertaken to better understand the mechanisms by which cells expressing 15-LO bring about oxidative modification of LDL. LDL incubated 1-2 h with the 15-LO-enriched cells showed a much higher lipoperoxide (LOOH) content than did LDL incubated with control cells. By far the largest absolute increase occurred in cholesteryl ester hydroperoxide (CE-OOH), a much lesser increase in free fatty acid hydroperoxides (FFA-OOH), and only a very small increase in phospholipid hydroperoxides (PL-OOH). Addition of EDTA to the medium abolished these increases in LDL lipid hydroperoxides. Enrichment of LDL with probucol or vitamin E also prevented CE-OOH accumulation. Incubation of LDL with linoleic acid hydroperoxide in the absence of cells also caused a significant increase in CE-OOH and this was markedly inhibited by EDTA. These findings provide further evidence for the potential of 15-LO to participate in LDL oxidation by way of a mechanism involving introduction of LOOH into the LDL particle followed by metal-catalyzed propagation.

There is strong experimental evidence that oxidized low density lipoprotein (Ox-LDL) plays an important role in atherosclerosis. However, the mechanisms by which Ox-LDL is formed in vivo are unknown. To test whether 15-lipoxygenase (15-LO) could play a role in oxidation of LDL by cells, we expressed 15-LO activity in murine fibroblasts, which do not normally have 15-LO activity, and tested their ability to modify LDL. Using a retroviral vector, we prepared fibroblasts that expressed 2- to 20-fold more 15-LO activity than control fibroblasts infected with a vector containing beta-galactosidase (lacZ). Compared with LDL incubated with lacZ cells, LDL incubated with 15-LO-containing cells were enriched with lipid hydroperoxides. When these LDL samples were subsequently subjected to oxidative stress, they were more susceptible to further oxidative modification, as judged by increased conjugated diene formation and by increased ability to compete with 125I-Ox-LDL for uptake by macrophages. These findings establish that cellular 15-LO can contribute to oxidative modification of LDL, but the quantitative significance of these findings to the in vivo oxidation of LDL remains to be established.

Cyclic GMP accumulation in endothelial cells-smooth muscle cells (EC-SMC) coculture induced by both receptor-dependent (thrombin, bradykinin, BK) and receptor-independent (Ca(2+)-ionophore A23187) stimulation, was inhibited by preincubation with low-density lipoprotein (LDL) in time- and concentration-dependent manner. At least 5 min was necessary for the complete blockade with LDL (protein 1 mg/ml). LDL did not affect cyclic GMP-increase by sodium nitroprusside (SNP), a direct stimulator of SMC, but oxidized (ox)LDL (50-250 micrograms/ml) markedly reduced it. An increase of cyclic GMP accumulation in SMC by eluate from stimulated EC columns was completely blocked by 10-min pre-incubation of the column with LDL with or without superoxide dismutase (SOD). In contrast, preincubation of the SMC dish with LDL did not affect cyclic GMP accumulation by the eluate from the stimulated EC column, but preincubation with oxLDL (protein 50-100 micrograms/ml) greatly reduced it. Exposure time of released EDRF to LDL in both coculture and column experiments was < 40-45 s. These results suggest that a brief exposure of EC to pathophysiologic concentration of LDL exclusively affects EC functions, attenuating endothelium-derived relaxing factor (EDRF) release through intracellular mechanisms, and consumption of released EDRF by LDL does not appear to be involved in this LDL inhibitory effect. Possible inhibitory mechanisms of LDL are discussed.

A prospective, randomized study was done to compare the results of dynamic external fixation (the Clyburn device) with those of static external fixation (the AO/ASIF device) in the treatment of fifty unstable fractures of the distal part of the radius. Mobilization of the wrist from neutral to 30 degrees of flexion was begun in the dynamic-fixator group at approximately two weeks, and full motion, allowing 30 degrees of extension, was started at approximately four weeks. The external fixation frames in both groups were kept in place for approximately ten weeks. Mobilization of the wrist in the dynamic-fixator group provided little gain in the mean motion of the wrist at the time of the removal of the fixator or at the one, six, or twelve-month evaluation. The static-fixator group had greater flexion of the wrist and radial deviation at the early and late follow-up examinations, while the dynamic-fixator group demonstrated only greater ulnar deviation one month after the fixator had been removed. Motion of the wrist in the dynamic-fixator group resulted in a statistically significant loss of radial length compared with that in the static-fixator group (four millimeters compared with one millimeter, p < 0.001). Complications were more frequent in the dynamic-fixator group. As evaluated with a modification of the scoring system of Gartland and Werley, 92 percent of the results at one year were excellent or good in the static-fixator group and 76 percent, in the dynamic-fixator group. The results of this study cannot support the concept of early mobilization with a dynamic external fixator for the treatment of unstable fractures of the distal part of the radius.

Changes of intracellular activity of lysolecithin acyltransferase (LAT) during an interaction between endothelial cells (EC) and low-density lipoprotein (LDL) were investigated. Following an incubation of EC with LDL, endothelial LAT activity was assayed using [3H]lysophosphatidylcholine as the substrate. Stimulation of EC with either thrombin (0.01-1 U/ml) or Ca(2+)-ionophore A23187 (10(-10)-10(-7) M) dose- and time-dependently enhanced LAT activity in the presence of LDL (1 mg protein/ml), but no enhancement was observed in quiescent cells. Ionomycin together with 1-oleoyl-2-acetyl glycerol, a synthetic analog of diacylglycerols enhanced LAT activity in a similar degree to thrombin in the presence of LDL. Either staurosporine, a protein kinase C inhibitor or neomycin, a phospholipase C inhibitor completely blocked an increase of LAT activity in stimulated EC. Stimulation of EC with various agonists including 12-o-tetradecanoylphorbol-13-acetate, an activator of protein kinase C caused a marked increase in cellular uptake of LDL, and staurosporine inhibited the uptake. These results suggest that the transport of LDL into EC is facilitated by stimulation with thrombin and other agonists, and LDL subsequently activates intracellular LAT. Protein kinase C seems to mediate LDL uptake into EC. Intracellular regulatory roles of LDL in the presence of vasoactive substances were discussed.

New non-steroidal estrogen-receptor antagonists, R1128 A, B, C and D, were isolated from the cultured broth of Streptomyces sp. No. 1128 by solvent extraction, silica gel chromatography, reverse phase chromatography and preparative HPLC. These compounds inhibited estrogen binding to its receptor. The IC50 values of R1128 A, B, C and D for partially purified rat uterine cytosol receptor were 1.1 x 10(-7) M, 1.2 x 10(-7) M, 2.6 x 10(-7) M and 2.7 x 10(-7) M, respectively.

The cDNA sequence encoding precursor forms of human cathepsin E (CE), an intracellular aspartic proteinase, was expressed in Chinese hamster ovary cells using an SV40 promotor-driven expression vector. By immunoelectron microscopic studies using an anti-human CE antibody and by Percoll density gradient fractionation, the expressed CE was found to be in two different intracellular fractions; the cytosolic compartment and the vacuolar system. The CEs in both the cytosolic and the vacuolar fractions were highly purified by a simple method involving Percoll density gradient fractionation, chromatography on concanavalin A-Sepharose, Mono Q, and TSK-GelG2000SW, and termed s-CE and v-CE, respectively. The v-CE was further separated into a major (v-CE1) and a minor (v-CE2) form by Mono Q chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting revealed that the s-CE and v-CE1 consists of two polypeptides of 90 and 84 kDa, whereas v-CE2 is composed of 84- and 82-kDa polypeptides. The NH2-terminal amino acid sequence analyses showed that the 90- and 84-kDa proteins from both s-CE and v-CE started with Ser3 and Lys30 of the sequence of human gastric CE predicted from its cDNA sequence, respectively, and that the NH2 terminus of the 82-kDa protein of v-CE2 is the Ile37. Upon acid treatment at pH 3.5 and 37 degrees C for 5 min, the 90- and 84-kDa forms are rapidly converted to the 82-kDa form, indicating that the 90-, 84- and 82-kDa proteins are the pro-CE, the intermediate form, and the mature CE, respectively. All the forms of CE are N-glycosylated with high-mannose-type oligosaccharides. The catalytic properties of s-CE and v-CE are comparable to those of natural human CE. These results suggest that the recombinant CE is initially synthesized on membrane-bound ribosomes as a N-glycosylated preproenzyme and that, after cleavage of the signal segment, the 90-kDa proenzyme is proteolytically processed to the intermediate (84 kDa) and mature (82 kDa) forms by the transport system.

Because determination of neurologic integrity after severe limb trauma is crucial in patient care, the authors assessed magnetic resonance (MR) imaging as a tool to map denervated motor units of skeletal muscle in patients with traumatic peripheral neuropathy. Denervation was confirmed in 22 patients with use of electromyography, surgery, or both. MR imaging was performed with moderately T1- and T2-weighted spin-echo and short-tau inversion-recovery (STIR) sequences. MR imaging was unreliable in depicting acute denervation. Muscles of patients with subacute denervation had prolonged T1 and T2, which contributed to conspicuous hyperintensity on STIR images. Chronically denervated muscles showed marked atrophy, variable changes on STIR images, and conspicuous fatty infiltration on T1-weighted images. Normal variants in motor unit anatomy were seen in denervated muscle volumes outside the expected distribution of the injured nerve. MR imaging is promising for the noninvasive mapping and monitoring of denervated muscle in subacute and chronic phases of peripheral neuropathy.

A precursor of biphenomycin A in mixed culture of Streptomyces griseorubiginosus No. 43708 with Pseudomonas maltophilia No. 1928 was isolated and characterized. The structure of the precursor, designated biphenomycin C was determined to be a peptide which is composed of biphenomycin A and arginylserine residue (Fig. 1), on the basis of chemical and spectroscopic evidence.

A five-year-old boy is presented with multiple finger and toe amputations, secondary to meningococcemia. The child developed a bimanual use pattern of the upper extremities with a significant amount of soft tissue scarring. The left hand was reconstructed according to Ilizarov's method by a combination of distraction lengthening of the metacarpals with two mini-Hoffman distractors and gradual interdigital space widening with web deepening accompanied by a modified Ilizarov apparatus. One year after removal of the external fixation frame, the web space is preserved and the child is adapting to the pincer-like function of his hands.

Production of biphenomycin A by Streptomyces griseorubiginosus 43708 was stimulated by a mixed culture with a partner strain, Pseudomonas maltophilia 1928. This stimulatory effect on biphenomycin A accumulation by the mixed culture was caused by the enzyme activity which strain 1928 possessed. It is suggested that in a mixed culture strain 43708 produces a precursor of biphenomycin A in culture broth and that strain 1928 converts the precursor to biphenomycin A.

Data from several studies suggest that tachykinins may play an important role in the pathophysiology of airway diseases, especially asthma. Our aim is to discover tachykinin antagonists which exhibit therapeutically useful anti-asthmatic activity. In our search for activities inhibiting the binding of [3H]substance P to guinea-pig lung membrane preparations, we have found that the fermentation product, WS9326A, isolated from Streptomyces violaceusniger, is a potent tachykinin receptor antagonist.

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 x 10(-6) M and 6.7 x 10(-7) M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.

Composite grafts of skin and subcutaneous fat harvested from the glabrous non-weight-bearing areas of the foot were used to graft 34 fingertips after separation of 23 complete syndactyly webs in 13 patients. Simple complete syndactylies accounted for 17% and complex complete syndactylies accounted for 83%; synonychia was encountered in 70%. Follow-up averaged 13.9 months (minimum, 2 months, maximum 33 months). All patients had 100% take of the composite graft. Subjective gradings were 94% good, 6% fair, and there were no poor results. This technique provides a relatively normal contour and satisfactory pad to the fingertip.

WS-7338 A, B, C and D, novel endothelin receptor antagonists, have been isolated from fermentation broth of Streptomyces sp. No. 7338. These antagonists were purified from the culture mycelium by extraction with acetone, followed by carbon column chromatography and HPLC. Among them, WS-7338 B showed good activity in an endothelin receptor binding assay with an IC50 of 2.7 x 10(-7) M.

Clinical evaluation of the locomotor system has long been hampered by difficulty in assessing the morphologic and functional integrity of skeletal muscles. Diagnostic imaging represents a major advance in the diagnosis and management of patients with locomotor dysfunction through the possibility of probing beyond overlying soft tissues to identify muscle lesions, determine their extent, characterize their composition, direct invasive procedures, and monitor therapies. Magnetic resonance imaging (MRI) appears to be the most promising of available imaging methods, because of its great sensitivity to changes in muscle water distribution and fat content. Also, it can distinguish between individual deep and superficial muscles. Serial evaluations of many muscles are practical because of the safety of MRI. While the cost effectiveness in the workup of locomotor dysfunction remains to be determined, the scientific and practical clinical information now available merits further investigation by clinicians and radiologists alike. The purpose of this review is to describe the potential role of skeletal muscle MRI in evaluating the locomotor system.

Excessive longitudinal segmentation of the radial portion of the limb bud results in the clinical presentation of duplicated and triphalangeal thumbs. These are common congenital problems with various possible associated anomalies and variable inheritance patterns. Reconstruction of a thumb with stable joints, muscle balance, and good alignment requires attention to each tissue component at the time of the initial surgery.

Three human pancreatic cancer cell lines, designated as KP-1N, KP-2 and KP-3 have been established in both tissue cultures and in nude mice. The KP-1N and KP-3 tumors were obtained from liver metastases of pancreatic tumors and the KP-2 tumors was of primary pancreatic origin. The patients' tumors from which KP-1N and KP-2 were derived showed characteristics of adenocarcinoma, and the KP-3 tumor had adenosquamous carcinoma characteristics. Inoculations of samples from surgical specimens into athymic nude mice resulted in tumor formation, with the tumors histologically closely resembling the original neoplasms. Subcutaneous injections of the established cell lines also induced tumor formation and the tumors histologically resembled the original lesion in the cases of KP-2 and KP-3 tumors, but the KP-1N tumors in the mice were histologically different from the surgical specimen. The KP-1N, KP-2 and KP-3 cell lines have been cultured continuously in a medium supplemented with 10% fetal calf serum for more than 20, 21 and 17 months, respectively. The KP-2 and KP-3 cell lines produced and released carbohydrate antigen 19-9 into the spent medium but the KP-1N cell line did not. KP-1N and KP-3, produced liver metastases after intrasplenic injection into nude mice, whereas KP-2 produced few liver colonies. Cell lines highly metastatic to the liver, KP-1NLs and KP-3Ls, were isolated from the liver colonies of KP-1N and KP-3, respectively.

Streptoverticillium fervens produced a new antibiotic, FR-900848, which has a high specific activity against filamentous fungi. Purified by solvent extraction and column chromatography, the compound appears as colorless crystals. Its structure is C32H43N3O6, which consists of 5'-amino-5'-deoxy-5,6-dihydrouridine with an unsaturated fatty acid having unprecedented four serial and one isolated cyclopropane rings.

FR112123 is a new oligopeptide antibiotic produced by Streptomyces viridochromogenes No. 7587. The structure of FR112123 is elucidated as N-(N6-(N2-glycyl-L-glutaminyl)-D-lysyl)-D-alanine (1) by spectroscopic and chemical evidence. It resembles a partial structure of peptidoglycan in bacteria. The compound has a superior activity against an Escherichia coli mutant sensitive to inhibitors of cell wall synthesis, although it has a weak activity against the parent strain. These suggest that FR112123 might act on the biosynthesis of bacterial cell wall.

WS1358A1 (FR104007) and B1 (FR104008), new potent inhibitors of renal dehydropeptidase, were isolated from the culture broth of strain No. 1358 which was identified as Streptomyces parvulus subsp. In vitro inhibitory activities (IC50 value) of WS1358A1 and B1 against porcine renal DHP were 3 and 600 nM, respectively.

FR109615, a new antibiotic active against Candida, was isolated from Streptomyces setonii No. 7562. Based on the spectroscopic data, the structure of FR109615 was elucidated as cis-2-aminocyclopentane-1-carboxylic acid (1). The compound showed the excellent in vivo efficacy in a generalized infection test of mice.

A new antitumor antibiotic, FR900840, was isolated from a culture broth of Streptomyces strain No. 8727 as a pale yellowish prism and the molecular formula was determined to be C7H11N3O5. The antibiotic exhibited prominent antitumor effects on human tumor cell lines both in vitro and in vivo.

Biphenomycin A, C23H28N4O8, and biphenomycin B, C23H28N4O7, were isolated from the cultured broth of Streptomyces griseorubiginosus No. 43708. The antibiotics are active in vitro and in vivo against bacteria, and are especially potent against Gram-positive bacteria. The acute toxicity of biphenomycin A is very low in mice.

Recently, there has been an increasing interest in the diagnostic and prognostic usefulness of tumor-associated antigen of embryonic and fetal origin. Many approaches have been attempted to make an early diagnosis of the pancreatic cancer, where a specific screening blood test for the pancreatic cancer is required. By using antiserum to fetal pancreas, Banwo et al, discovered an oncofetal antigen that was present in human fetal pancreas, pancreatic tumor tissue, and sera from patients with the pancreatic cancer. Pancreatic oncofetal antigen (POA) was considered to be an oncofetal antigen for human pancreas, and its measurement seemed to be useful in the diagnosis of pancreatic cancer. But elevated levels of POA were also observed in the serum of some patients with cancer of the stomach, lung, colon, or liver as well as in the serum of some pregnant women and others with certain benign conditions. In summary, combined assay with various tumor markers was considered to be useful for the diagnosis of pancreatic cancer.

Traumatic disruption of the acetabular triradiate physeal cartilage is an infrequent injury. When it occurs during adolescence, subsequent growth changes in acetabular morphology and congruency of the hip joint are unlikely. However, in younger children, especially those who are less than ten years old, acetabular growth abnormality is a frequent complication of this injury and may result in a shallow acetabulum similar to that seen in patients with congenital disease of the hip. By the time of skeletal maturity, disparate growth increases the incongruency of the hip joint and may lead to progressively more severe subluxation of the hip. Acetabular reconstruction may be necessary to correct the gradual subluxation of the femoral head. Variable irregularities of growth at the proximal end of the femur also may occur. In this series, nine patients with triradiate physeal-cartilage injury were classified according to the degree of displacement and the probable type of growth-plate disruption. Two main patterns of injury occurred. The first was a shearing type-1 or 2 growth-mechanism injury, with central displacement of the distal portion of the acetabulum. This injury pattern seems to have a favorable prognosis for continued normal acetabular growth, although premature closure of the triradiate physes may occur. The other pattern appeared to be a crushing type-5 growth-mechanism injury. This type has a poor prognosis, with premature closure of the triradiate physes occurring secondary to the formation of a medial osseous bridge. In either pattern, the prognosis is dependent on the age of the patient at the time of injury and on the extent of chondro-osseous disruption.

Lavendomycin, a new basic peptide antibiotic containing novel amino acids, has been isolated from the culture broth of a streptomyces designated as Streptomyces lavendulae subsp. brasilicus. The antibiotic obtained as colorless crystals (C29H50N10O8, MW 666) is active against Gram-positive bacteria in vitro and in vivo, however, inactive against Gram-negative bacteria and fungi. An acute toxicity of the antibiotic in mice was LD50 greater than 2 g/kg by subcutaneous injection.

The structures of biphenomycins A and B, novel peptide antibiotics produced by a strain of Streptomyces, have been established as 1 and 2, respectively, on the basis of spectroscopic and chemical evidence. They are unique in that they are cyclic peptides containing a biphenyl moiety included in a 15-membered ring and show potent antibacterial activities especially against Gram-positive bacteria.

Rat liver cytosol was previously shown to contain at least three NADPH-dependent enzymes which catalyze the hydrogenation of chloral hydrate. Two of them had previously been shown to catalyze the hydrogenation of long-chain aliphatic and aromatic aldehydes or aromatic ketones in addition to halogenated acetaldehydes. The present paper demonstrates that one of these enzymes also catalyzes the reversible hydrogenation of 3-oxosteroids to 3 alpha-hydroxysteroids. We confirmed that the enzyme catalyzes the reversible hydrogenation of C23, C24 and C26 3-oxo bile acids with a 1:1 stoichiometry. The substitution at C-12 with a hydroxyl group markedly decreased the reaction rate, and the rate of dehydrogenation of C20, C23, C26, C24, and C25 bile acids decreased in the descending order. In general, the conjugation with glycine or taurine increased the reaction rate, while the replacement of the terminal carboxyl group of the C24 compound with an isobutyl group markedly decreased it. 3 alpha-Hydroxy bile acids with A/B trans configuration were also preferable substrates for the enzyme, although the reaction rate was relatively low compared with that of those with A/B cis configuration. The enzyme may be involved in the biosynthesis of lithocholic acid from cholesterol through 3 alpha-hydroxy-5-cholen-24-oic acid, which was proposed by Mitropoulos and Myant (Mitropoulos & Myant (1967), Biochem. J. 103, 472--479).

MCNU is a new derivative of nitrosourea and experimental studies have shown equal or superior activity to known nitrosourea compounds. Twenty one cases were entered into our clinical studies with a phase II study. Nineteen cases have had a several courses of prior chemotherapy. Four out of 21 cases achieved a partial response (each one of lymphoepithelioma, parotid gland cancer, recurrent uterine cancer and recurrent breast cancer). The major toxicity encountered during treatment was myelosuppression. Full recovery of myelosuppression was delayed and was seen six to eight weeks after each injections. These initial results justify further clinical investigations with MCNU.