Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases

To define better the risk of epipodophyllotoxin-related acute myeloid leukemia (AML) after extended follow-up and to assess responses to intensive salvage therapy, all patients who developed this complication after treatment for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) in consecutive clinical trials at St Jude Children's Research Hospital from 1979 to 1994 were studied. Cases with 'lineage switch' or 'clonal selection' were excluded. Epipodophyllotoxin-related AML developed in 32 of 1140 patients treated for ALL and in three of 332 treated for NHL; it was a first adverse event in 25 and two cases, respectively. The complication was diagnosed at 12-130 months (median 34 months) after the initiation of treatment with epipodophyllotoxins; all but one of the cases occurred within 73 months, indicating that the risk is negligible after 6 years. The predominant karyotypic feature was 11q23 translocations (71% of cases); 21q22 rearrangements were rare. In a stepwise Cox regression analysis, two factors increased the risk of this complication: weekly or twice weekly administration of epipodophyllotoxins (P < 0.001); and the administration of asparaginase immediately before epipodophyllotoxin therapy (P < 0.001). Initial responses to salvage therapy were comparable to those reported for de novo AML: 92% of the evaluable patients entered complete remission after combination treatment. Single-agent therapy with 2-chlorodeoxyadenosine induced complete or partial remissions in one-half of the patients treated. The long-term survival rate was dismal. Of the 17 evaluable patients treated exclusively with chemotherapy, only one is alive at 84 months, compared to three of 16 patients who underwent bone marrow transplantation (alive at 10, 23 and 73 months). Cases of epipodophyllotoxin-related AML constitute a unique clinical syndrome that will require innovative strategies for cure.     

Basal cell carcinomas of the auricular region: a study of 23 cases

Basal cell carcinomas (BCCs) of the auricular region are not frequently reported, especially in the Japanese literature. Predisposing conditions such as sun exposure or frostbite are possibly involved in their development. In this study, we report our cases of auricular BCCs, discussing the obtained results, the possible significance of predisposing conditions, and the correlation with the histologic subtypes involved. Among 1094 patients with BCCs, auricular tumors were observed in 23 patients (2.1%), 4 women and 19 men. All of them were present on the external sun-exposed auricular side. Histologic patterns were nodular and micronodular (13 cases) and infiltrative (10 cases). No differences were observed between sexes. The relative degree of elastosis was higher in men than in women. Frostbite was recorded in 4 cases. The ear is an anatomical region that is heavily exposed to sun-light and equally prone to frostbite. Our data showed that all the lesions were located on the auricular region more or less exposed to sunlight. There was a recorded previous history of predisposing factors in most cases, and the high degree of elastosis suggests the involvement of these predisposing factors. Moreover, the high prevalence of infiltrative subtypes observed in our survey suggests a possible correlation between some histologic subtypes, sun-exposure, and frostbite. The differences between the relatively high number of auricular BCCs reported in the literature in contrast with the Japanese observations suggest the involvement of social or local conditions.     

Comparative anti-anaerobic activity of Men 10700, a penem antibiotic

Previous studies suggested that yeast ribosomal protein L26 was a candidate for the ribosomal subunit interface region. The present study used protein-protein cross-linking to identify neighboring proteins in intact 80S ribosomes of Saccharomyces cerevisiae. To facilitate identification of cross-linked pairs involving L26, 80S ribosomes were first treated with 5-iodoacetamidofluorescein to selectively label L26. Protein cross-links were produced with dithiobis[succinimidyl] propionate or N-succinimidyl-3-[2-pyridyldithio] propionate and analyzed by electrophoresis on two-dimensional diagonal polyacrylamide gels containing SDS. L26 was detected under UV and its cross-linked partner, detectable after staining with Coomassie blue, was located below the diagonal and was coincident with L26 on a single vertical axis. The identity of the partner was determined by its co-migration with 60S and 40S ribosomal protein markers on two-dimensional gels. Two protein pairs involving L26 and 40S subunit proteins were identified. The finding provided experimental evidence to support that L26 is located at the ribosomal subunit interface. A model that incorporates the present findings and the published data on intra-subunit protein pairs is proposed for the yeast 80S ribosome.     

Antiviral and interferon-inducing activity of a new glutarimide antibiotic, 9-methylstreptimidone

Leucocyte migration inhibition by autologous breast tumour cell fractions was mediated by a soluble factor synthesized and released by mononuclear leucocytes and active against migrating granulocytes. This mechanism is similar to that previously described in respect to cell-mediated sensitivity to microbial antigens. Alternative mechanisms involving directly reactive granulocytes or cytophilic antibodies were rarely operative in the migration tests.     

Reduced immunotoxicity and preservation of antibacterial activity in a releasable side-chain carbapenem antibiotic

A carbapenem antibiotic, L-786,392, was designed so that the side chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain upon opening of the beta-lactam ring retained antibacterial activity while safely expelling the immunodominant epitope. L-786,392 was well tolerated in animal safety studies and had significant in vitro and in vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.     

The empirical antibiotic therapy of patients with acute leukemias: the results of a multicenter study

AIM: To evaluate efficacy of ampicilline/sulbactame and fluconasole in the regimen of empirical antibiotic therapy in patients with acute leukemia. MATERIALS AND METHODS: The trial covered 14 hematological departments of Russia and 1 of Ukraine. Acute myeloid leukemia patients were included. 92 cases of fever in 56 patients with analysis of efficacy in 66 cases were considered. At the first stage of empirical antibiotic therapy, cefoperason (4 g/day) and gentamycin (240 mg/day) were administered. If no response was reached, ampicilline/sulbactam (7.5 g/day) was added. This was the second stage. If no response occurred for 5 days the three drugs were joined by fluconasol (400 mg followed by 200 mg). RESULTS: Fever of unclear genesis was cured in 82% (28 of 34), clinical infection--in 80% (20 of 25), microbiologically confirmed infection--in 4 of 7 cases. A complete response to the empirical antibiotic therapy was registered in 52 of 66 cases (79%). 7(10.5%) patients died of infectious complications. 7(10.5%) received other antibiotics.     

Physical activity and minority women: a qualitative study

Few physical activity research studies have been conducted with minority women. The purpose of this study was to explore patterns of physical activity among minority women. Focus groups were conducted with volunteers older than age 40. Each group was led by a trained moderator familiar with the ethnic community targeted. The sessions were audiotaped and professionally transcribed. Constructs were researched and codes were developed. Data were analyzed using NUD*IST qualitative analysis program. While participants did not identify themselves as "exercisers," they indicated they got enough physical activity from caregiving, housekeeping, and workday activities. The most common environmental barriers to becoming more physically active included safety, availability, and cost. Personal barriers included lack of time, health concerns, and lack of motivation. Results indicate the importance of terminology and assessment when conducting physical activity research in these populations. Also, results suggest many barriers are changeable with policies and interventions.     

Chronic auditory agnosia following Landau-Kleffner syndrome: a 23 year outcome study

We report a 27-year-old woman with chronic auditory agnosia following Landau-Kleffner Syndrome (LKS) diagnosed at age 4 1/2. She grew up in the hearing/speaking community with some exposure to manually coded English and American Sign Language (ASL). Manually coded (signed) English is her preferred mode of communication. Comprehension and production of spoken language remain severely compromised. Disruptions in auditory processing can be observed in tests of pitch and duration, suggesting that her disorder is not specific to language. Linguistic analysis of signed, spoken, and written English indicates her language system is intact but compromised because of impoverished input during the critical period for acquisition of spoken phonology. Specifically, although her sign language phonology is intact, spoken language phonology is markedly impaired. We argue that deprivation of auditory input during a period critical for the development of a phonological grammar and auditory-verbal short-term memory has limited her lexical and syntactic development in specific ways.     

Antitumor activity of free and liposome-entrapped annamycin, a lipophilic anthracycline antibiotic with non-cross-resistance properties

The lipophilic anthracycline antibiotic annamycin (Ann) was entrapped in liposomes of different size [median diameter: 1.64 microns, multilamellar liposomal Ann (L-Ann); 0.030 micron, small unilamellar Ann (S-Ann)] with > 90% entrapment efficiency and tested in vitro against four pairs of sensitive and multidrug-resistant (MDR) tumor cell lines and in vivo by the i.v. route in five tumor models: advanced s.c. B16 melanoma; s.c. M5076 reticulosarcoma; lung metastases of Lewis lung carcinoma; and s.c. KB and KB-V1 xenografts in nude mice. Predetermined optimal doses of the different formulations were used and the results were compared with doxorubicin (Dox). In vitro, Ann, either in suspension in 10% dimethyl sulfoxide (F-Ann) (1 mg/ml) or entrapped in liposomes, was able to partially overcome resistance in all four pairs of sensitive and MDR KB, 8226, P388, and CEM cell lines (resistance indexes 63, 269, 333, and 356 for Dox versus 4, 5, 19, and 8.7 for L-Ann, respectively). In vivo, both F-Ann and liposome-entrapped Ann were slightly more effective than Dox in inhibiting the growth of advanced s.c. B16 melanoma tumors. L-Ann was markedly more effective than Dox and moderately more effective than F-Ann in prolonging the life span of animals bearing s.c. M5076 and lung metastases of Lewis lung carcinoma tumors. All drugs were equally effective at optimal doses in delaying the growth of s.c. KB xenografts, whereas all Ann formulations were markedly more effective than Dox in delaying the growth of s.c. KB-V1 (MDR) xenografts. In all in vivo experiments, S-Ann was consistently more effective than L-Ann and L-Ann was more effective than F-Ann. These results indicate that (a) Ann is more effective than Dox by the i.v. route against several tumor models and that MDR tumors are partially not cross-resistant to Ann both in vitro and in vivo, (b) liposomes enhance the in vivo antitumor properties of Ann, and (c) small liposomes are more effective than large liposomes in enhancing Ann antitumor activity.     

Knowledge-based structure prediction of MHC class I bound peptides: a study of 23 complexes

BACKGROUND: The binding of T-cell antigenic peptides to MHC molecules is a prerequisite for their immunogenicity. The ability to identify binding peptides based on the protein sequence is of great importance to the rational design of peptide vaccines. As the requirements for peptide binding cannot be fully explained by the peptide sequence per se, structural considerations should be taken into account and are expected to improve predictive algorithms. The first step in such an algorithm requires accurate and fast modeling of the peptide structure in the MHC-binding groove. RESULTS: We have used 23 solved peptide-MHC class I complexes as a source of structural information in the development of a modeling algorithm. The peptide backbones and MHC structures were used as the templates for prediction. Sidechain conformations were built based on a rotamer library, using the 'dead end elimination' approach. A simple energy function selects the favorable combination of rotamers for a given sequence. It further selects the correct backbone structure from a limited library. The influence of different parameters on the prediction quality was assessed. With a specific rotamer library that incorporates information from the peptide sidechains in the solved complexes, the algorithm correctly identifies 85% (92%) of all (buried) sidechains and selects the correct backbones. Under cross-validation, 70% (78%) of all (buried) residues are correctly predicted and most of all backbones. The interaction between peptide sidechains has a negligible effect on the prediction quality. CONCLUSIONS: The structure of the peptide sidechains follows from the interactions with the MHC and the peptide backbone, as the prediction is hardly influenced by sidechain interactions. The proposed methodology was able to select the correct backbone from a limited set. The impairment in performance under cross-validation suggests that, currently, the specific rotamer library is not satisfactorily representative. The predictions might improve with an increase in the data.     

Multiply antibiotic-resistant gram-negative bacilli in a long-term-care facility: a case-control study of patient risk factors and prior antibiotic use

A cross-sectional multicenter study was conducted to estimate the direct costs for each cause of spinal cord injury in the United States. Random samples of 227 new injuries and 508 persons 2-16 years postinjury were selected. Prospective data were collected during one year on all charges for emergency medical services, hospitalizations, attendant care, equipment, supplies, medications, environmental modifications, physician and outpatient services, nursing homes, household assistance, vocational rehabilitation, and miscellaneous items. In 1995 dollars, first year charges averaged $233,947 for vehicle crashes, $217,868 for violence, $295,643 for sports, $185,019 for falls and $208,762 for other causes. Recurring annual charges for each cause averaged $33,439, $17,275, $27,488, $26,238 and $23,510, respectively. Using average age at time of injury for each cause, a 2% real discount rate, and the most recent survival data from the National Spinal Cord Injury Statistical Center, average lifetime charges for each cause were $969,659, $613,345, $950,973, $630,453 and $673,749, respectively. Given an estimated 10,000 new cases of spinal cord injury occurring each year of which 35.9% are caused by vehicle crashes, 29.5% are caused by violence, 20.3% are caused by falls, 7.3% are caused by sports, and 7% result from other causes, annual aggregate direct costs of traumatic spinal cord injury in the United States are $3.48 billion for vehicle crashes, $1.81 billion for violence, $1.28 billion for falls, $694 million for sports and $472 million for other causes. Total direct costs for all causes of SCI in the United States are $7.736 billion.     

Pyrrolnitrin from Burkholderia cepacia: antibiotic activity against fungi and novel activities against streptomycetes

AIM OF THE STUDY: The aim of the study was to document the nutritional status and the calorie demands of patients suffering from severe chronic airflow obstruction (BPCO) who were on continuous domiciliary oxygen therapy (OCD) and to correlate this information with the clinical picture, the severity of the respiratory disease and the daily distance walked, this to be measured in a prospective manner. PATIENTS AND METHODS: Fifty clinically stable patients with chronic airflow obstruction on continuous oxygen therapy for 33 months (range 4-106) in whom the following measures were made at home: pulmonary function, maximal static inspiratory and expiratory pressure (PIMAX and PEMAX), strength of hand, grip, the mean distance walked daily (wearing a pedometer for one week), body mass index (IMC), and the body composition by electrical bio-impedence and calorie requirements. RESULTS: Thirty four per cent of patients presented with an excessive body mass (IMC > 27 kg/m2), 42 per cent had normal nutrition (IMC 20-27 kg/m2) and 24 per cent were malnourished (IMC < 20 kg/m2). Malnourished patients had, in a statistically significant manner, airflow obstruction of greater severity and a lower oxygen saturation and a PEMAX as well as a lower daily distance compared to over weight subjects. However, their net calorie requirements were markedly higher (39 +/- 5 Kcal/kg/j) compared to patients having normal weight (29 +/- 11 kcal/kg/j) or excess weight (25 +/- 8 kcal/kg/j). From the clinical standpoint no malnourished patient fulfilled the clinical criteria of chronic bronchitis. By contrast 61 per cent of subjects with normal nutrition and 94 per cent of subjects with excessive weight were chronic bronchitics. CONCLUSION: In the group of patients with severe airflow obstruction on domiciliary oxygen, 25 per cent were malnourished and this was in spite of netly increased calorie consumption which is superior to their theoretical need. This suggests that the solution of increasing supplements to their dietary requirements would be a difficult to realise. These subjects presented also with a more marked ventilatory handicap and a clinical picture characterised by the absence of the classical signs of chronic bronchitis.     

Brasilinolide A, a new macrolide antibiotic produced by Nocardia brasiliensis: producing strain, isolation and biological activity

A new 32-membered macrolide antibiotic, brasilinolide A was isolated from the fermentation broth of Nocardia sp. IFM 0406. The producer was identified as Nocardia brasiliensis. The antibiotic was only active against Aspergillus niger, but not active against other fungi including yeasts as well as other filamentous like fungi and bacteria. Brasilinolide A exerted an immunosuppressive activity in the assay system of a mixed lymphocyte reaction (MLR).     

Flow and fracture of a multiphase alloy MP35N for study of workability

The flow and fracture of MP35N (35 Co, 35 Ni, 20 Cr, 10 Mo) has been studied by uniaxial com-pression and plane strain bending in the temperature range 1000 to 1200 °C and strain rate range 0.01 to 10 s^•1. This covers the normal bar rolling production conditions (∼1100 °C and 1 to 5 s“^•1). The strain to fracture in plane strain bending was found to increase with increasing strain rate, roughly coinciding with the increase of the strain to the peak stress in the flow curves. Within most of the temperature and strain rate ranges investigated and under plane strain bending deformation conditions, microvoid nucleation was found to be concurrent with or greatly enhanced by the onset of dynamic recrystallization. Under these deformation conditions, flow concentration or localization along the soft layers of newly recrystallized grains oriented along the maximum shear stress directions near the surface generated microvoid nucleation and damage, in effect overriding the stress relieving and crack isolation effects normally associated with the occurrence of dynamic recrystallization. As the tem-perature was decreased toward 1000 °C and the strain rate was increased toward 10 s^•1, an apparent transition to a microvoid nucleation mode by wedge cracking was observed, even at the maximum rate of 10 s^•1. A further decrease in deformation temperature to 900 °C at a strain rate of 10 s^•1, however, removed all evidence of microvoid nucleation (of the wedge type or otherwise) as well as any trace of dynamic recrystallization within the maximum strain imposed in the plane strain bending tests.     

beta-Lactamase activity in mycobacteria including Mycobacterium avium and suppression of their growth by a beta-lactamase-stable antibiotic

beta-Lactamase has been reported from only a few mycobacteria. It is widely assumed that Mycobacterium avium strains do not contain the enzyme, but earlier assays were done using insensitive methods. Thus the beta-lactamase activity in cell-free extracts of ten selected strains of mycobacteria, including four strains of M. avium, was determined using a highly sensitive spectrophotometric method. The results showed that all the mycobacteria tested possess the enzyme, which explains their resistance to beta-lactam antibiotics. However, some of the bacteria differed from others in the action of the inhibitors, clavulanate, sulbactam and tazobactam against their beta-lactamases. Growth of the mycobacteria was suppressed by novel combinations of the beta-lactam/beta-lactamase-inhibitors, and by a new beta-lactamase-stable cephalosporin, Cefepime (aminothiazolyl methoxyimino cephalosporin). The results presented, as well as reports of previous studies in vivo, suggest that the intracellular growth of the bacilli or the high partition coefficient of a beta-lactamase inhibitor such as sulbactam does not impede the antimycobacterial action of these compounds.     

Efficacy of an intraperitoneal antibiotic to reduce the incidence of infection in the trauma patient: a prospective, randomized study

BACKGROUND: Antibiotic therapy in patients with blunt trauma remains an area of investigation. This study was undertaken in trauma patients evaluated with diagnostic peritoneal lavage to determine the effect of an intraperitoneal antibiotic on the following factors: infectious complications, length of hospital stay, and mortality. METHODS: A prospective, randomized double-blinded study compared using either 500 mg of intraperitoneal kanamycin or a saline control in 69 adult trauma patients requiring diagnostic peritoneal lavage was conducted over a 24-month period. Advanced trauma life support indications for performing diagnostic peritoneal lavage were used. Patients were randomized to receive 50 mL of solution intraperitoneally through a lavage catheter and were evaluated for all septic complications, length of hospital stay, and outcome. RESULTS: Over a 24-month period, 40 patients received kanamycin, and 29 patients received a placebo. Of patients receiving kanamycin, 27.5 percent experienced infectious complications compared to 65.5 percent of the control patients (p = 0.001, chi-square analysis). The average length of stay in the intensive care unit was 4.18 days in the kanamycin group and 6.96 days in the control group (p = 0.04, chi-square analysis). The average length of stay was 12.32 days for patients receiving kanamycin and 17.36 days for the control group (p = 0.03, chi-square analysis). The mortality rate for each group was 13 percent. CONCLUSIONS: Intraperitoneal kanamycin given to trauma patients requiring diagnostic peritoneal lavage within the first three hours following injury reduces the incidence of infectious complications and shortens intensive care unit and hospital stay.     

Clinical and economic outcomes of empiric parenteral antibiotic therapy for pneumonia: a retrospective study of 1,032 hospitalized patients

Systemic organ blood flow was longitudinally determined with fluorescent microspheres after severe thermal injury in unanesthetized sheep. After chronic instrumentation, 20 sheep were subjected to combined injury with 40% body surface area third-degree burn and 48 breaths of cotton smoke insufflation. During the next 72 h of the experimental period, all animals were resuscitated with Ringer's lactate following the Parkland formula. To test the effect of systemic administration of ibuprofen, animals were assigned to the control group (n=11) or the ibuprofen group (n=9). In the ibuprofen group, animals received ibuprofen as a 12 mg/kg bolus injection 1 h after injury and 6 mg/kg/h as a continuous infusion for the next 47 h. After this combined injury, animals exhibited a biphasic hemodynamic alteration, with an initial shock period and a later hyperdynamic period, a phenomenon often seen in severely burned patients. Among multiple organs, the splanchnic organs exhibited more dominant and sustained decreases in regional blood flow, whereas heart and kidney blood flow were maintained at more than 90% of baseline level even in the initial hypovolemic phase. In the postresuscitation period, no organ except the heart showed increased regional blood flow, despite a more than 20% increase in cardiac output. Ibuprofen had effects on early recovery from the initial shock period, and it improved intestinal organ blood flow, suggesting a potential benefit of this drug for severe thermal injury.