Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia.

Treatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with phosphatase and tensin homolog (PTEN) deletions and resultant phosphatidylinositol 3'-kinase (PI3K)-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on the expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment-resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T-ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes and in 33% of bim homozygous mutants (P=0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.

Artificial ionospheric layers during pump frequency stepping near the 4th gyroharmonic at HAARP.

We report on artificial descending plasma layers created in the ionosphere F region by high-power high-frequency (HF) radio waves from High-frequency Active Auroral Research Program at frequencies f(0) near the fourth electron gyroharmonic 4f(ce). The data come from concurrent measurements of the secondary escaping radiation from the HF-pumped ionosphere, also known as stimulated electromagnetic emission, reflected probing signals at f(0), and plasma line radar echoes. The artificial layers appeared only for injections along the magnetic field and f(0)>4f(ce) at the nominal HF interaction altitude in the background ionosphere. Their average downward speed ~0.5 km/s holds until the terminal altitude where the local fourth gyroharmonic matches f(0). The total descent increases with the nominal offset f(0)-4f(ce).

Observations of Earth space by self-powered stations in Antarctica.

Coupling of the solar wind to the Earth magnetosphere/ionosphere is primarily through the high latitude regions, and there are distinct advantages in making remote sensing observations of these regions with a network of ground-based observatories over other techniques. The Antarctic continent is ideally situated for such a network, especially for optical studies, because the larger offset between geographic and geomagnetic poles in the south enables optical observations at a larger range of magnetic latitudes during the winter darkness. The greatest challenge for such ground-based observations is the generation of power and heat for a sizable ground station that can accommodate an optical imaging instrument. Under the sponsorship of the National Science Foundation, we have developed suitable automatic observing platforms, the Automatic Geophysical Observatories (AGOs) for a network of six autonomous stations on the Antarctic plateau. Each station housed a suite of science instruments including a dual wavelength intensified all-sky camera that records the auroral activity, an imaging riometer, fluxgate and search-coil magnetometers, and ELF/VLF and LM/MF/HF receivers. Originally these stations were powered by propane fuelled thermoelectric generators with the fuel delivered to the site each Antarctic summer. A by-product of this power generation was a large amount of useful heat, which was applied to maintain the operating temperature of the electronics in the stations. Although a reasonable degree of reliability was achieved with these stations, the high cost of the fuel air lift and some remaining technical issues necessitated the development of a different type of power unit. In the second phase of the project we have developed a power generation system using renewable energy that can operate automatically in the Antarctic winter. The most reliable power system consists of a type of wind turbine using a simple permanent magnet rotor and a new type of power control system with variable resistor shunts to regulate the power and dissipate the excess energy and at the same time provide heat for a temperature controlled environment for the instrument electronics and data system. We deployed such systems and demonstrated a high degree of reliability in several years of operation in spite of the relative unpredictability of the Antarctic environment. Sample data are shown to demonstrate that the AGOs provide key measurements, which would be impossible without the special technology developed for this type of observing platform.

A familial case of pleuropulmonary blastoma.

PURPOSE: Pleuropulmonary blastoma (PPB) is a rare intrathoracic neoplasm of early childhood arising in the lung or visceral pleura. Approximately 150 cases have been reported in the literature, with only one previously documented case of PPB in siblings. PATIENTS AND METHODS: We present the case of two brothers diagnosed with PPB. RESULTS: A two month-old boy with an abnormal breathing pattern was referred for evaluation of a cystic mass discovered on chest radiograph. Computed tomography (CT) of the chest was performed at our institution which revealed findings compatible with congenital cystic adenomatoid malformation (CCAM) of the right middle and lower lobes. The patient underwent urgent thoracic exploration one week later after developing severe respiratory distress. Histological examination revealed PPB type I (cystic). The patient's 15-month-old brother was presumed to have a CCAM noted radiographically months earlier during an asthma exacerbation. He underwent elective cyst resection and was also found to have type I PPB. The index patient was treated with adjuvant chemotherapy due to the large size of the PPB and intraoperative spillage of cystic fluid during the emergent surgery. In contrast, the brother is being followed without adjuvant chemotherapy, given the much smaller size of the PPB, wide margins of resection, and lack of spillage. Family history included an uncle diagnosed at age 11 with an unusual form of T cell acute lymphoblastic leukemia. CONCLUSION: Although PPB is known to have a familial association with other neoplasms, this case represents only the second report of PPB occurring in siblings. The importance of thoroughly investigating and resecting pulmonary cystic masses in the pediatric population is highlighted by these cases.

[Content validity of an information system used for head injury rehabilitation based on an analysis of medical records]. / Validation par les dossiers médicaux d'un système d'informationdédié à la clientèle victime d'un traumatisme crânien.

OBJECTIVE: This study examines the content validity of the TCC-Québec Information System based on an analysis of rehabilitation medical records. The goal was to determine the agreement between the variables of the TCC-Québec Information System identified by experts and based on an extensive literature review and those found in medical records. METHOD: The medical records of 82 adults with a head injury were reviewed. The individuals had been hospitalized from 1997 to 1998 at three different acute care facilities or three rehabilitation centers. The abstractor determined if the information pertaining to a variable (e.g. personal history, impairments, or disabilities relating to sensori-motor function) was present in the record. A standardized and reliable procedure was used to ensure the quality of data extraction. The percentage of variables found in the medical records and the number of records in which each variable was documented were calculated for each clinical setting (acute care or rehabilitation) and for the different geographical regions. RESULTS: The results suggest that a large discrepancy exists between what experts desired to be included in the information system and what is really documented clinically. No discrepancy exists between the different regions. Only 23% of variables were found in more than 70% of records. CONCLUSION: This study provides recommendations about the most relevant variables to be included in an information system based on clinicians'information needs and the clinical reality. As such, these results should facilitate the use and implementation of the information system under study.

Kinetic studies of guinea pig liver transglutaminase reveal a general-base-catalyzed deacylation mechanism.

Guinea pig liver transglutaminase (TGase) reacts with 0.1 mM N-Cbz-L-Glu(gamma-p-nitrophenyl ester)Gly (5, prepared herein, K(M) = 0.02 mM) to undergo rapid acylation that can be followed spectrophotometrically at 400 nm (pH 7.0, 25 degrees C). Deacylation of the transiently formed thiolester acyl enzyme intermediate via catalytic aminolysis was studied in the presence of six primary amines of widely varying basicity (pK(NH+) = 5.6-10.5). Steady-state kinetic studies were performed to measure k(cat) and K(M) values for each amine substrate. A Brønsted plot constructed through the correlation of log(k(cat)/K(M)) and pK(NH+) for each amine substrate displays a linear free-energy relationship with a slope beta(nuc) = -0.37 +/- 0.08. The shallow negative slope is consistent with a general-base-catalyzed deacylation mechanism in which a proton is removed from the amine substrate during its rate-limiting nucleophilic attack on the thiolester carbonyl. Kinetic isotope effects were measured for four acceptor substrates (water, kie = 1.1 +/- 0.1; aminoacetonitrile, kie = 5.9 +/- 1.2; glycine methyl ester, kie = 3.4 +/- 0.7; N-Ac-L-lysine methyl ester, kie = 1.1 +/- 0.1) and are consistent with a proton in flight at the rate-limiting transition state. The active site general-base implicated by these kinetic results is believed to be His-334, of the highly conserved TGase Cys-His-Asp catalytic triad.

Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy.

In murine models of allogeneic bone marrow transplantation (BMT), MHC-mismatched recipients given a delayed infusion of donor leukocytes (DLI) at 21 days posttransplant develop significant GVHD whereas MHC-matched recipients do not. The current study was initially designed to test the hypothesis that small numbers of T cells in the MHC-mismatched donor bone marrow (BM) graft exacerbated graft-vs-host disease (GVHD) when DLI was administered at 21 days after BMT. Ex vivo depletion of Thy1+ cells from the donor BM had no impact on the severity of GVHD after DLI. However, depletion of donor T cells in vivo with a Thy1 allele-specific mAb given after BMT resulted in significantly more severe GVHD after DLI. Similar results were obtained in a MHC-matched model of allogeneic BMT, indicating that this was a general phenomenon and not model dependent. These results indicated that a population of donor-derived Thy1+ cells suppressed graft-vs-host reactivity after DLI. Results of experiments with thymectomized recipients demonstrated that an intact thymus was required for generation of the immunoregulatory donor cells. Experiments using TCR beta-chain knockout mice as BM donors indicated that the immunosuppressive Thy1+ cells coexpressed alphabetaTCR heterodimers. Similar experiments with CD4 and CD8 knockout donor BM suggested that the immunoregulatory Thy1+alphabetaTCR+ cells consisted of two subpopulations: a CD4+CD8- subpopulation and a CD4-CD8- subpopulation. Together, these results show that thymus-derived, Thy1+alphabetaTCR+ donor cells generated early after allogeneic BMT suppress the graft-vs-host reactivity of T cells given as DLI. These cells may mediate dominant peripheral tolerance after allogeneic BMT.

Validating the quality of emergency room services.

An inappropriate patient transfer from the emergency room results in less-than-quality care, cost concerns, and patient and staff dissatisfaction. The emergency room physicians at a 162-bed community hospital reported that patients were being transferred needlessly from the emergency room to other acute care facilities. An investigation of the issue documented lost revenues and concerns about the quality of patient care. Based on the findings of the investigation, specific recommendations were proposed to monitor and evaluate the quality of patient care provided in the emergency room.

Nosocomial pneumonia: interdisciplinary quality monitoring.

Nosocomial pneumonia is a serious and potentially fatal occurrence in the hospital today. Medical and nursing management influence the susceptibility of an individual as well the outcome of the episode. Due to the importance of the actions of the nurse and of the physician, monitoring the risk factors of the patient, the events preceding the episode and the pneumonia management may provide an opportunity to improve patient care. A study was conducted on patients with nosocomial pneumonia that identified areas of deficits and focused educational efforts.

Protein and other compositional differences of the extracellular material from slimy and non-slimy colonies of non-mucoid Pseudomonas aeruginosa.

The composition of extracellular material produced by non-mucoid strains of Pseudomonas aeruginosa differed when grown on surfaces that either did or did not induce the formation of slime under conditions where the medium was identical. The nature of the changes in protein composition indicated that protein expression differed in the course of growth on the two surfaces, and hence that there were physiological consequences associated with growth under conditions which do or do not lead to slime formation. The compositional differences also included elevated levels in extracellular material from the slimy colonies of two virulence factors, protease and rhamnolipids.

Extrapyramidal reactions. Neuropsychiatric mimics in patients with AIDS.

The use of neuroleptic medication as antiemetics, or in the treatment of neuropsychiatric disorders in patients with AIDS, may be associated with extrapyramidal side effects and lead to difficulty with diagnosis and management. Two cases are presented that describe severe extrapyramidal syndromes occurring in two patients with AIDS, one treated with prochlorperazine and the other with prochlorperazine and metoclopropramide. It is possible that the neuropathologic lesions found in patients with the AIDS dementia complex may pre-dispose to extrapyramidal side effects of neuroleptic medication. The differential diagnosis and treatment of delirium, dementia, depression, and extrapyramidal reactions in patients with AIDS is discussed.

Pneumocystis carinii choroidopathy. A new clinical entity.

A 43-year-old black woman with acquired immunodeficiency syndrome developed bilateral multifocal choroidopathy characterized by slowly enlarging round to oval lesions in the posterior pole and midperiphery. Systemic evaluation revealed no evidence of mycobacterial, fungal, or spirochetal disease. Fluorescein angiography of the lesions showed early hypofluorescence with late staining of the lesions, which appeared deep to the retinal circulation. There was no evidence of retinal involvement. Over a 4-month period of observation, the lesions appeared to enlarge slowly, with no evidence of vitreous cells or debris in the overlying retina. A transscleral choroidal biopsy was performed, and electron microscopy showed numerous cystic structures characteristic of Pneumocystis carinii within necrotic choroid. The lack of inflammatory changes clinically, by fluorescein angiography, and histopathologically was striking.

Interaction of cultured mammalian cells with WR-2721 and its thiol, WR-1065: implications for mechanisms of radioprotection.

An isothermal microcalorimeter was used to measure changes in heat flow when radioprotective drugs were added to cultured mammalian cells. The heat produced when WR-2721 was added continued for at least 90 min. WR-2721 was dephosphorylated by the cells to thiol (WR-1065) which oxidizes to disulphide. In the microcalorimeter, thiols give an immediate burst of heat due to this oxidation. A biological oxygen monitor revealed that WR-1065 and cysteamine rapidly consumed all the oxygen in culture medium. (10 mM WR-1065 deoxygenated medium in 2 min.) Rapid consumption of oxygen by radioprotective thiols indicates that they will not co-exist with oxygen for long in cells. This has two important implications with respect to mechanisms of radioprotection: (1) oxygen in tissues will be consumed rapidly and could result in local hypoxia; and, (2) at modest doses of protective agents the thiol will be consumed in oxic cells and hence very little will be available for reactions such as hydrogen donation. Our results indicate that anoxia is probably the principal mechanism of protection by aminothiols in mammals and aerated cells. This has major implications for clinical applications of radioprotectors and these are discussed.

Voluntary heart rate deceleration: a critical evaluation.

This experiment was designed as a test of the view that the human heart rate (HR) deceleration response can be brought under voluntary control, when some form of exteroceptive feedback is available. Sixteen female volunteers were randomly assigned to two groups. The first group received instructions to decrease their HR plus a continuous negative (failure) binary feedback, while the second group received only the instructions. Each subject was given four sessions of HR deceleration training. Two identical tests were presented, one before and the other after the series of training sessions. These tests were divided into two parts. In the first part, subjects attempted to decrease their HR while undergoing an ischemic arm pain stress. In the second part, subjects performed a 40-trial HR discrimination task. The results indicate that all subjects decrease HR during both rest and voluntary control periods within each training session, but there are no significant group differences, no improvement in HR deceleration control over the four training sessions, and no difference in performance between rest and voluntary control periods. Similarly HR, blood pressure (BP), and the HR x BP product levels during the ischemic stress condition and the HR discrimination performance do not show group differences. It is suggested that the HR deceleration response may not meet the criteria generally applied to the definition of a voluntary response.

Effects of metoprolol on effort angina during the postprandial state.

To determine whether beta blockers prevent the more rapid onset of effort angina during the postprandial state, metoprolol 100 mg was given before and after an 800-calorie meal in 12 male patients with stable angina and coronary artery disease. Three graded treadmill exercise tests were done daily on 2 days. After an overnight fast the first test on each day was done after a placebo to detect day-to-day variations. The second test was done 90 min after metoprolol or placebo given orally in a double-blind randomized fashion. Immediately thereafter the patients ate their meal and did their third test 30 min later. There was no significant difference between the first test on each day. After placebo the postprandial state was associated with an earlier onset of effort angina (310 and 370 sec, p less than 0.01) and with greater heart rate and systolic blood pressure rises for any work load. After metoprolol, however, there was no significant difference between the pre- and postprandial findings. During the postprandial state metoprolol delayed the onset of angina more than placebo (385 and 310 sec) and positive electrocardiogram (310 and 228 sec) and induced lowering of maximal heart rate (120 and 144 bpm) and systolic blood pressure (157 and 187 mm Hg) (p less than 0.01). Metoprolol slowed the rapid onset of effort agina during the postprandial state.

Vascular thrombosis in the upper extremity. A case report implicating a relationship between trauma, oral contraceptives, and smoking.

PIP: A 40-year old white female who was a heavy smoker and who was on oral contraceptives presented at the Maine Medical Center Emergency Room with widespread vascular thrombosis in the forearm and hand six days after injury. Brachial, ulnar and radial arteriotomies were performed and blood flow was restored to all of the hand except the distal ring finger. The patient was forbidden to smoke but resumed smoking on the 8th postoperative day. Thrombosis rapidly progressed and 4 weeks later she underwent amputation of the ring and little fingers. The widespread thrombosis on the patient's hand was attributed to nicotine which increases peripheral vasoconstriction. Smoking has been associated with increased platelet adhesions and subsequent coagulation. It has also been implicated in occlusive vascular disease of the hand and is said to have a mark effect on both digital perfusion and digital wound healing in a patient with ulnar artery thrombosis. Pills also increase coagulability and contributes to widespread thrombotic disease. Early diagnosis of patient's thrombosis and aggressive management including arteriography would have prevented our patient's thrombosis with its sequelae of loss of 2 digits and cold sensitive hand.^ieng

Pseudogonococcal ophthalmia neonatorum. Branhamella (Neisseria) catarrhalis conjunctivitis.

A culture from conjunctivitis occurring in a neonate in association with a recurrent fever yielded a nearly pure growth of Branhamella (Neisseria) catarrhalis. The conjunctivitis was not appreciated and effectively treated until a second hospitalization in the fourth week of life. Partial suppression of symptoms had followed short-term parenteral antibiotic therapy during the first admission. Resolution quickly occurred in response to instillation of sodium sulfacetamide ophthalmic solution. Although B. catarrhalis is considered a non-pathogen, the literature reviewed included a number of diverse infections, but no previous instance of conjunctivitis. The organism's close similarities to Neisseria gonorrhoeae necessitate isolation and correct biochemical differentiation. Misdiagnosis of gonococcal conjunctivitis carries obvious social, psychological and medical impact.

Effect of dosage regimen on natriuretic response to furosemide.

We have examined the differences in urinary excretion of water, sodium, potassium, chloride, urea, and creatinine produced by different dosage regimens offurosemide in normal volunteers. Three oral dosage regimens were compared: 20 mg daily, 20 mg twice daily, and 40 mg daily. Furosemide, 20 mg, did not produce a significant weight loss, diuresis, or natriuresis in 12 normal subjects. With 40 there was a significant weight loss, diuresis, natriuresis, and chloruresis over 24 hr. Comparison of the divided regimen with 40 mg daily revealed significantly greater sodium excretion, and chloride excretion with 20 mg twice daily. The divided dosage regimen produced a different pattern of diuresis with most of the sodium and water excretion occurring after the second dose. These differences in response to different regimens are predictable from pharmacokinetic considerations and may have clinical significance.