Velocity–pressure loops for continuous assessment of ventricular afterload: influence of pressure measurement site

VPloop, the graphical representation of pressure versus velocity, and its characteristic angles, GALA and β, can be used to monitor cardiac afterload during anesthesia. Ideally VPloop should be measured from pressure and velocity obtained at the same arterial location but standard of care usually provide either radial or femoral pressure waveforms. The purpose of this study was to look at the influence of arterial sites and the use of a transfer function (TF) on VPloop and its related angles. Invasive pressure signals were recorded in 25 patients undergoing neuroradiology intervention under general anesthesia with transesophageal flow velocity monitoring. Pressures were recorded in the descending thoracic aorta, abdominal aorta, femoral and radial arteries. We compared GALA and β from VPloops generated from each location and in high and low risk patients. GALA was similar in the central locations (55°[49–63], 52°[47–61] and 54°[45–62] from descending thoracic to femoral artery, median[interquartile], p?=?0.10), while there was a difference in β angle (16°[4–27] to 8°[3–15], p?<?0.0001). GALA and β obtained from radial waveforms were different (39°[31–47] compared to 46°[36–54] and 6°[2–14] compared to 16°[4–27] for GALA and β angles respectively, p?<?0.001) which was corrected by the use of a TF (45°[32–55] and 17°[5–28], p?=?ns). GALA and β are underestimated when measured with a radial catheter. Using pressure waveforms from femoral locations alters VPloops, GALA and β in a smaller extend. The use of a TF on radial pressure allows to correctly plot VPloops and their characteristic angles for routine clinical use.     

Serum autotaxin measurement in haematological malignancies: a promising marker for follicular lymphoma

Autotaxin (ATX) is a tumour cell motility-stimulating factor originally isolated from melanoma cell supernatants. ATX is identical to lysophospholipase D, which produces a bioactive lipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine. ATX is overexpressed in various malignancies, including Hodgkin lymphoma, and ATX may stimulate tumour progression via LPA production. The present study measured the serum ATX antigen levels in patients with haematological malignancies using a recently developed automated enzyme immunoassay. The serum ATX antigen levels in patients with B-cell neoplasms, especially follicular lymphoma (FL), were higher than those in healthy subjects. Serum ATX antigen levels in FL patients were associated with tumour burden and changed in parallel with the patients' clinical courses. The serum ATX antigen levels were little affected by inflammation, unlike the soluble interleukin-2 receptor and beta2-microglobulin levels. As expected, the plasma LPA levels in FL patients were correlated with the serum ATX antigen levels. Given that leukaemic tumour cells from FL patients expressed ATX, the shedding of ATX from lymphoma cells probably leads to the elevation of serum ATX antigen levels. Our results suggest that the serum ATX antigen level may be a promising and novel marker for FL.     

Diagnosis and management of scrofula in children

Atypical myobacterial infection in humans appears to be of low virulence and is acquired from the environment with no evidence of transmission ever from human contact. The majority of infected patients are never symptomatic and the disease is self-limited. When symptomatic disease does occur, it is usually in children. Treatment should be confined to patients with symptomatic cervical adenitis; surgical excision of the subcutaneous abscess and of the offending caseous lymph node is sufficient. Adjacent hyperplastic nodes should not be excised, and chemotherapy is not indicated.     

Bacteriology of mastoid subperiosteal abscess in children

OBJECTIVE: Subperiosteal abscess (SA) is the most frequent complication of acute mastoiditis (AM). Of pathogens cultured from the external auditory canal or middle ear during myringotomy, 15% may be different from microorganisms isolated from the SA. We suggest, therefore, that only cultures obtained from the abscess cavity can truly reflect the bacteriology of this complication of AM. The purpose of our study was to analyze the infectious agents which cause SA and mastoid cortex erosion in children. MATERIAL AND METHODS: The medical records of 35 children who underwent mastoidectomy for SA between May 1984 and April 2002 were evaluated. RESULTS: Mastoid cortex erosion was found at surgery in 72.7% of abscesses Purulent discharge was obtained from the SA cavity in 28 cases. The commonest pathogens isolated in these cases, as well as in 18 cases of mastoid cortex erosion, were Staphylococcus aureus and Streptococcus pyogenes, followed by Streptococcus pneumoniae. Hemophilus influenzae, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Sterile culture was found in 25% of cases. CONCLUSIONS: Mastoid SA is a unilateral disease that can recur. Early administration of anti-Staphylococcus medications should be considered for patients with SA as a complication of AM.     

Influence of p53 and caspase 3 activity on cell death and senescence in response to methotrexate in the breast tumor cell

The influence of p53 function and caspase 3 activity on the capacity of the antifolate, methotrexate, to promote senescence arrest and apoptotic cell death was investigated in breast tumor cells. In p53 wild-type, but caspase 3 deficient MCF-7 breast tumor cells, death of approximately 40% of the cell population was observed immediately after acute exposure to 10 microM methotrexate (the IC80 value for a 2 h drug exposure). There was no evidence of either DNA fragmentation, a sub G0 population or morphological alterations indicative of apoptosis; however, PARP cleavage was detected. Cell death was succeeded by growth arrest for at least 72 h--where arrest was characterized by expression of the senescence marker, beta-galactosidase. The response to methotrexate in MCF-7/E6 cells with attenuated p53 function was also primarily growth arrest--but lacking characteristics of senescence. In contrast, MCF-7 cells which expressed caspase 3 demonstrated a gradual and continuous loss of cell viability and unequivocal morphological evidence of apoptosis. DNA fragmentation indicative of apoptosis was also detected after exposure to methotrexate in p53 mutant MDA-MB231 breast tumor cells which also express caspase 3. Methotrexate-induced both p53 and p21waf1/cip1 in MCF-7 cells within 6 h; however, no significant DNA strand breakage was evident before 18 h, suggesting that the induction of p53 reflects a response to cellular stress other than DNA damage, such as nucleotide depletion. Overall, these studies suggest that the nature of the cellular response to methotrexate depends, in large part, on p53 and caspase function. p53 appears to be required for methotrexate-induced senescence, but not apoptosis, caspase 3 is required for DNA fragmentation and the morphological changes associated with apoptosis, while neither p53 nor caspase 3 are required for methotrexate-induced growth arrest. Furthermore, the senescence phenotype may occur in the absence of direct DNA damage.     

DPC 681 and DPC 684: potent, selective inhibitors of human immunodeficiency virus protease active against clinically relevant mutant variants

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).     

Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma

The treatment of patients with relapsed and refractory Hodgkin lymphoma (HL), especially those who relapse after autologous stem cell transplantation, remains challenging. Patients with HL whose disease relapses after stem cell transplantation are rarely cured with current treatment modalities, and have a median survival of less than 3 years. Since no new drugs have been approved by the FDA for HL in more than three decades, there is a clear unmet medical need for drug development for this patient population. New treatment strategies that are based on targeting oncogenic signaling pathways are currently explored. This review will focus on emerging new treatment modalities that are currently under investigation for patients with relapsed classical HL.