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Biomedical subjects

B Brenner

Publications and source records attributed to B Brenner.

At least 55 records · Page 3Linked to original sources
PubMed2001

Cancer and thrombosis revisited.

Remarkable progress has been made since the first description of the association between cancer and thrombosis by Trousseau over 100 years ago. Now, it is clear that there is a two-way connection between coagulation and cancer as tumor results in alterations in hemostatic balance, and thrombosis may promote tumor cell growth. A variety of clinical thrombotic syndromes may present in cancer patients including local and systemic venous and arterial thromboses. More evidence is now being gathered on the potential of antithrombotic regimens to prolong survival of cancer patients. Whether the use of novel antithrombotic drugs may result in a better outcome remains to be determined.

Fibrinolytic Agents↗
PubMed2001

HIV drug resistance and implications for the introduction of antiretroviral therapy in resource-poor countries.

The development and transmission of HIV drug-resistant viruses is of serious concern and has been shown to significantly diminish the effectiveness of antiretroviral therapy. In addition, cross-resistance between drugs of the same class can seriously limit therapeutic options and may potentially be most problematic in resource-poor settings where new drugs are not widely available. Strategies based on avoidance of virological failure are therefore essential for the long-term success of therapy. In this regard, regionally adapted programs to facilitate proper adherence with therapy need to be urgently implemented, concomitant with expanded access to new antiretroviral drugs. The value of genotypic resistance testing as a prognostic tool to help guide therapeutic decisions has been established. However, the relatively high cost of this novel technology does not warrant its routine utilization at this time in resource-poor countries. Lastly, the genetic barrier of the antiretroviral agents that are prescribed is also an important consideration that needs to be integrated with knowledge of HIV-1 subtypes, drug pharmacology, and medical management of concurrent illnesses. The selection of appropriate first-line antiretroviral combination regimens may be an even more important consideration in developing than developed countries, given that options in the aftermath of treatment failure may be more limited in such settings.

Antiretroviral Therapy, Highly Active↗
PubMed2001

Inaccuracy of "personal best" peak expiratory flow rate reported by inner-city patients with acute asthma.

Percent predicted peak expiratory flow (PEF) is used to determine the severity of asthma exacerbation and the appropriateness of discharge from the emergency department (ED). The 1995 Global Initiative for Asthma and 1997 National Asthma Education and Prevention Program guidelines recommend using a patient's "personal best" PEF, if available, as a better measurement than the predicted PEF obtained from population-based nomograms. We evaluated the accuracy of personal best PEF as provided by inner-city ED patients with acute asthma. One hundred four patients with acute asthma agreed to return to the ED for repeat PEF measurements on days 3, 7, 12, 21, and 24 after their initial ED visits for acute asthma. At the ED visit, only 29% (30/104) of patients were able to report a personal best PEF. Over the 24 days of follow-up, 45% (10/22) of these patients had a measured PEF greater than their reported personal best. If a predicted PEF of at least 70% was used as the criterion for ED discharge, as several asthma guidelines recommend, then using patients' reported personal best PEF would have led to inappropriate ED discharge for some patients.

Acute Disease↗
PubMed2001

Prophylactic therapy with enoxaparin during L-asparaginase treatment in children with acute lymphoblastic leukemia.

Forty-one consecutive children with acute lymphoblastic leukemia (ALL) received prophylaxis therapy with the low molecular weight heparin (LMWH) enoxaparin during L-asparaginase treatment. Enoxaparin was given every 24 h subcutaneously at a median dose of 0.84 mg/kg per day (range, 0.45-1.33 mg/kg per day) starting at the first dose of L-asparaginase until 1 week after the last dose. Molecular analysis for thrombophilic polymorphisms documented prothrombin G20210A mutation in 3/27 (11%), homozygosity for MTHFR C677T mutation in 5/27 (18.5%, and heterozygosity for factor V Leiden mutation in 5/27 (18.5%) children. There were no thrombotic events during 76 courses of L-asparaginase in 41 patients who had received enoxaparin. One patient suffered brain infarct 7 days after enoxaparin was stopped. There were no bleeding episodes. In a historical control group of 50 ALL children who had not received prophylactic enoxaparin during L-asparaginase treatment, two had thromboembolisms (one deep vein thrombosis and one pulmonary embolism). Enoxaparin is safe and seems to be effective in prevention of thromboembolism in ALL patients during L-asparaginase therapy. This study provides pilot data for a future randomized trial of the use of LMWH during ALL therapy for the prevention of asparaginase-associated thrombotic events.

Adolescent↗
PubMed2000

Expression and characterization of the naturally occurring mutation L394R in human gamma-glutamyl carboxylase.

Patients with mutation L394R in gamma-glutamyl carboxylase have a severe bleeding disorder because of decreased biological activities of all vitamin K-dependent coagulation proteins. Vitamin K administration partially corrects this deficiency. To characterize L394R, we purified recombinant mutant L394R and wild-type carboxylase expressed in baculovirus-infected insect cells. By kinetic studies, we analyzed the catalytic activity of mutant L394R and its binding to factor IX's propeptide and vitamin KH(2). Mutant L394R differs from its wild-type counterpart as follows: 1) 110-fold higher K(i) for Boc-mEEV, an active site-specific, competitive inhibitor of FLEEL; 2) 30-fold lower V(max)/K(m) toward the substrate FLEEL in the presence of the propeptide; 3) severely reduced activity toward FLEEL carboxylation in the absence of the propeptide; 4) 7-fold decreased affinity for the propeptide; 5) 9-fold higher K(m) for FIXproGla, a substrate containing the propeptide and the Gla domain of human factor IX; and 6) 5-fold higher K(m) for vitamin KH(2). The primary defect in mutant L394R appears to be in its glutamate-binding site. To a lesser degree, the propeptide and KH(2) binding properties are altered in the L394R mutant. Compared with its wild-type counterpart, the L394R mutant shows an augmented activation of FLEEL carboxylation by the propeptide.

Amino Acid Substitution↗
PubMed2000

[Breast cancer after mantle field irradiation for Hodgkin's disease].

Effective use of modern therapeutic modalities results in the cure of 75%-80% of Hodgkin's disease patients, regardless of stage. The major threat to continued survival is, therefore, not recurrent disease but development of second malignancies. Recent reports have firmly established the increased risk of breast cancer developing in women treated with mantle field irradiation. We describe 3 women who developed breast carcinoma following mantle field irradiation for Hodgkin's disease. Their clinical course was consistent with that reported in larger series. They were relatively young when irradiated and there was a long interval between radiation therapy and the diagnosis of breast cancer. Review of the literature shows that there may be a role for prophylactic mastectomy after irradiation for Hodgkin's disease.

Adult↗
PubMed2000

Prevalence of HIV-1 resistant to antiretroviral drugs in 81 individuals newly infected by sexual contact or injecting drug use. Investigators of the Quebec Primary Infection Study.

OBJECTIVE: Prolonged treatment with antiretroviral drugs results in the selection of HIV-1 variants with mutations conferring resistance to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTI and NNRTI) or to protease inhibitors (PI). There is serious concern about transmission of resistant viruses to newly infected persons. This study monitored the prevalence of resistant viruses in individuals undergoing primary HIV infection. DESIGN: Resistance testing was performed on 81 individuals infected between 1997 and 1999 by injecting drug use (n =21), sexual (n = 56), or unknown (n = 4) transmission. METHODS: Automated sequencing was used to genotype the reverse transcriptase (RT) and protease regions of virus isolated from patients' plasma. The phenotypic susceptibility of stimulated peripheral blood mononuclear cells to antiretroviral drugs was assayed. Line probe assays detected quasispecies variations in wild-type and mutated RT codons. RESULTS: A high prevalence of PI and RT genotypic variants, associated with high-level resistance to antiretroviral drugs, was observed in individuals newly infected by injecting drug use (PI = 24%, RT = 24%) or sexual transmission (PI = 12%, RT = 22%). The PI mutations, L101, V82A, and L90M, were found in 10.5, 3 and 4% of cases, respectively; whereas for RT, primary mutations at positions T215Y (zidovudine), M184V (lamivudine), T69D/A (zalcitabine), and K103N (multi-NNRTI) were present in 8, 5, 4, and 4% of subjects, respectively. Resistance to NRTI was demonstrated by phenotypic, genotypic, and line probe analyses. Transmission of multidrug (NRTI/NNRTI/PI) resistance in eight subjects (9.9%) was confirmed by showing that source partners possessed viruses of similar genotype. CONCLUSIONS: The transmission of drug-resistant HIV is a serious problem that merits further attention by public health officials as well as virologists and clinicians.

Anti-HIV Agents↗
PubMed2000

Multiple retinal arteriolar occlusions associated with coexisting primary antiphospholipid syndrome and factor V Leiden mutation.

PURPOSE: To investigate a case of a young woman with both primary antiphospholipid syndrome and factor V Leiden mutation who developed multiple retinal arteriolar occlusions. METHOD: Case report of a 25-year-old woman with history and laboratory tests confirming the diagnosis of both primary antiphospholipid syndrome and factor V Leiden mutation who presented with blurred vision in both eyes. RESULTS: Multiple retinal arteriolar occlusions were observed in both of her eyes. The patient was treated first with heparin and then with warfarin. CONCLUSIONS: Primary antiphospholipid syndrome and factor V Leiden mutation, as well as other forms of thrombophilia, should be considered in the differential diagnosis of unexplained retinal vascular occlusions. The coexistence of several thrombophilic disorders may carry a particularly high risk for thrombotic manifestations.

Activated Protein C Resistance↗
PubMed2000

Cross-bridge attachment during high-speed active shortening of skinned fibers of the rabbit psoas muscle: implications for cross-bridge action during maximum velocity of filament sliding.

To characterize the kinetics of cross-bridge attachment to actin during unloaded contraction (maximum velocity of filament sliding), ramp-shaped stretches with different stretch-velocities (2-40,000 nm per half-sarcomere per s) were applied to actively contracting skinned fibers of the rabbit psoas muscle. Apparent fiber stiffness observed during such stretches was plotted versus the speed of the imposed stretch (stiffness-speed relation) to derive the rate constants for cross-bridge dissociation from actin. The stiffness-speed relation obtained for unloaded shortening conditions was shifted by about two orders of magnitude to faster stretch velocities compared to isometric conditions and was almost identical to the stiffness-speed relation observed in the presence of MgATPgammaS at high Ca(2+) concentrations, i.e., under conditions where cross-bridges are weakly attached to the fully Ca(2+) activated thin filaments. These data together with several control experiments suggest that, in contrast to previous assumptions, most of the fiber stiffness observed during high-speed shortening results from weak cross-bridge attachment to actin. The fraction of strongly attached cross-bridges during unloaded shortening appears to be as low as some 1-5% of the fraction present during isometric contraction. This is about an order of magnitude less than previous estimates in which contribution of weak cross-bridge attachment to observed fiber stiffness was not considered. Our findings imply that 1) the interaction distance of strongly attached cross-bridges during high-speed shortening is well within the range consistent with conventional cross-bridge models, i.e., that no repetitive power strokes need to be assumed, and 2) that a significant part of the negative forces that limit the maximum speed of filament sliding might originate from weak cross-bridge interactions with actin.

Actins↗
PubMed2000

Resistance to antiretroviral drugs in patients with primary HIV-1 infection. Investigators of the Quebec Primary Infection Study.

The widespread use of antiretroviral agents (ARVs) and the growing occurrence of HIV strains resistant to these drugs have given rise to serious concerns regarding the transmission of resistant viruses to newly infected persons. Plasma viral RNA from 80 individuals newly infected between 1997 and 1999 was genotyped by automated sequencing to analyze the profile of viruses resistant to nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs) and to protease inhibitors (PIs). The prevalence of mutations that conferred primary resistance to PIs (L10I, D30Y, V82A, L90M) was 15% of the cohort. RT genotypic variants, associated with high-level resistance to ARVs, were observed in 21% of individuals, including NRTI, NNRTI and multidrug (MDR) resistance in 6, 5, and 10% of cases, respectively. The phenotypic susceptibility of viral isolates to ARVs was also assayed and showed transmission of high-level resistance to ZDV, 3TC, and PIs in those individuals with MDR. The transmission of drug-resistant HIV genotypic variants is a serious problem that merits further attention by public health officials, virologists, and clinicians.

Anti-HIV Agents↗
PubMed2000

Molecular characterization of four novel mutations causing factor VII deficiency.

INTRODUCTION: Hereditary deficiency of factor VII (FVII) is a rare coagulation defect. We previously studied the molecular basis of the FVII deficiency in Israeli patients and found that the majority of them bore the Ala244Val mutation. In the present study we further analysed FVII deficient patients. PATIENTS AND METHODS: Three patients with severe FVII deficiency (FVII activity < or =1%) and one with partial deficiency (25%) were studied. In all four patients, the FVII gene was amplified and sequenced. RESULTS: Four novel mutations have been identified: IVS 2+1G-->C Phe 24 deletion, Leu300Pro and Arg277His. Homozygosity for the IVS2+1G-->C mutation was lethal, whereas homozygosity for the Phe 24 deletion was accompanied by a severe bleeding tendency. FVII modeling showed that Phe 24 is located in the Gla domain. Both Arg 277 and Leu 300 are within the catalytic domain, although Arg 277 is also involved in tissue factor binding. CONCLUSION: We have analysed four mutations, two of which (IVS2+1G-->C, Phe 24 deletion) were associated with severe bleeding tendency in the homozygous state, facilitating prenatal diagnosis. Hypothetically, using FVII modeling, Arg 277 replacement by histidine may weaken the tissue factor, while deletion of Phe 24 and Leu300Pro mutation might be associated with abnormal folding of the Gla and catalytic domains, respectively.

Adolescent↗
PubMed2000

Comparison of clinical performance, histology and single-fiber contractility in free neurovascular muscle flaps.

The aim of this study was to obtain further insights about muscle regeneration processes in free neurovascular flaps. In cases of insufficient functional return of muscle strength, several factors, such as diminished axonal ingrowth, fatty degeneration, or connective tissue proliferation are discussed. In the study, free neurovascular latissimus dorsi (LD) flaps were examined after a regeneration period of 2 to 6 years. Clinical function (M1 to M4) and histopathologic characteristics of the muscle grafts were correlated. The rare instances of secondary procedures, such as tenolysis or scar correction, were used for biopsies of the muscle graft. Free neurovascular LD flaps were examined after a regeneration period between 2 and 6 years. The grafted LD was compared to normal, healthy LD muscle. Normal LD muscle showed a typical homogeneous pattern of types 1 and 2 fibers in a ratio of almost 1:1. No significant differences concerning fiber distribution and fiber diameters in three anatomic areas of the LD (proximal, medial, caudal) could be detected. After regeneration, the authors found the following: type grouping of muscle fiber types, fiber splitting, and groups of hypertrophic and atrophic fibers. Most of the muscle fibers were not reinnervated by axons and were atrophic or degenerated. The essential proliferation of connective and fatty tissue was absent. Normal and hypertrophic fibers were found mainly in the muscle grafts with good clinical results. In muscle grafts with good contraction force (M4), 46 percent of reinnervated muscle fibers were found; M3 contractility was correlated with 31 percent of reinnervated muscle fibers; M2 with 24 percent; and M1 with 21 percent of reinnervated fibers. The force of a free muscle graft seems to depend mainly on the quality of nerve regeneration. Characteristics of the muscle fiber itself were not examined extensively, because the single-fiber contractility of the regenerated fibers was similar to the contractility of normal, healthy fibers.

Adult↗
PubMed2000

Echocardiography in nonbacterial thrombotic endocarditis: from autopsy to clinical entity.

Bacteria-free verrucae, frequently termed "non-bacterial thrombotic endocarditis," have been recognized in autoimmune disorders as well as in neo-plastic diseases. The antemortem diagnosis of non-bacterial thrombotic endocarditis is rare, and most existing data result from postmortem examinations. In 3 prospective echocardiographic studies we found typical cardiac valvular lesions in patients with primary antiphospholipid syndrome, myelo-proliferative disorders, and solid malignant tumors. Cardiac lesions associated with these 3 different entities had common echocardiographic appearance and correlated positively with thromboembolic events. The possibility of common pathogenesis is suggested, and clinical significance is discussed.

Antiphospholipid Syndrome↗
PubMed2000

Oral etoposide for Merkel cell carcinoma in patients previously treated with intravenous etoposide.

We describe three patients with advanced Merkel cell carcinoma who were treated with etoposide given orally for recurrent regional lymph node involvement 18 to 30 months after exposure to etoposide given intravenously. Etoposide given orally (100 mg/day) was given for 10 to 14 consecutive days and repeated every 21 to 28 days for a median of three courses (range: two to four). Toxicity was minimal and mainly hematologic. Two patients showed a complete response and one a partial response, all of very rapid onset. All three patients are alive 6, 9, and 42 months from the start of oral treatment. Two remain progression free, and one had a recurrence 1 month after completion of chemotherapy. We suggest that orally administered etoposide, a topoisomerase II inhibitor, has a strong antitumor effect in advanced Merkel cell carcinoma, even in patients previously treated parenterally with the same drug. This action may be explained by the greater dependence of the drug's efficacy on the duration of administration rather than the dose intensity.

Administration, Oral↗
PubMed2000

Inherited thrombophilia and fetal loss.

Acquired thrombophilia is a well-established cause of pregnancy loss. Increasing numbers of recent observations suggest that inherited thrombophilia is not only associated with gestational thromboembolism but is also a major cause of fetal loss. This review focuses on association of fetal loss with inherited thrombophilias, including dysfibrinogenemia and protein C, protein S, and antithrombin III deficiencies. Activated protein C resistance and factor V Leiden mutation are frequent causes of pregnancy loss. Thrombophilic states such as factor V Leiden and hyperhomocysteinemia may also play a role in other gestational vascular complications, including intrauterine growth restriction, preeclampsia, and placental abruption. Preliminary reports suggest that antithrombotic therapy may be of value in this setting. The potential application of antithrombotic modalities to prevent fetal loss in women with thrombophilia is discussed.

Abortion, Habitual↗