Biomedical subjects
M Klein
Publications and source records attributed to M Klein.
Immunization with recombinant canarypox vectors expressing membrane-anchored glycoprotein 120 followed by glycoprotein 160 boosting fails to generate antibodies that neutralize R5 primary isolates of human immunodeficiency virus type 1.
Antibodies generated by candidate HIV-1 vaccines in a phase I clinical trial were assessed for neutralizing activity with a panel of eight well-characterized, genetically diverse clade B primary isolates having an R5 phenotype. The vaccines consisted of one of three different recombinant canarypox vectors expressing membrane-anchored HIV-1(MN)gp120 (ALVAC vCP205, vCP1433, and vCP1452) followed by boosting with a soluble gp160 hybrid consisting of MNgp120 and the majority of gp41 from strain IIIB. Serum samples from a subset of volunteers in each arm of the trial, containing moderate to high titers of neutralizing antibodies to HIV-1 MN, were analyzed. Competition assays with peptides revealed that the majority of neutralizing activity was specific for the MN-V3 loop. Despite MN-specific neutralization titers that sometimes exceeded 1:500, no neutralization of primary isolates was detected and, in some cases, mild infection enhancement was observed. In addition, little or no neutralization of the HIV-1 IIIB heterologous T cell line-adapted strain of virus was detected. These results reinforce the notion that monovalent HIV-1 ENV is a poor immunogen for generating cross-reactive neutralizing antibodies.
The relevance of adjuvant therapy in primary carcinoma of the fallopian tube, stages I and II: irradiation vs. chemotherapy.
INTRODUCTION: Primary carcinoma of the Fallopian tube (FTC) is a rare but extremely aggressive neoplasm. It must be expected to cause up to 40% of tumor-related deaths even in Stage I, and up to 57% in Stage II. Due to its rarity, there exist only a few and divergent reports on the value of adjuvant therapy. Therefore the present study aims at evaluating the influence of postoperative adjuvant therapy on FTC by studying the effects of irradiation and chemotherapy on the overall survival of patients in Stages I and II. PATIENTS AND METHODS: We investigated 95 cases of FTC in Stages I (n = 66) and II (n = 29) in a retrospective multicenter study. Group I (n = 32) are patients who underwent a complete irradiation with cobalt or photon energies of 23 MV (administering a daily dose of 2 Gy resulted in a total of 45-52 Gy in the pelvic areas). Group II (n = 31) consists of those cases who received postoperative chemotherapy with platinum. Thirty-two women were excluded from this study because they had other chemotherapies, incomplete irradiation, or no adjuvant therapy at all. RESULTS: Median survival time was 57 months in Group I patients (95% confidence interval 33-81 months), compared to 73 months (95% confidence interval, 68-78 months) in the chemotherapeutically treated Group II. This difference did not prove to be statistically significant (p = 0.476).If primary surgical therapy is included in the evaluation, and patients with total abdominal hysterectomy (TAH) and bilateral salpingo-oophorectomy (BSO) are compared to those with additional radical lymphadenectomy (TAH+BSO+lymph nodes), the latter group's overall survival essentially improves but fails to reach statistical significance. Their 5-year survival rate is 83% against 58% in the TAH+BSO group (p = 0.12). CONCLUSION: Chemotherapy and irradiation are two adjuvant therapies that are similarly effective in FTC of Stages I and II, with chemotherapy being preferred at the present time. Primary surgical treatment, however, is of crucial impact on the prognosis of FTC.
Spontaneous pattern formation in an effectively one-dimensional dielectric-barrier discharge system
In a dielectric-barrier discharge between diametrically opposite sides of a narrow tube, discharge filaments stabilize at regular intervals along the tube's length. Three types of periodic patterns are observed, as is a disordered state in which filaments fire at apparently random positions and times. Time-resolved current measurements indicate that for each spatial pattern, a particular number of discharge stages occur during the voltage half-cycle. A preliminary model of the pattern-formation dynamics is described, motivating further work on time-resolved imaging and investigations of surface charge distributions.
The clinical value of serum concentrations of cancer antigen 125 in patients with primary fallopian tube carcinoma: a multicenter study.
BACKGROUND: Primary fallopian tube carcinoma (PFTC) is a rare disease, and data on the serum concentration of tumor marker cancer antigen 125 (CA 125) in patients with this disease are sparse. The authors assessed the clinical value of the serum concentration of CA 125 as a prognostic and monitoring marker in patients with surgically treated PFTC. METHODS: In a multicenter study, the concentration of CA 125 was measured in 406 serum samples from 53 patients with PFTC. The results were correlated with clinical data. RESULTS: The pretreatment median serum CA 125 level was 183 U/mL (range, 6.5-5440.0 U/mL) in patients with PFTC. In a univariate Cox regression model, tumor stage and serum CA 125 level were associated significantly with shortened disease free survival (P = 0.006 and P < 0.001, respectively) and with overall survival (P = 0.03 and P = 0. 001, respectively). Lymph node involvement, tumor grade, and patient age were not associated with the length of survival. A multivariate Cox regression model showed that pretreatment the serum CA 125 level was a prognostic factor of disease free and overall survival, independent of tumor stage (P = 0.005 and P = 0.01, respectively). The pretreatment serum CA 125 level was correlated with tumor stage (P < 0.001) but not with lymph node involvement (P = 0.8), histologic grade (P = 0.3), or patient age (P = 0.2). The serum CA 125 level during chemotherapy was correlated significantly with Gynecologic Oncology Group response criteria to chemotherapy (P = 0. 001). During the follow-up of patients, serum CA 125 levels reached sensitivity, specificity, positive predictive value, and negative predictive value of 92%, 90%, 67%, and 98%, respectively, for differentiating between no evidence of disease and the presence of recurrent disease. In 90% of the patients, an increase of serum CA 125 level preceded the clinical or radiologic diagnosis of recurrent disease with a median lead time of 3 months (range, 0.5-7.0 months). CONCLUSIONS: This is the largest study to date with respect to serum CA 125 levels in patients with PFTC. The current data indicate that the pretreatment serum CA 125 level is an additional independent prognostic factor of disease free and overall survival in patients with PFTC. The serum CA 125 level adequately defines the response to chemotherapy and displays good sensitivity and specificity characteristics during the follow-up of patients with PFTC.
Recombinant viruses as a tool for therapeutic vaccination against human cancers.
Viral vectors can be used to express a variety of genes in vivo, that encode tumor associated antigens, cytokines, or accessory molecules. For vaccination purposes, the ideal viral vector should be safe and enable efficient presentation of expressed antigens to the immune system. It should also exhibit low intrinsic immunogenicity to allow for its re-administration in order to boost relevant specific immune responses. Furthermore, the vector system must meet criteria that enable its industrialization. The characteristics of the most promising viral vectors, including retroviruses, poxviruses, adenoviruses, adeno-associated viruses, herpes simplex viruses, and alphaviruses, will be reviewed in this communication. Such recombinant viruses have been successfully used in animal models as therapeutic cancer vaccines. Based on these encouraging results, a series of clinical studies, reviewed herein, have been undertaken. Human clinical trials, have as of today, allowed investigators to establish that recombinant viruses can be safely used in cancer patients, and that such recombinants can break immune tolerance against tumor-associated antigens. These promising results are now leading to improved immunization protocols associating recombinant viruses with alternate antigen-presentation platforms (prime-boost regimens), in order to elicit broad tumor-specific immune responses (humoral and cellular) against multiple target antigens.
p53 expression in fallopian tube carcinomas.
Sixty-three women treated for primary carcinoma of the fallopian tube (PFTC) from 1980-1995 were retrospectively analyzed to study the impact of p53 expression on survival in primary carcinoma of the fallopian tube. The mean age of the patients was 61.2 years (range 37.3-80.2). Twenty-four (38%) patients were FIGO stage I, 11 (18%) stage II, 19 (30%) stage III and nine (14%) stage IV. Complete radical resection was achieved in 45 (71%) patients. In 56 (89%) women, surgery involved removal of the uterus, the adnexa, and/or the omentum or lymph nodes. Adjuvant therapy consisted of either chemotherapy (n: 31; 49%) or irradiation (n: 21; 33%). The 5-year survival rate for all cases was 43%. For stages I+II and III+IV the 5-year survival rate was 59 and 19%, respectively (P<0.00001). Twelve samples (19%) were p53-negative (tumours with <10% of nuclear staining) and 51 (81%) samples were p53 positive tumours with >10% of nuclear staining. The median survival for the p53-negative group was 40 and 21 months for the p53 positive group. No statistical significance between p53 expression and different FIGO stages was observed, however, a trend for a slightly better survival for the p53-negative group was observed.
Air quality and pediatric emergency room visits for asthma in Atlanta, Georgia, USA.
Pediatric emergency room visits for asthma were studied in relation to air quality indices in a spatio-temporal investigation of approximately 130,000 visits (approximately 6,000 for asthma) to the major emergency care centers in Atlanta, Georgia, during the summers of 1993-1995. Generalized estimating equations, logistic regression, and Bayesian models were fitted to the data. In logistic regression models comparing estimated exposures of asthma cases with those of the nonasthma patients, controlling for temporal and demographic covariates and using residential zip code to link patients to spatially resolved ozone levels, the estimated relative risk per 20 parts per billion (ppb) increase in the maximum 8-hour ozone level was 1.04 (p < 0.05). The estimated relative risk for particulate matter less than or equal to 10 microm in aerodynamic diameter (PM10) was 1.04 per 15 microg/m3 (p < 0.05). Exposure-response trends (p < 0.01) were observed for ozone (>100 ppb vs. <50 ppb: odds ratio = 1.23, p = 0.003) and PM10 (>60 microg/m3 vs. <20 microg/m3: odds ratio = 1.26, p = 0.004). In models with ozone and PM10, both terms became nonsignificant because of collinearity of the variables (r= 0.75). The other analytical approaches yielded consistent findings. This study supports accumulating evidence regarding the relation of air pollution to childhood asthma exacerbation.
From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents on the mutagenic activity of 4-nitrobiphenyl in Salmonella typhimurium. Part I. Substituents ortho to the nitro group and in 2'-position.
Eleven alkyl substituted derivatives of 4-nitrobiphenyl (4NBp) and two corresponding nitroso compounds were synthesised and tested for mutagenic potency in strains TA98 and TA100 of Salmonella typhimurium. The mutagenicity of compounds substituted ortho to the nitro group (3-methyl-, 3-ethyl-, 3-isopropyl-, 3-tertbutyl-, 3, 5-diethyl-, 3,5-diisopropyl-, and 3,5-ditertbutyl-4NBp) decreased with growing steric demand of the alkyl substituents in both tester strains. The most sterically hindered compounds were non-mutagenic even at highest concentrations. This reduction of mutagenicity is correlated with deviations from the coplanar orientation of the nitro group relative to the aromatic plane. Since a comparable decrease of mutagenicity for the nitroso compounds (4NOBp and 3-tertbutyl-4NOBp) was not observed, the first reduction step of non-planar nitro groups must be inhibited. Alkyl groups in the 2'-position of 4NBp (2'-methyl-, 2'-ethyl-, 2'-isopropyl-, and 2',4', 6'-trimethyl-4NBp) also reduced mutagenic activity with increasing size and removed it completely for the most sterically hindered species (2'-isopropyl-, 2',4',6'-trimethyl-4NBp). In this case, the co-planarity of the nitro group is not affected but the twisting of the two aromatic rings, which is associated with a less effective charge delocalisation of the nitrenium ion. The experimental mutagenicities of all nitro compounds were compared to predicted values, that are based on recently developed empirical equations. While there was reasonable correspondence for the parent compound (4NBp), its ortho methylated derivative (3-methyl-4NBp) and two highly hydrophobic dialkylated species (3,5-diisopropyl- and 3, 5-ditertbutyl-4NBp), predictions for all other alkyl substituted compounds were too high. Thus, steric parameters should be included to improve the general validity of predictions by means of quantitative structure-activity relationships (QSAR).
From mutagenic to non-mutagenic nitroarenes: effect of bulky alkyl substituents on the mutagenic activity of nitroaromatics in Salmonella typhimurium. Part II. Substituents far away from the nitro group.
Derivatives of 4-nitrobiphenyl, 4-nitrosobiphenyl, 2-phenyl-5-nitropyridine (2-aza-4-nitrobiphenyl) and 2-nitrofluorene, bearing various alkyl substituents far away from the nitro group (4'-position in nitrobiphenyls, 7-position in 2-nitrofluorenes) were synthesised and tested for mutagenic potency in strains TA98 and TA100 of Salmonella typhimurium. In the absence of S9 in both strains, mutagenicity of all4'-Ad (Ad=adamantyl). Changes of the molecular shape from 'planar' to non-planar caused by the bulk of the introduced substituents (without influencing the twisting of the nitro substituent or the phenyl rings in the biphenyl compounds) may be responsible for this effect by interfering with an efficient intercalation into DNA.A comparison between experimental and theoretical values as calculated from recently developed equations (QSAR) confirmed our previous results (see the preceding paper) that mutagenicity of alkyl-substituted nitroaromatics cannot be predicted by hydrophobicity and LUMO-energies alone without including steric parameters.
Neutron polarization induced by radio frequency radiation
We have measured that an unpolarized ultracold neutron beam gets polarized through its interaction with a resonant radio frequency field. Both spin components pass through the field and end up in one single spin state. We present a simple description for this surprising effect together with first experimental results.
Plasmid DNA encoding the respiratory syncytial virus G protein is a promising vaccine candidate.
Respiratory syncytial virus (RSV) remains a major cause of severe respiratory diseases in infants, young children, and the elderly. However, development of a RSV vaccine has been hampered by the outcome of the infant trials in the 1960s with a formalin-inactivated RSV preparation. Enhanced lung disease was induced by the vaccination post-RSV exposure. Previous studies in mice primed with RSV G protein either formulated in adjuvants or delivered by recombinant vaccinia viruses have indicated that enhanced lung pathology resulted from a Th2-type host immune response against the viral G protein. However, in the present report, we have demonstrated that vaccination with plasmid vectors encoding either a full-length or a secreted G protein (DNA-G) clearly elicited balanced systemic and pulmonary Th1/Th2 cytokine responses in mice and did not induce an atypical pulmonary inflammatory reaction post-RSV challenge in cotton rats. DNA-G immunization also induced marked virus neutralizing antibody responses and protection against RSV infection of the lower respiratory tract of both mice and cotton rats. So far, only genetic immunization has been able to induce a balanced Th1/Th2 response with the RSV G protein, reminiscent of that induced by live RSV. Therefore, DNA-G is a promising immunogen for inclusion in a nucleic acid RSV vaccine.
Switching off and on of synaptic sites at aplysia sensorimotor synapses.
Using the highly plastic synapses between mechanoreceptor sensory neurons and siphon motor neurons of Aplysia as a model, we have investigated whether switching off and on of individual synaptic release sites is a strategy that is used by neurons in forms of short-term synaptic modulation with a time course of minutes to hours. We have modified some of the techniques of classical quantal analysis and examined the kinetics of synaptic depression under different stimulation protocols to answer this question. Our analysis shows that both synaptic depression caused by homosynaptic activity and synaptic facilitation induced by an endogenous facilitatory transmitter occur by means of the shutting off and turning on, respectively, of synaptic sites, without intermediate changes in the probability of release. Our findings imply that other forms of plasticity at these synapses, such as post-tetanic potentiation, long-term facilitation, and long-term potentiation, are also expressed by all-or-none changes in activity at individual sites. We thus show that in addition to the mechanisms of synaptic integration that are known to operate in single cells and networks, neurons can exercise a further layer of fine control, at the level of individual release sites.
Preoperative localization of parathyroid adenoma in patients with concomitant thyroid nodular disease.
We have previously demonstrated the role of high-resolution ultrasonography (US) in preoperative localization of parathyroid adenoma in patients with primary hyperparathyroidism (PHPT) and no thyroid abnormalities. The present study prospectively evaluated the possible additional value of 99mTc-sestamibi (MIBI) in patients with PHPT and concomitant multinodular thyroid disease (MND). Patients with PHPT underwent US and MIBI scintigraphy prior to neck exploration. Imaging data were correlated with the site and pathology of the parathyroid tissue removed and were analyzed separately for patients with MND and those with a normal thyroid gland. Among 77 patients with a solitary parathyroid adenoma at surgery, 40 had concomitant MND, whereas 37 patients had no morphologic changes in the thyroid gland, on US or at surgery. Prior to surgery, MIBI scintigraphy depicted 58 of the 77 adenomas (75%) and US localized 51 (66%): the combined sensitivity was 87% (67/77). Among the 37 patients with no thyroid nodules, MIBI located 29 (78%) and US identified 30 (81%) of the adenomas; the combined sensitivity was 89%. In the 40 patients with MND, MIBI identified 29 adenomas (73%) and US localized only 53% (21/40); the combined sensitivity was 85%. Overall, the positive predictive value (PPV) of MIBI for detecting a solitary parathyroid adenoma was 94%, for US it was 88%, and with the two tests combined it was 97%. In patients with no thyroid abnormalities, the PPV of MIBI and US was 97%, but it decreased to 91% and 78%, respectively, in patients with MND. Two patients with false-positive findings on both MIBI and US had associated thyroid disease. Hence MIBI scintigraphy contributes to localization of a solitary parathyroid adenoma mainly in patients with concomitant MND. The combined MIBI and US modalities result in sparing these patients bilateral neck exploration.
[A rare cause of muscle pain and elevated creatine kinase level--the paroxysmal non-hereditary angioedema].
Systemic capillary leak syndrome is a rare idiopathic disorder characterized by recurrent episodes of hypotension and hemoconcentration due to sudden transient extravasation of up to 70% of plasma. Less than 40 cases have appeared in the literature. Mortality rates 5 years after diagnosis have been reported to be up to 75%. Clinical findings are generalized edema and intravasal fluid deficiency. Laboratory features include hypoalbuminemia and extreme hemoconcentration. A common finding is a monoclonal gammopathy. Rare manifestation of this syndrome is rhabdomyolysis due to increased compartment pressure and ischemic myonecrosis. Early diagnosis and exclusion of other clinical disorders like rheumatic myopathies and myositis are critical concerning prognosis and therapy. We describe a 46-year-old woman with rhabdomyolysis and systemic capillary leak syndrome whose condition is stable for a total of 30 months under a prophylactic regimen with oral terbutaline plus theophylline. A brief survey of the literature is given.
Successful pregnancy and birth after sequential cotreatment with growth hormone and gonadotropins in a woman with panhypopituitarism: a new treatment protocol.
OBJECTIVE: To report a successful pregnancy in a woman with panhypopituitarism who received 3 months of pretreatment with growth hormone (GH) before ovulation induction. Prior attempts at ovulation induction had failed for this patient. DESIGN: Case report. SETTING: Department of Endocrinology. PATIENT(S): A 32-year-old woman with panhypopituitarism and secondary infertility. INTERVENTION(S): GH (1 IU/day) alone for 3 months; during the next cycle, 1 IU/day of GH; 3 ampules of hMG per day during days 1-21; 1 ampule of hCG on day 21. GH was discontinued on day 35 when a pregnancy test was positive. MAIN OUTCOME MEASURE(S): Pregnancy and delivery. RESULTS: Pregnancy and birth of a normal child after a single ovulation stimulation using GH and gonadotropins. CONCLUSION(S): This case report suggests interest in a new protocol for follicular stimulation in women with hypopituitarism who are responding poorly to gonadotropin therapy.
The prevention of sports injuries in children.
With the explosion of the number of youth participating in sports activities has come an epidemic of injuries. Myriad factors make their prevention a great challenge for society. This article presents an overview of statistics, factors contributing to sports injuries, a review of significant prevention efforts, barriers to prevention, and recommendations for the future.
Molecular evidence for genus level diversity of bacteria capable of catalyzing anaerobic ammonium oxidation.
Recently, a bacterium capable to oxidize ammonium anaerobically at a high rate was identified as novel member of the Planctomycetales (Strous, M., Fuersi, J. A., Kramer, E. H. M., Logemann, S., Muyzer, G., van de Pas-Schoonen, K. T., Webb, R. I., Kufnen, J. G., and Jetten, M. S. M.: Nature 400, 446-449, 1999). Here we investigated the microbial community structure of a trickling filter biofilm with a high anaerobic ammonium oxidation activity. Fluorescence in situ hybridization (FISH) with a set of nine probes designed for specific identification of the recently described anaerobic ammonium oxidizer demonstrated that only one probe hybridized to bacteria within the biofilm. For phylogenetic characterization of putative biofilm anaerobic ammonium oxidizers a full-cycle 16S rDNA approach was performed by using a Planctomycetales-specific forward primer for PCR amplification. Of the twenty-five 16S rDNA fragments (1364 bp in length) amplified from the biofilm, nine were affiliated to the Planctomycetales. Comparative analysis showed that these sequences were more than 98.9% similar to each other but only distantly related to the previously recognized anaerobic ammonium oxidizer (below 91% similarity) and all other organisms represented in public 16S rRNA databases (similarities of below 79%). The retrieved sequences and the previously recognized anaerobic ammonium oxidizer represent two well-separated groups of a deep-branching lineage within the Planctomycetales. Quantitative FISH analysis with a newly designed specific probe showed that the novel bacterium, provisionally classified as "Candidatus Kuenenia stuttgartiensis" constituted the dominant fraction of the biofilm bacteria. In situ probing revealed that ammonia-oxidizing bacteria of the beta-subclass of Proteobacteria were also present, albeit in significant smaller amounts, within the anoxic biofilm. Comparative sequence analysis of a stretch of the gene encoding ammonia-monooxygenase (amoA) demonstrated the occurrence of the DNA of at least three different populations of beta-subclass ammonia oxidizers within the biofilm.