Biomedical subjects

S A Klein

Publications and source records attributed to S A Klein.

At least 19 recordsLinked to original sources

PubMed2006

Forced and unforced ocean temperature changes in Atlantic and Pacific tropical cyclogenesis regions.

Previous research has identified links between changes in sea surface temperature (SST) and hurricane intensity. We use climate models to study the possible causes of SST changes in Atlantic and Pacific tropical cyclogenesis regions. The observed SST increases in these regions range from 0.32 degrees C to 0.67 degrees C over the 20th century. The 22 climate models examined here suggest that century-timescale SST changes of this magnitude cannot be explained solely by unforced variability of the climate system. We employ model simulations of natural internal variability to make probabilistic estimates of the contribution of external forcing to observed SST changes. For the period 1906-2005, we find an 84% chance that external forcing explains at least 67% of observed SST increases in the two tropical cyclogenesis regions. Model "20th-century" simulations, with external forcing by combined anthropogenic and natural factors, are generally capable of replicating observed SST increases. In experiments in which forcing factors are varied individually rather than jointly, human-caused changes in greenhouse gases are the main driver of the 20th-century SST increases in both tropical cyclogenesis regions.

Atlantic Ocean↗

PubMed2005

Amplification of surface temperature trends and variability in the tropical atmosphere.

The month-to-month variability of tropical temperatures is larger in the troposphere than at Earth's surface. This amplification behavior is similar in a range of observations and climate model simulations and is consistent with basic theory. On multidecadal time scales, tropospheric amplification of surface warming is a robust feature of model simulations, but it occurs in only one observational data set. Other observations show weak, or even negative, amplification. These results suggest either that different physical mechanisms control amplification processes on monthly and decadal time scales, and models fail to capture such behavior; or (more plausibly) that residual errors in several observational data sets used here affect their representation of long-term trends.

Journal Article↗

PubMed2004

Is hydroxyapatite cement an alternative for allograft bone chips in bone grafting procedures? A mechanical and histological study in a rabbit cancellous bone defect model.

To evaluate in vivo performance of hydroxyapatite cement (HAC) as a porous bone graft substitute, HAC was mixed (1:1 ratio) with either porous calcium-phosphate granules (80% tricalcium phosphate, 20% hydroxyapatite) or defatted morsellized cancellous bone (MCB) allograft and implanted bilaterally in cylindrical drill holes in distal femurs of rabbits. Groups with empty defects and impacted MCB were used for reference. After 8 weeks, one femur from each pair was examined histologically. All contralateral specimens and Time-0 specimens were used for mechanical indentation tests. Histology showed that some empty defects were filled with newly formed osteopenic bone after 8 weeks. The impacted MCB showed remodeling into new vital bone. Incorporation of the HAC/MCB composite was incomplete, whereas minimal new bone ingrowth was found in the HAC/granule composites. Though not different from each other, both composites were significantly stronger than empty defects, incorporated impacted MCB, and intact cancellous bone. At Time 0, the mechanical behavior of impacted MCB was similar to both HAC composites. In conclusion, composites of HAC and porous biomaterials can maintain relatively high strength over 8 weeks in vivo, but their incorporation into a new bony structure is slower than impacted MCB. The HAC/MCB composite showed favorable incorporation behavior.

Animals↗

PubMed2003

Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia: disease status by marrow blasts is the strongest prognostic factor.

We analyzed predictive factors for the outcome of 113 acute myeloid leukemia patients receiving reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation (HSCT). Patients were ineligible for conventional-intensity HSCT. Conditioning consisted of fludarabine and 50% of the conventional dose of busulfan (n=93) or total body irradiation (n=20). The source of stem cells was blood in 102 patients, marrow in 10, and both in one. In total, 50 (44.2%) donors were HLA-matched siblings, 50 (44.2%) unrelated fully matched and 13 (11.5%) partially mismatched family (n=1) or unrelated (n=12) donors. In all, 107 (94.6%) patients showed neutrophil and platelet engraftment after a median time of 13.5 and 13 days. The probabilities of event-free survival (EFS) (median follow-up: 12 months) were 49% for patients with less than 5% blasts in the marrow, 24% for patients with 5-20% blasts (P=0.002) and 14% with >20% blasts (P<or=0.001). Death occurred because of relapse in 29 patients (25.6%), infection in 12 patients (10.6%), acute graft-versus-host disease in eight patients (7.0%) and organ toxicity in nine patients (7.9%). In multivariate analysis, higher number of blasts in the marrow, alternative donors and low Karnofsky performance score were independent adverse prognostic factors for EFS.

Adolescent↗

PubMed2002

Prednisolone induces interleukin-18 expression in mononuclear blood and myeloid progenitor cells.

OBJECTIVE: Interleukin (IL)-18 is involved in host defense mechanisms and inflammatory diseases, among them rheumatoid arthritis (RA). High levels of IL-18 expression in RA joints are contrasted by reduced IL-18 expression in RA peripheral blood mononuclear cells (PBMC). Here, we investigated a putative IL-18 regulating role of corticosteroids. METHODS: IL-18 transcript and protein levels in PBMC from untreated and prednisolone treated RA patients, and from healthy donors were assessed by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting. IL-18 regulation was determined in PBMC and U937 cells upon exposure to prednisolone in vitro by RT-PCR and Northern Blot analysis, by ELISA in cell culture supernatants, and in transiently transfected THP-1 cells by IL-18 promoter activity luciferase assays. RESULTS: In RA PBMC, IL-18 transcript levels were dose dependently restored, in parallel with administered prednisolone treatment, to subnormal levels. The corresponding intracellular IL-18 deposits in contrast were depleted. In cultured PBMC and promonocytic cell lines, prednisolone up-regulated IL-18 transcription in parallel with increasing the IL- 18 protein release into cell culture supernatants. CONCLUSION: Prednisolone increases IL-18 expression and release in PBMC and monocytic cell lines.

Adult↗

PubMed2002

Therapy with imatinib mesylate (Glivec) preceding allogeneic stem cell transplantation (SCT) in relapsed or refractory Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL).

Imatinib has pronounced antileukemic activity in Ph+ALL, although responses are usually short. To determine whether imatinib may facilitate allogeneic SCT in relapsed or refractory Ph+ALL, we evaluated 46 consecutive, not previously transplanted patients who were enrolled in phase II studies of imatinib. Of 30 patients eligible for SCT, 22 (73%) were actually transplanted. Ten patients were in complete hematologic remission (CHR) (n = 5) or had a complete marrow response (CMR) (n = 5) at the time of SCT, 12 patients had again relapsed or were refractory. After SCT, 18 patients were in complete remission, one patient was refractory, three patients died prior to response assessment. Seven patients (32%) are in ongoing complete remission with a median follow-up of 9.4 (range 1.7-23.8) months. Seven patients (32%) relapsed a median of 5.2 months after SCT. Transplant-related mortality (TRM) was 36%. Probability of disease-free survival (DFS) is 25.5 +/- 9.8% overall and 51.4 +/- 17.7% when SCT was performed in CHR or CMR, compared with 8.3 +/- 8% for SCT during overt leukemia (P = 0.06). In conclusion, imatinib is a well-tolerated salvage therapy prior to allogeneic SCT in patients with Ph+ALL, but requires that SCT be performed within a few weeks of starting treatment to avoid resistance. Disease status at time of transplantation is an important determinant of DFS and TRM.

Adolescent↗

PubMed2001

TNP-470 reduces collagen and macrophage accumulation in expanded polytetrafluoroethylene tube implants.

BACKGROUND: TNP-470 is a potent angiogenic inhibitor that has been demonstrated to decrease the rate of cutaneous wound healing. This study investigated the effect that TNP-470 has upon collagen growth and macrophage infiltration into expanded polytetrafluoroethylene (e-PTFE) tube implants. METHODS: e-PTFE tubes (1.0 cm in length) were implanted into the dorsum of male Swiss-Webster mice (8-10 weeks old). TNP-470 was administered subcutaneously in doses of 0.5, 1.0, or 5.0 mg/kg for determination of hydroxyproline accumulation on day 18 after implantation. Additionally, TNP-470 was administered at 5.0 mg/kg for determination of macrophage infiltration on days 4, 8, 13, and 18 after implantation. RESULTS: Administration of TNP-470 at doses of 1.0 and 5.0 mg/kg on days 0, 2, and 4 significantly (P < 0.05) decreased hydroxyproline accumulation in e-PTFE implants on day 18 after implantation. Administration of 0.5 mg/kg of TNP-470 yielded no significant difference vs the vehicle control (P < 0.81). Additionally, administration of TNP-470 at 5.0 mg/kg on days 0, 2, and 4 significantly (P < 0.05) decreased macrophage infiltration into e-PTFE implants on day 4 after implantation. There was also a significantly (P < 0.05) increased percentage of macrophages in the e-PTFE implants on day 13 after wounding. No significant differences were observed between the experimental and control groups on days 8 and 18. CONCLUSIONS: Administration of TNP-470 significantly decreases hydroxyproline accumulation in e-PTFE implants. These data suggest that while TNP-470 is administered, macrophage infiltration is impaired; however, upon discontinuing administration, macrophage infiltration increases. Possible mechanisms to account for these findings are discussed.

Angiogenesis Inhibitors↗

PubMed2001

Antenatal steroids and neonatal periventricular leukomalacia.

OBJECTIVE: To evaluate the effect of antenatal steroid treatment on the development of neonatal periventricular leukomalacia. METHODS: This retrospective cohort study included 1161 neonates with gestational ages of 24-34 weeks and birth weights of 500-1750 g, divided into two groups on the basis of antenatal steroid treatment. Neonatal neurosonograms were done on days 3 and 7 of life and labeled normal or abnormal. The abnormal outcomes evaluated were periventricular leukomalacia or intraventricular hemorrhage, periventricular leukomalacia with intraventricular hemorrhage, and isolated periventricular leukomalacia. The group treated with antenatal steroids was compared with the untreated group for these outcomes. RESULTS: Antenatal steroids were associated with significantly less periventricular leukomalacia or intraventricular hemorrhage (23% versus 31%, P =.005), periventricular leukomalacia with intraventricular hemorrhage (5% versus 11%, P =.001), and isolated periventricular leukomalacia (3% versus 7%, P =.009). Logistic regression analysis of antenatal steroid treatment, controlling for confounding maternal and neonatal characteristics, indicated that neonates treated with antenatal steroids had a 56% lower likelihood of periventricular leukomalacia with intraventricular hemorrhage (adjusted odds ratio [OR] 0.44, 95% confidence interval [CI] 0.25, 0.77) and a 58% lower likelihood of isolated periventricular leukomalacia (adjusted OR 0.42, 95% CI 0.20, 0.88). CONCLUSION: Antenatal steroid treatment was associated with over 50% reduction in the incidence of periventricular leukomalacia in preterm neonates. Increased use of antenatal steroid therapy might improve long-term neonatal neurologic outcomes.

Betamethasone↗

PubMed2001

Electrophysiological estimate of human cortical magnification.

OBJECTIVE: The cortical magnification factor characterizes the area of human primary visual cortex activated by a stimulus as a function of angular distance from an observer's line of sight. This study estimates human cortical magnification using an electrophysiological method with excellent temporal resolution: visual evoked potential (VEP) dipole source localization. METHODS: For each of 60 independently modulated checkerboard patches within the central 18 deg of the visual field, location, orientation, magnitude, and time-course of the dipole current source that best described the VEP distribution across a multi-electrode array was obtained. At numerous eccentricities, cortical magnification was determined using two different techniques: (1) the distance between each pair of adjacent stimulus patches was matched to the corresponding distance between adjacent cortical sources; and (2) the area of each stimulus patch was matched to the magnitude of the corresponding cortical source (which was assumed to be proportional to cortical area). RESULTS: The estimates of human cortical magnification using our electrophysiological method were similar to previous estimates from psychophysics, cortical stimulation, and functional magnetic resonance imaging. CONCLUSIONS: The concordance of results provided by these disparate technologies, with differing spatial and temporal limitations, supports their combination in studying the spatio-temporal dynamics of human brain function.

Adult↗

PubMed2001

Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation.

We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT).

Antineoplastic Agents↗

PubMed2001

Older patients with high-risk fungal infections can be successfully allografted using non-myeloablative conditioning in combination with intensified supportive care regimens.

Leukaemic patients with advanced disease and severe fungal infections as well as older patients with substantial co-morbidity are usually excluded from conventional allotransplantation because of increased morbidity and mortality. We approached allogeneic transplantation in four patients with a median age of 62 years (one chronic myeloid leukaemia in blast crisis, one high-risk acute myeloid leukaemia (AML) in first complete remission (CR1), one AML in 2nd relapse, one AML in CR2 with pre-existing fungal lung infections (two aspergillus, two mucor) and additional co-morbidity (diabetes n = 2, aortic aneurysm n = 1, arterial sclerosis n = 2) by combining non-myeloablative conditioning with an intensified supportive care regimen, including amphotericin B and 4-12 (median 9) prophylactic granulocyte transfusions from granulocyte colony-stimulating factor (G-CSF)-stimulated volunteer donors. G-CSF was also given to patients until neutrophil recovery. All four patients recovered to a neutrophil count of 0.5 x 109/l after a median of 11.5 d (range 11-13 d). Prophylactic granulocyte transfusions also reduced the need for platelet transfusions and minimized mucositis. All patients were discharged at a median of 25 d (range 18-59 d) and are alive and well after a median follow-up of > 390 d (range 336-417 d) without evidence of leukaemia. Regression of the fungal lesions was documented in three patients, with a slight progression detected by computerized tomography scan of the chest in one patient. We conclude that pulmonary fungal infections are not a contraindication for allogeneic stem cell transplantation, if non-myeloablative conditioning regimens are used in combination with granulocyte transfusions, intravenous amphotericin B and G-CSF.

Acute Disease↗

PubMed2001

A new approach to evaluating intestinal acute graft-versus-host disease by transabdominal sonography and colour Doppler imaging.

An objective and non-invasive method to assess the extent, severity, course and prognosis of acute graft-versus-host disease (aGvHD) of the gastrointestinal tract would be of great importance. As high-resolution ultrasonography (HRU) and colour Doppler imaging (CDI) are used in inflammatory and ischaemic bowel diseases, we introduced these techniques to evaluate acute intestinal GvHD. In this study, 12 patients with suspected intestinal and/or severe cutaneous aGvHD were investigated by HRU and CDI. The structure and thickness of the bowel wall and the blood flow pattern in the superior mesenteric artery (SMA) as well as in the bowel wall were evaluated. All patients showed thickened bowel wall segments, especially in the ileocaecal region. Even in patients without any clinical signs of intestinal involvement (3/12), sonographic changes were observed. In six patients with severe diarrhoea, sonographic signs of secretory diarrhoea were observed. In 4/12 patients, an increased arterial blood flow in the bowel wall was demonstrated as a typical characteristic of an inflammatory bowel process. In contrast, in 4/12 patients, ischaemic bowel wall lesions with high-resistance flow pattern in the SMA were found. These patients did not respond to immunosuppressive therapy and died. In conclusion, HRU is a useful tool for detecting acute bowel GvHD even before clinical symptoms. Moreover, HRU and CDI can be applied to define the severity of aGvHD and to identify patients with a poor prognosis.

Acute Disease↗

PubMed2001

Surround modulation of perceived contrast and the role of brightness induction.

We studied iso- and cross-orientation surround modulation of perceived contrast (contrast-contrast phenomenon) with a contrast-matching method. Our results indicate (1) iso-oriented surrounds at all contrasts suppress perceived contrast of the test pattern. Cross-orientation surrounds, however, tend to enhance the perceived contrast of the test, particularly for high-contrast test patterns. Iso-orientation modulation acts over larger distances than does cross-orientation modulation. Surround modulation of perceived contrast is not accompanied by a simultaneous change of discrimination threshold. (2) Iso-orientation surround suppression is phase insensitive when brightness induction due to local luminance contrast is eliminated by a small center-surround gap. (3) Perceived contrast is similarly affected when the surround spatial frequency is equal to or higher than the center spatial frequency, but lower spatial frequency surrounds markedly enhance perceived contrast as a result of brightness induction. These data indicate that the contrast-contrast phenomenon is often mixed with brightness induction when it is measured with sinusoidal grating stimuli, and we suggest that this may account for some of the individual differences. After excluding the role of brightness induction, surround modulation of perceived contrast appears to be a second-order process that is phase independent and not tuned or very broadly tuned to spatial frequency.

Contrast Sensitivity↗

PubMed2001

Measuring, estimating, and understanding the psychometric function: a commentary.

The psychometric function, relating the subject's response to the physical stimulus, is fundamental to psychophysics. This paper examines various psychometric function topics, many inspired by this special symposium issue of Perception & Psychophysics: What are the relative merits of objective yes/no versus forced choice tasks (including threshold variance)? What are the relative merits of adaptive versus constant stimuli methods? What are the relative merits of likelihood versus up-down staircase adaptive methods? Is 2AFC free of substantial bias? Is there no efficient adaptive method for objective yes/no tasks? Should adaptive methods aim for 90% correct? Can adding more responses to forced choice and objective yes/no tasks reduce the threshold variance? What is the best way to deal with lapses? How is the Weibull function intimately related to the d' function? What causes bias in the likelihood goodness-of-fit? What causes bias in slope estimates from adaptive methods? How good are nonparametric methods for estimating psychometric function parameters? Of what value is the psychometric function slope? How are various psychometric functions related to each other? The resolution of many of these issues is surprising.

Bias↗

PubMed2000

Interaction of angiogenesis inhibitor TNP-470 with basic fibroblast growth factor receptors.

TNP-470 is a synthetic analogue of fumagillin that acts as a potent angiogenesis inhibitor. Recently, our laboratory demonstrated that systemic administration of TNP-470 (5.0 mg/kg) decreased the rate of cutaneous wound healing by greater than 20%. In this study, we tested the hypothesis that TNP-470 interferes with the wound repair-stimulating action of basic fibroblast growth factor (bFGF) by competing with endogenous bFGF for its binding sites on the receptor protein. The influence of TNP-470 was examined in vitro in a ligand competition assay of high- and low-affinity receptor binding to (125)I-bFGF in NIH/3T3 cells. Results demonstrated that recognition of (125)I-bFGF by low-affinity growth factor binding sites was significantly decreased (P < 0.01) in the presence of TNP-470. However, TNP-470 inhibition of radiolabeled bFGF binding to high-affinity sites was not significantly affected (P = 0.07). In view of recent studies demonstrating that the low-affinity receptors of bFGF were heparan sulfate proteoglycans, we suggest that the influence of TNP-470 on diminished wound healing is due to its direct recognition by these molecules.

3T3 Cells↗

PubMed2000

Detecting disorder in spatial vision.

In normal foveal vision, visual space is accurately mapped from retina to cortex. However, the normal periphery, and the central field of strabismic amblyopes have elevated position discrimination thresholds, which have often been ascribed to increased 'intrinsic' spatial disorder. In the present study we evaluated the sensitivity of the human visual system (both normal and amblyopic) to spatial disorder, and asked whether there is increased 'intrinsic' topographical disorder in the amblyopic visual system. Specifically, we measured thresholds for detecting disorder (two-dimensional Gaussian position perturbations) either in a horizontal string of N equally spaced samples (Gabor patches), or in a ring of equally spaced samples over a wide range of feature separations. We also estimated both the 'equivalent intrinsic spatial disorder' and sampling efficiency using an equivalent noise approach. Our results suggest that both thresholds for detecting disorder, and equivalent intrinsic disorder depend strongly on separation, and are modestly increased in strabismic amblyopes. Strabismic amblyopes also show markedly reduced sampling efficiency. However, neither amblyopic nor peripheral vision performs like ideal or human observers with added separation-independent positional noise. Rather, the strong separation dependence suggests that the 'equivalent intrinsic disorder' may not reflect topographic disorder at all, but rather may reflect an abnormality in the amblyopes' Weber relationship.

Adolescent↗

PubMed2000

Seeing circles: what limits shape perception?

Humans are remarkably adept at judging shapes and discriminating forms. Forms and shapes are initially sampled by discrete localized visual filters (or receptive fields) in 'early' stages of visual processing. However, more complex higher level filters which integrate or pool information from many local filters may be needed to discern shapes. In order to understand the mechanisms that limit shape perception we asked observers to detect distortions in the shape of briefly presented circles constructed out of samples (Gabor patches, which are well matched to the early visual filters), and varied the radius of the circle, and the number and orientation of the samples. Our results show that shape perception is determined by two factors: the primary determinant is the separation between the samples; however, the orientation of the samples can modulate performance. At small separations, performance is best when the samples are aligned with the global shape, poorer when they are orthogonal, and intermediate when they are all horizontal or vertical. At larger separations these contextual differences disappear; however at all separations, performance is reduced when the orientations of the samples are mixed (i.e. each sample is randomly either aligned or orthogonal, or randomly either horizontal or vertical.). These results suggest an important role for sample separation in shape perception for sampled shapes and suggest that the mechanisms involved in feature binding may modulate the responses of the mechanisms underlying shape perception.

Form Perception↗

PubMed2000

Unmasking the mechanisms for Vernier acuity: evidence for a template model for Vernier acuity.

The goal of this study was to evaluate the mechanisms underlying Vernier acuity, over a range of spatial scales using narrow-band Vernier stimuli and oblique masking. Specifically, the test stimuli consisted of a pair of vertical ribbons of horizontal cosine grating with a vertical Vernier offset between the ribbons. These stimuli have two important advantages for studying Vernier acuity: (1) they are relatively well localized in vertical spatial frequency, and (2) they are localized in their horizontal extent (width). We measured the orientation, spatial frequency and width tuning of Vernier acuity over a wide range of ribbon spatial frequencies, using a simultaneous oblique masking paradigm. Our masking results suggest that the mechanisms underlying Vernier acuity are tuned to the orientation, spatial frequency and width of the ribbon stimuli. The peak of the bimodal orientation tuning function varies systematically with the spatial frequency of the ribbon. The peak of the spatial frequency tuning function varies systematically with both the ribbon spatial frequency, and the ribbon width (i.e. the grating length). A 'template' model, in which the 'mechanism' is a windowed version of the stimulus is able to account for many features of the data, including results which cannot be easily accounted for by standard multi-scale filter models. Specifically, the template model can account for: (i) the bimodal orientation tuning function, (ii) the systematic variation in the peak of the orientation and spatial frequency tuning functions with spatial frequency, and (iii) the systematic effect of ribbon width on spatial frequency tuning.

Contrast Sensitivity↗