Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received αβ T- and B-cell-depleted allografts from ...haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRαβ and anti-CD19 Abs and immunomagnetic microbeads. The γδ T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/μL, >200 CD19+ cells/μL and >200 CD56+ cells/μL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/μL), for CD3+4+ at day +30 (58 vs 11 cells/μL) and for CD56+ at day +14 (622 vs 27 cells/μL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received alpha beta T- and B-cell-depleted ...allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCR alpha beta and anti-CD19 Abs and immunomagnetic microbeads. The gamma delta T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III-IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/ mu L, >200 CD19+ cells/ mu L and >200 CD56+ cells/ mu L for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/ mu L), for CD3+4+ at day +30 (58 vs 11 cells/ mu L) and for CD56+ at day +14 (622 vs 27 cells/ mu L). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial.
Soil quality indicators (SQIs) can be used to evaluate sustainability of land use and soil management practices in agroecosystems. The objective of this study was to identify appropriate SQI from ...factor analysis (FA) of five treatments: no-till corn (
Zee mays) without manure (NT), no-till corn with manure (NTM), no-till corn–soybean (
Glycine max) rotation (NTR), conventional tillage corn (CT), and meadow (M) in Coshocton, Ohio. Soil properties were grouped into five factors (eigenvalues
>
1) for the 0–10
cm depth as: (Factor 1) water transmission, (Factor 2) soil aeration, (Factor 3) soil pore connection 1, (Factor 4) soil texture and (Factor 5) moisture status. Factor 2 was the most dominant, with soil organic carbon (SOC) the most dominant measured soil attribute contributing to this factor. For the 10–20
cm depth, factors identified were: (Factor 6) soil aggregation, (Factor 7) soil pore connection 2, (Factor 8) soil macropore, and (Factor 9) plant production. At 10–20
cm depth, Factor 6 was most dominant with SOC the most dominant measured soil attribute. Management
×
sample and slope position
×
sample interactions were significant among some factors for both depths. Overall, SOC was the most dominant measured soil attribute as a SQI for both depths. Other key soil attributes were field water capacity, air-filled porosity, pH and soil bulk density for the 0–10
cm depth, and total N and mean weight diameter of aggregates for the 10–20 depth. Therefore, SOC could play an important role for monitoring soil quality.
Determining soil carbon (C) with high precision is an essential requisite for the success of the terrestrial C sequestration program. The informed choice of management practices for different ...terrestrial ecosystems rests upon accurately measuring the potential for C sequestration. Numerous methods are available for assessing soil C. Chemical analysis of field-collected samples using a dry combustion method is regarded as the standard method. However, conventional sampling of soil and their subsequent chemical analysis is expensive and time consuming. Furthermore, these methods are not sufficiently sensitive to identify small changes over time in response to alterations in management practices or changes in land use. Presently, several different in situ analytic methods are being developed purportedly offering increased accuracy, precision and cost-effectiveness over traditional ex situ methods. We consider that, at this stage, a comparative discussion of different soil C determination methods will improve the understanding needed to develop a standard protocol.
Identifying drivers of contact rates among individuals is critical to understanding disease dynamics and implementing targeted control measures. We studied the interaction patterns of 149 female elk ...(
Cervus canadensis
) distributed across five different regions of western Wyoming over three years, defining a contact as an approach within one body length (∼2 m). Using hierarchical models that account for correlations within individuals, pairs, and groups, we found that pairwise contact rates within a group declined by a factor of three as group sizes increased 33-fold. Per capita contact rates, however, increased with group size according to a power function, such that female elk contact rates fell in between the predictions of density- or frequency-dependent disease models. We found similar patterns for the duration of contacts. Our results suggest that larger elk groups are likely to play a disproportionate role in the disease dynamics of directly transmitted infections in elk. Supplemental feeding of elk had a limited impact on pairwise interaction rates and durations, but per capita rates were more than two times higher on feeding grounds. Our statistical approach decomposes the variation in contact rate into individual, dyadic, and environmental effects, and provides insight into factors that may be targeted by disease control programs. In particular, female elk contact patterns were driven more by environmental factors such as group size than by either individual or dyad effects.
Langerhans cell histiocytosis (LCH) is a clonal histiocytic disorder with recurrent mutations of
BRAF
and
MAP2K1
, but data on the impact of genetic features on progression and long-term sequelae are ...sparse. Cases of pediatric LCH with long-term follow-up from our institution were analyzed for mutations in
BRAF
V600
and
MAP2K1
exons 2 and 3 by immunostaining with mutation-specific VE1 antibody, as well as allele-specific PCR and sequencing, respectively. Clinical and follow-up data were obtained from our files and a questionnaire sent to all former patients. Sixteen of 37 (43%) evaluable cases showed
BRAF
V600E
, one case a
BRAF
V600D
and eleven (30%) a
MAP2K1
mutation. Nine cases were unmutated for both genes. All cases with risk organ involvement showed either
BRAF
V600
or
MAP2K1
mutation. Patients with
BRAF
V600
mutation excluding Hashimoto-Pritzker cases had a significantly higher risk for relapses (
p
= 0.02). Long-term sequelae were present in 19/46 (41%) patients (median follow-up 12.5 years, range 1.0 to 30.8) with a trend for higher rates in mutated cases (mutated = 9/17, 53% versus non-
BRAF
V600
/
MAP2K1
mutated = 2/7, 29%). In addition, 8/9 cases with skin involvement including all Hashimoto-Pritzker cases (
n
= 3) were positive for
BRAF
V600E
. Infants below 2 years more frequently had
BRAF
V600
mutations (
p
= 0.013). Despite favorable prognosis, pediatric LCH shows a high frequency of relapses and long-term medical sequelae.
Background
An increasing fraction of gastric cancer patients present with distant metastases at diagnosis. The objective of the present 11-year population-based trend analysis was to assess the ...survival rates in patients who underwent and in patients who did not undergo palliative gastrectomy.
Methods
Patients with metastatic gastric cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database between 1998 and 2009. Time trend and impact of palliative gastrectomy on survival were assessed by both a multivariate Cox proportional hazards model and propensity score matching.
Results
We identified 8249 patients with stage IV gastric cancer. The rate of metastatic disease increased from 31.0 % in 1998 to 37.5 % in 2009 (
P
< 0.001). The palliative gastrectomy rate dropped from 18.8 to 10.2 % (
P
= 0.004). The median survival for patients who underwent palliative gastrectomy (
N
= 1445, 17.4 %) and for patients who did not undergo palliative gastrectomy (
N
= 6804, 82.4 %) was 7 and 3 months, respectively. There was an increase in median overall survival from 2 months (1998) to 3 months (2009) in the no-gastrectomy group, and from 6.5 to 8 months in the gastrectomy group. The 3-year cancer-specific survival rates were 2.1 % (95 % confidence interval 1.7–2.5 %) for patients who did not undergo palliative gastrectomy and 9.4 % (95 % confidence interval 7.8–11.2 %) for patients who underwent palliative gastrectomy (
P
< 0.001). Palliative gastrectomy was associated with an increased cancer-specific survival in propensity-score-adjusted Cox regression analyses (hazard ratio 0.50, 95 % confidence interval 0.46–0.55,
P
< 0.001).
Conclusion
On a population-based level, only modest improvements in prognosis for metastatic gastric cancer were observed in patients who underwent and in patients who did not undergo palliative gastrectomy. Considering the low rate of midterm survivors in both groups, only a small subgroup of patients benefits from palliative gastrectomy.
Hyperintense vessels on baseline FLAIR MR imaging of patients with ischemic stroke have been linked to leptomeningeal collateralization, yet the ability of these to maintain viable ischemic tissue ...remains unclear. We investigated whether hyperintense vessels on FLAIR are associated with the severity of hypoperfusion and response to thrombolysis in patients treated with intravenous tissue-plasminogen activator.
Consecutive patients with ischemic stroke with an MR imaging before and within 24 hours of treatment, with proved vessel occlusion and available time-to-maximum maps were included (n = 62). The severity of hypoperfusion was characterized on the basis of the hypoperfusion intensity ratio (volume with severe/mild hypoperfusion time-to-maximum ≥ 8 seconds / time-to-maximum ≥ 2 seconds). The hypoperfusion intensity ratio was dichotomized at the median to differentiate moderate (hypoperfusion intensity ratio ≤ 0.447) and severe (hypoperfusion intensity ratio > 0.447) hypoperfusion. Good outcome was defined as a modified Rankin Scale score of ≤2.
Hyperintense vessels on FLAIR were identified in 54 patients (87%). Patients with extensive hyperintense vessels on FLAIR (>4 sections) had higher NIHSS scores, larger baseline lesion volumes, higher rates of perfusion-diffusion mismatch, and more severe hypoperfusion (hypoperfusion intensity ratio). In stepwise backward multivariate regression analysis for the dichotomized hypoperfusion intensity ratio (including stroke etiology, age, perfusion deficit, baseline lesion volume, smoking, and extent of hyperintense vessels on FLAIR), extensive hyperintense vessels on FLAIR were independently associated with severe hypoperfusion (OR, 6.8; 95% CI, 1.1-42.7; P = .04). The hypoperfusion intensity ratio was an independent predictor of a worse functional outcome at 3 months poststroke (OR, 0.2; 95% CI, 0.5-0.6; P < .01).
Hyperintense vessels on FLAIR are associated with larger perfusion deficits, larger infarct growth, and more severe hypoperfusion, suggesting that hyperintense vessels on FLAIR most likely indicate severe ischemia as a result of insufficient collateralization.
The basic science and clinical use of morphine and other “opioid” drugs are based almost exclusively on the extracts or analogues of compounds isolated from a single source, the opium poppy (Papaver ...somniferum). However, it now appears that biological diversity has evolved an alternative source. Specifically, at least two alkaloids isolated from the plant Mitragyna speciosa, mitragynine ((E)-2-(2S,3S)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo3,2-hquinolizin-2-yl-3-methoxyprop-2-enoic acid methyl ester; 9-methoxy coryantheidine; MG) and 7-hydroxymitragynine (7-OH-MG), and several synthetic analogues of these natural products display centrally mediated (supraspinal and spinal) antinociceptive (analgesic) activity in various pain models. Several characteristics of these compounds suggest a classic “opioid” mechanism of action: nanomolar affinity for opioid receptors, competitive interaction with the opioid receptor antagonist naloxone, and two-way analgesic cross-tolerance with morphine. However, other characteristics of the compounds suggest novelty, particularly chemical structure and possible greater separation from side effects. We review the chemical and pharmacological properties of these compounds.
PDF
