Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.Leukemia advance online publication, 20 November 2015; doi:10.1038/leu.2015.281.

Long-term results of endoscopic third ventriculostomy: an outcome analysis.

OBJECT Endoscopic third ventriculostomy (ETV) is the procedure of choice in the treatment of obstructive hydrocephalus. The excellent clinical and radiological success rates are well known. Nevertheless, very few papers have addressed the very long term outcomes of the procedure in very large series. The authors present a large case series of 113 patients who underwent 126 ETVs, and they highlight the initial postoperative outcome after 3 months and long-term follow-up with an average of 7 years. METHODS All patients who underwent ETV at the Department of Neurosurgery, Mainz University Hospital, between 1993 and 1999 were evaluated. Obstructive hydrocephalus was the causative pathology in all cases. RESULTS The initial clinical success rate was 82% and decreased slightly to 78% during long-term follow-up. Long-term success was analyzed using Kaplan-Meier curves. Overall, ETV failed in 31 patients. These patients underwent a second ETV or shunt treatment. A positive impact on long-term success was seen for age older than 6 months, and for obstruction due to cysts or benign aqueductal stenosis. The complication rate was 9% with 5 intraoperative and 5 postoperative events. CONCLUSIONS The high clinical success rate in short-term and long-term follow-up confirms ETV's status as the gold standard for the treatment of obstructive hydrocephalus, especially for distinct pathologies. The patient's age and underlying pathology may influence the outcome. These factors should be considered carefully preoperatively by the surgeon.

Long-distance transport of alkali metals in maturing wheat

The alkali metals cesium, rubidium, lithium and sodium were introduced together with strontium via flaps into leaf laminas or into the stem of maturing, intact winter wheat (Triticum aestivum L. cv. Arina) grown in a field. Long-distance transport of these elements and the influence of the application date and of different application positions were investigated. The phloem-immobile Sr served as a marker for the distribution of the xylem sap in the plants. Dry matter accumulation in the grains and the transpiration per shoot were not markedly affected by the treatments as compared to control plants. The phloem mobility was rather high for Cs and Rb. Li was almost immobile in the phloem (similarly to Sr). An application into the cut stem xylem below the second leaf node contributed more to the contents in the grains than an application into the flag leaf. An earlier feeding date led to a higher accumulation in the grains. The marked losses of the elements applied during maturation (most pronounced for Li) can be explained by leakage in the rain.

Hit-and-run trophallaxis of small hive beetles

Some parasites of social insects are able to exploit the exchange of food between nestmates via trophallaxis, because they are chemically disguised as nestmates. However, a few parasites succeed in trophallactic solicitation although they are attacked by workers. The underlying mechanisms are not well understood. The small hive beetle (=SHB), Aethina tumida, is such a parasite of honey bee, Apis mellifera, colonies and is able to induce trophallaxis. Here, we investigate whether SHB trophallactic solicitation is innate and affected by sex and experience. We quantified characteristics of the trophallactic solicitation in SHBs from laboratory-reared individuals that were either bee-naïve or had 5 days experience. The data clearly show that SHB trophallactic solicitation is innate and further suggest that it can be influenced by both experience and sex. Inexperienced SHB males begged more often than any of the other groups had longer breaks than their experienced counterparts and a longer soliciting duration than both experienced SHB males and females, suggesting that they start rather slowly and gain more from experience. Successful experienced females and males were not significantly different from each other in relation to successful trophallactic interactions, but had a significantly shorter soliciting duration compared to all other groups, except successful inexperienced females. Trophallactic solicitation success, feeding duration and begging duration were not significantly affected by either SHB sex or experience, supporting the notion that these behaviors are important for survival in host colonies. Overall, success seems to be governed by quality rather than quantity of interactions, thereby probably limiting both SHB energy investment and chance of injury (<1%). Trophallactic solicitation by SHBs is a singular example for an alternative strategy to exploit insect societies without requiring chemical disguise. Hit-and-run trophallaxis is an attractive test system to get an insight into trophallaxis in the social insects.

Long-distance transport of cobalt and nickel in maturing wheat

Cobalt, nickel and strontium were introduced via flaps into leaf laminas or into the stem of maturing, intact winter wheat (Triticum aestivum L., cv. `Arina') grown under natural conditions in a field. Long-distance transport of these elements and the influence of the application date and of different application positions were investigated. The dry-matter accumulation in the grains was not markedly affected by the treatments as compared to untreated control plants. The phloem-immobile strontium served as a marker for the distribution of the xylem sap in the plants. After foliar application, nickel accumulated more rapidly and in higher quantities in the grains than cobalt. Therefore, nickel has a slightly better phloem mobility than cobalt. Regardless of the application date, a higher percentage of the two elements was transported from the flag leaf lamina than from the second or third lamina from the top to the grains. These results indicate that the leaf position is highly relevant for the transfer of the heavy metals investigated to the ear. Introduction into the stem led to a higher accumulation of nickel and cobalt in the grains than introduction into one of the leaves. An earlier feeding date caused a higher accumulation of nickel and cobalt in the grains when introduced into the stem. In contrast, no major differences between earlier and later feeding dates were detected when the elements were introduced into the leaves. Losses of the applied elements were detected during maturation and can be explained by leakage in the rain.

The role of sensory neuron outgrowth in long-term sensitization of the tail-elicited tail-siphon withdrawal reflex of Aplysia

Neuronal outgrowth has been proposed in many systems as a mechanism underlying memory storage. For example, sensory neuron outgrowth is widely accepted as an underlying mechanism of long-term sensitization of defensive withdrawal reflexes in Aplysia. The hypothesis is that learning leads to outgrowth and consequently to the formation of new synapses, which in turn strengthen the neural circuit underlying the behavior. However, key experiments to test this hypothesis have never been performed. ^ Four days of sensitization training leads to outgrowth of siphon sensory neurons mediating the siphon-gill withdrawal response in Aplysia . We found that a similar training protocol produced robust outgrowth in tail sensory neurons mediating the tail siphon withdrawal reflex. In contrast, 1 day of training, which effectively induces long-term behavioral sensitization and synaptic facilitation, was not associated with neuronal outgrowth. Further examination of the effect of behavioral training protocols on sensory neuron outgrowth indicated that this structural modification is associated only with the most persistent forms of sensitization, and that the induction of these changes is dependent on the spacing of the training trials over multiple days. Therefore, we suggest that neuronal outgrowth is not a universal mechanism underlying long-term sensitization, but is involved only in the most persistent forms of the memory. ^ Sensory neuron outgrowth presumably contributes to long-term sensitization through formation of new synapses with follower motor neurons, but this hypothesis has never been directly tested. The contribution of outgrowth to long-term sensitization was assessed using confocal microscopy to examine sites of contact between physiologically connected pairs of sensory and motor neurons. Following 4 days of training, the strength of both the behavior and sensorimotor synapse and the number of appositions with follower neurons was enhanced only on the trained side of the animal. In contrast, outgrowth was induced on both sides of the animal, indicating that although sensory neuron outgrowth does appear to contribute to sensitization through the formation of new synapses, outgrowth alone is not sufficient to account for the effects of sensitization. This indicates that key regulatory steps are downstream from outgrowth, possibly in the targeting of new processes and activation of new synapses. ^

History of Jewish coinage, and of money in the Old and New Testament

by Frederic W. Madden

Long-term hyperexcitability of sensory and motor axons in Aplysia californica: Induction by axotomy, serotonin, and transient depolarization

Neuropathic pain is a debilitating neurological disorder that may appear after peripheral nerve trauma and is characterized by persistent, intractable pain. The well-studied phenomenon of long-term hyperexcitability (LTH), in which sensory somata become hyperexcitable following peripheral nerve injury may be important for both chronic pain and long-lasting memory formation, since similar cellular alterations take place after both injury and learning. Though axons have previously been considered simple conducting cables, spontaneous afferent signals develop from some neuromas that form at severed nerve tips, indicating intrinsic changes in sensory axonal excitability may contribute to this intractable pain. Here we show that nerve transection, exposure to serotonin, and transient depolarization induce long-lasting sensory axonal hyperexcitability that is localized to the treated nerve segment and requires local translation of new proteins. Long-lasting functional plasticity may be a general property of axons, since both injured and transiently depolarized motor axons display LTH as well. Axonal hyperexcitability may represent an adaptive mechanism to overcome conduction failure after peripheral injury, but also displays key features shared with cellular analogues of memory including: site-specific changes in neuronal function, dependence on transient, focal depolarization for induction, and requirement for synthesis of new proteins for expression of long-lasting effects. The finding of axonal hyperexcitability after nerve injury sheds new light on the clinical problem of chronic neuropathic pain, and provides more support for the hypothesis that mechanisms of long-term memory storage evolved from primitive adaptive responses to injury. ^

THE SHORT- AND LONG-TERM EFFECTS OF A HANDBOOK ON THE ANTIMICROBIAL PRESCRIBING PATTERNS OF HOSPITAL PHYSICIANS

This study evaluates the effect of a specially designed, physician-oriented handbook of antimicrobial use on the prescribing patterns of a group of fifty doctors at a university hospital. Data were evaluated over a peroid of one-and-one-half years, before and after the distribution of the handbook. For the purposes of this study, antimicrobial therapy was classified: (1) inappropriate if it violated one of a number of recognized principles of antimicrobial therapy, (2) appropriate if it agreed with specific recommendations or alternatives given in the distributed reference handbook, and (3) acceptable if it was neither inappropriate nor appropriate as defined by the handbook. An initial survey of antimicrobial prescribing patterns was made. Five months later the handbook was distributed and a two-week orientation program, consisting of the distribution and promotion of the problem-oriented, pocket-size handbook of appropriate antimicrobial therapy, was conducted. The handbook, which was developed by the authors and reviewed and approved by a panel of infectious disease specialists, presented guidelines for appropriate and efficacious usage of antimicrobial agents as most currently accepted in common clinical infections. Subsequent surveys were then conducted two weeks, three months, and six months after distribution of the handbook. A statistically significant difference (p < 0.01) in antimicrobial prescribing patterns was noted between the survey conducted two weeks after the introduction of the handbook and the other surveys. In this survey, while therapy classified inappropriate decreased from 44% to 28%, therapy appropriate as recommended increased from 31% to 53%. The findings of this study demonstrate that the introduction and promotion of the handbook decreases abuse and increases proper use of antimicrobial therapy, although the effect is sustainable for only a short duration--no longer than three months. These results indicate the need for a vigorous, updated program to achieve and maintain current appropriate antibotic therapy in clinical medicine. ^

Long-term impact of a weight management summer camp on obese children

Background: interventions that focus on improving eating habits, increasing physical activity, and reducing sedentary behaviors on weight status and body mass index percentile and z-scores in youths have not been well documented. This study aimed to determine the short and long term effects of a 2-week residential weight management summer camp program for youths on weight, BMI, BMI percentile, and BMI z-score. ^ Methods: A sample of 73 obese multiethnic 10-14 years old youths (11.9 ± 1.4) attended a weight management camp called Kamp K'aana for two weeks and completed a 12-month follow-up on height and weight. As part of Kamp K'aana, participants received a series of nutrition, physical activity and behavioral lessons and were on an 1800 kcal per day meal plan. Anthropometric measurements of height and weight were taken to calculate participants' BMI percentiles and z-scores. Paired t-tests, chi square test and ANCOVA, adjusting for age, gender, and ethnicity were used to assess changes in body weight, BMI, BMI percentiles and BMI z-scores pre to two-weeks post-camp and 12 months post-camp. ^ Results: Significant reductions in body weight of 3.6 ± 1.4 (P = 0.0000), BMI of 1.4 ± 0.54 (P = 0.0000), BMI percentile of 0.45 ± 0.06 (P = 0.0000), and BMI z-score of 0.1 ± 0.06 (P = 0.0000) were observed at the end of the camp. Significant reductions in BMI z-scores (P < 0.001) and BMI percentile (P < 0.001) were observed at the 12-month reunion when compared to pre- and two-weeks post camp data. There was a significant increase in weight and BMI (P = 0.0000) at the 12-month reunion when compared to pre and post camp measurements. ^ Conclusion: Kamp K'aana has consistently shown short-term reductions in weight, BMI, BMI percentile, and BMI z-score. Results from analysis of long-term data suggest that this intervention had beneficial effects on body composition in an ethnically diverse population of obese children. Further research which includes a control group, larger sample size, and cost-analysis should be conducted.^

The cGMP -PKG pathway is critical for inducing long-term sensitization of identified nociceptive sensory neurons

In various species, peripheral injury produces long-lasting sensitization of central and peripheral neurons representing the affected area. In Aplysia, memory-like traces (lasting days or weeks) of noxious peripheral stimulation include enhancement of central synaptic transmission and enhanced excitability of the central soma and peripheral branches of nociceptive sensory neurons. An important role for the cAMP-PKA-CREB pathway in consolidating long-term memory and inducing transcription-dependent synaptic potentiation has also been indicated by studies in rodents and Drosophila. ^ Much less attention has been paid to the cGMP-PKG pathway for transcription-dependent plasticity. Nevertheless, the cGMP-PKG pathway has been implicated in activity-dependent neural alterations lasting hours, and may trigger some forms of persistent pain. Recent evidence indicates PKG can regulate gene expression in the brain and several properties make it an attractive candidate for inducing long-term memories. ^ This dissertation reports that brief, noxious stimulation of a behaving, semi-intact preparation from mollusc, Aplysia californica, produces transcription-dependent, long-term hyperexcitability (LTH) of nociceptive sensory neurons that requires a nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and which lasts for at least 24 hours. Intracellular injection of cGMP is sufficient to induce LTH. Similarly, body wall injury induces LTH which can be blocked with specific inhibitors of the NO-cGMP-PKG pathway such as L-NMMA, ODQ, Rp-8-cGMPS, PKI-G and KT5823 by isolated perfusion of pleural ganglion sensory cells in or directly by intracellular injection. In contrast, specific inhibitors of the cAMP-PKA pathway (Rp-8-cAMPS, PKI-A and H-89) failed to block injury-induced LTH. Interestingly, co-injection of the cAMP-responsive element (CRE) blocked the induction of both cAMP and injury-induced LTH, but not cGMP-induced LTH. Furthermore, co-injection of cAMP and cGMP with the Ca2+ buffer BAPTA in reduced Ca2+ seawater blocked cAMP-, but not cGMP-induced LTH. These findings demonstrate that the NO-cGMP-PKG pathway and at least one other pathway (perhaps mediated by Ca2+), but not the cAMP-PKA pathway, are critical for inducing LTH during transient, noxious stimulation.^

Long-term Evaluation of Hybrid, Nitrogen, and Potassium Interactions in Continuous Corn

A long-term experiment was established in 2009 to study continuous corn responses to potassium (K), nitrogen (N), and hybrid rootworm resistance. Previous research suggested a need for this study. A long-term trial conducted until 2001 at the ISU Northern Research Farm showed that the maximum corn yield level and the N rate that maximized yield was higher when K was optimal or greater. In contrast, the relative yield response to N and the N rate that maximized yield were similar for soil-test phosphorus (P) levels ranging from very low to very high. Other studies have shown that rootworm resistance often increases yield compared with untreated susceptible hybrids. Also, that rootworm resistance does not consistently affect the K rate that maximizes yield, but increases K removal because of the higher yield levels. Therefore, this new study evaluates possible interactions between rootworm resistance and N and K fertilization in corn.