Intestinal pseudo-obstruction as an initial presentation of systemic sclerosis in two children

Two children are reported in whom intestinal pseudo-obstruction was the initial manifestation of systemic sclerosis. Gastrointestinal symptoms and skin changes resolved or improved in both children following treatment with prednisone and penicillamine (case 1) or methotrexate (case 2), although radiological changes of the gastrointestinal tract persisted at 3 and 2 yr of follow-up, respectively.      

Adenosine, a metabolic trigger of the exercise pressor reflex in humans

There is substantial evidence that adenosine activates muscle afferent nerve fibers leading to sympathetic stimulation, but the issue remains controversial. To further test this hypothesis, we used local injections of adenosine into the brachial artery while monitoring systemic muscle sympathetic nerve activity (MSNA) with peroneal microneurography. The increase in MSNA induced by 3 mg intrabrachial adenosine (106+/-32%) was abolished if forearm afferent traffic was interrupted by axillary ganglionic blockade (21+/-19%, n=5, P:<0.05). Furthermore, the increase in MSNA induced by intravenous adenosine was 3.7-fold lower and later (onset latency 20.9+/-4.8 seconds versus 8.5+/-1 seconds) than intrabrachial adenosine. Finally, we used forearm exercise (dynamic handgrip at 50% and 15% maximal voluntary contraction, MVC), with or without superimposed ischemia, to modulate interstitial levels of adenosine (estimated with microdialysis) while monitoring MSNA. Fifteen minutes of intense (50% MVC) and moderate (15% MVC) exercise increased adenosine dialysate concentrations from 0.31+/-0.1 to 1.24+/-0.4 micromol/L (528+/-292%) and from 0.1+/-0.02 to 0.419+/-0.16 micromol/L (303+/-99%), respectively (n=7, P:<0.01). MSNA increased 88+/-25% and 38+/-28%, respectively. Five minutes of moderate exercise increased adenosine from 0.095+/-0.02 to 0.25+/-0.12 micromol/L, and from 0.095+/-0.02 to 0.48+/-0.19 micromol/L when ischemia was superimposed on exercise (n=7, P:=0.01). The percent increase in MSNA induced by the various interventions correlated with the percent increase in dialysate adenosine levels (r=0.96). We conclude that adenosine activates muscle afferent nerves, triggering reflex sympathetic activation.     

Twenty Years of Active Bacterial Core Surveillance

Active Bacterial Core surveillance (ABCs) was established in 1995 as part of the Centers for Disease Control and Prevention Emerging Infections Program (EIP) network to assess the extent of invasive bacterial infections of public health importance. ABCs is distinctive among surveillance systems because of its large, population-based, geographically diverse catchment area; active laboratory-based identification of cases to ensure complete case capture; detailed collection of epidemiologic information paired with laboratory isolates; infrastructure that allows for more in-depth investigations; and sustained commitment of public health, academic, and clinical partners to maintain the system. ABCs has directly affected public health policies and practices through the development and evaluation of vaccines and other prevention strategies, the monitoring of antimicrobial drug resistance, and the response to public health emergencies and other emerging infections.     

QT interval prolongation and increased plasma catecholamine levels in patients with mitral valve prolapse

The heart rate corrected QT interval (QTc) and plasma catecholamine (CA) and norepinephrine (NE) levels were measured in 15 symptomatic patients with idiopathic mitral valve prolapse (MVP) and in 19 control subjects. MVP patients showed longer mean QTc and were divided into two groups: group A normal QTc (greater than 440 msec) and group B prolonged QTc (less than 440 msec). In supine resting conditions CA levels were as follows: group A 0.420 +/- 0.035 ng/ml and group B 0.619 +/- 0.104 ng/ml (p less than 0.05); both were greater than control values (0.348 +/- 0.017 ng/ml, p less than 0.005). NE levels were as follows: group A 0.350 +/- 0.031 ng/ml and group B 0.376 +/- 0.052 ng/ml (NS); both were greater than control values (0.242 +/- 0.025 ng/ml, (p less than 0.05). When a standing position was assumed, CA and NE levels increased significantly in all groups but this was most marked in group B as compared to control levels (CA: 1.039 +/- 0.123 ng/ml versus 0.625 +/- 0.037 ng/ml; NE: 0.737 +/- 0.076 ng/ml versus 0.504 +/- 0.031 ng/ml) (p less than 0.001 and p less than 0.05, respectively). Thus the longest QTc was observed in patients with MVP who had the highest levels of CA and NE, in both supine and standing positions. These data may account, in part, for the occurrence of severe ventricular arrhythmias in some patients with MVP and may offer a rationale for adrenergic blockade in that subset of patients with MVP and markedly prolonged QTc.     

Interleukin-10 promoter polymorphisms in rheumatoid arthritis and Felty's syndrome

OBJECTIVE: To examine whether promoter polymorphisms associated with variation in interleukin-10 (IL-10) production are relevant to the development of rheumatoid arthritis (RA) or Felty's syndrome (FS). METHODS: DNA was obtained from 44 FS patients, 117 RA patients and 295 controls. The promoter region between -533 and - 1120 was amplified by polymerase chain reaction, and polymorphisms detected by restriction enzyme digest or sequence-specific oligonucleotide probing. RESULTS: We found no significant difference in allele or haplotype frequencies between the groups. CONCLUSION: There is no association between FS or RA and these recently identified IL-10 promoter polymorphisms. Other genetic or environmental factors could explain the alterations in IL-10 levels seen in these conditions.      

High-dose chemotherapy and stem cell transplantation for patients with stage IV breast cancer without clinically evident disease: correlation of CD34+ selection to clinical outcome

Forty-five patients with metastatic breast cancer without clinically evident disease were treated with thiotepa 750 mg/m2, mitoxantrone 40 mg/m2 and carboplatin 1000 mg/m2 followed by stem cell transplantation to determine the safety and efficacy of CD34+ selection of peripheral blood stem cells. Of these, 15 patients' (group I) stem cells were processed through Baxter Isolex 300 device for CD34+ selection, whereas 30 patients (group II) received unmanipulated stem cells. Toxicity, progression-free survival and survival were compared between these two groups. There was no difference in transfusion requirements, white cell count and platelet recovery and non-hematologic toxicity between the two groups. The survival of patients in group I was 27 months compared to 38 months in group II (P = 0.8). The progression-free survival was 12 months and 13.5 months for group I and group II patients, respectively (P = 0.6). Our results indicate that while there is no adverse effect, there is also no significant advantage of CD34+ selection in terms of progression-free survival and survival in patients with metastatic breast cancer without clinically evident disease. Bone Marrow Transplantation (2000).     

Ultra‐deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas

The recognition of cancer cells by T cells can impact upon prognosis and be exploited for immunotherapeutic approaches. This recognition depends on the specific interaction between antigens displayed on the surface of cancer cells and the T cell receptor (TCR), which is generated by somatic rearrangements of TCR α‐ and β‐chains (TCRb). Our aim was to assess whether ultra‐deep sequencing of the rearranged TCRb in DNA extracted from unfractionated clear cell renal cell carcinoma (ccRCC) samples can provide insights into the clonality and heterogeneity of intratumoural T cells in ccRCCs, a tumour type that can display extensive genetic intratumour heterogeneity (ITH). For this purpose, DNA was extracted from two to four tumour regions from each of four primary ccRCCs and was analysed by ultra‐deep TCR sequencing. In parallel, tumour infiltration by CD4, CD8 and Foxp3 regulatory T cells was evaluated by immunohistochemistry and correlated with TCR‐sequencing data. A polyclonal T cell repertoire with 367–16 289 (median 2394) unique TCRb sequences was identified per tumour region. The frequencies of the 100 most abundant T cell clones/tumour were poorly correlated between most regions (Pearson correlation coefficient, –0.218 to 0.465). 3–93% of these T cell clones were not detectable across all regions. Thus, the clonal composition of T cell populations can be heterogeneous across different regions of the same ccRCC. T cell ITH was higher in tumours pretreated with an mTOR inhibitor, which could suggest that therapy can influence adaptive tumour immunity. These data show that ultra‐deep TCR‐sequencing technology can be applied directly to DNA extracted from unfractionated tumour samples, allowing novel insights into the clonality of T cell populations in cancers. These were polyclonal and displayed ITH in ccRCC. TCRb sequencing may shed light on mechanisms of cancer immunity and the efficacy of immunotherapy approaches. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

High-affinity ouabain binding by yeast cells expressing Na+, K(+)-ATPase alpha subunits and the gastric H+, K(+)-ATPase beta subunit.

Recently, a beta subunit for the rat gastric H+,K(+)-ATPase (HK beta), which is structurally similar to the beta subunit of Na+, K(+)-ATPase, has been cloned and characterized. Using heterologous expression in yeast, we have tested the specificity of beta subunit assembly with different isoforms of the alpha subunit of Na+, K(+)-ATPase. Coexpression in yeast cells of the HK beta with both the sheep alpha 1 subunit and the rat alpha 3 subunit isoforms of Na+, K(+)-ATPase (alpha 1 and alpha 3, respectively) leads to the appearance of high-affinity ouabain-binding sites in yeast membranes. These ouabain-binding sites (alpha 1 plus HK beta, alpha 3 plus HK beta) have a high affinity for ouabain (Kd, 5-10 nM) and are expressed at levels similar to those formed with the rat beta 1 subunit of Na+, K(+)-ATPase (beta 1) (alpha 1 plus beta 1 or alpha 3 plus beta 1). Potassium acts as a specific antagonist of ouabain binding by alpha 1 plus HK beta and alpha 3 plus HK beta just like sodium pumps formed with beta 1. Sodium pumps formed with the HK beta, however, show quantitative differences in their affinity for ouabain and in the antagonism of K+ for ouabain binding. These data suggest that the structure of the beta subunit may play a role in sodium pump function.