Early decrease of skin blood flow in response to locally applied pressure in diabetic subjects

Pressure ulcers are common debilitating complications of diabetes that are caused by tissue ischemia. Skin blood flow in response to locally applied pressure might be impaired in diabetic patients because of the combined effects of a typically low skin temperature and alterations in microcirculatory function, and could be worsened by neuropathy. We measured skin blood flow by laser Doppler flowmetry over the internal anklebone in response to local pressure applied at 5.0 mmHg/min in three groups of diabetic patients (with clinical and subclinical neuropathy and without neuropathy) and in healthy matched control subjects at usual room temperature. Compared with in matched control subjects with comparable skin temperatures (29.3 +/- 0.4 vs. 28.7 +/- 0.4 degrees C), in diabetic patients the skin blood flow response to locally applied pressure was further impeded, even in those without neuropathy. Indeed, skin blood flow decreased significantly from baseline at much lower applied pressure (7.5 mmHg) in diabetic subjects, again even in those without neuropathy, than in control subjects (48.8 mmHg). The large difference between these pressures could partially explain diabetic patients' high risk of developing decubitus and plantar ulcers.     

Dynamics of local pressure-induced cutaneous vasodilation in the human hand

We recently demonstrated that a pressure-induced vasodilation results from local nonnociceptive stimulation of the skin of the human hand. We aimed to test the hypothesis that this vasodilation was not a short-lived response to a single type of pressure strain, but could be a widely activated and prolonged protective cutaneous response. We studied the dynamics of pressure-induced vasodilation during various ramp changes in local externally applied pressure using laser Doppler flowmetry. Changes from an adjacent control probe were subtracted from pressure-induced local changes. Following an initial transient decrease, continuous 4.4, 5.6, and 11.1 Pa.s(-1) increases of pressure resulted in a secondary increase of blood flow whose amplitude was maximal for 11.1 Pa.s(-1) (22.9 +/- 12.6% above baseline) (mean +/- SEM). The increase in flow was not noted at 16.7 Pa.s(-1). If the 16.7 Pa.s(-1) ramp pressure increase was interrupted at min 2 or 4, a prolonged vasodilation response was found, but not if it was stopped at min 8. When the 16.7 Pa.s(-1) increasing pressure was returned to zero after 4 min of pressure increase (-8.1 +/- 8.9% before pressure removal), vasodilation occurred and reached a maximum of 26.0 +/- 9.6% at 7 min after removal of pressure (P < 0.05 from baseline). Pressure-induced vasodilation is a slow-responding and transient adaptive phenomenon, initiated by a wide range of pressure changes below the range of noxious stimulation. We propose that this response is a protective mechanism without which certain pressure-associated lesions may develop.     

Mechanisms of the cutaneous vasodilator response to local external pressure application in rats: involvement of CGRP, neurokinins, prostaglandins and NO

1. Local pressure-induced vasodilation (PIV) is a neural vasodilator response to non-nociceptive externally applied pressure in the skin, previously described in humans. We first determined whether PIV exists in rats and depends on capsaicin-sensitive fibres as it does in humans. We then examined the mediators involved in the efferent pathway of PIV. 2. Cutaneous blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in local applied pressure in anaesthetized rats. The involvement of capsaicin-sensitive fibres in PIV was tested in rats treated neonatally with capsaicin. To antagonize CGRP, neurokinin-1, -2, or -3 receptors, different groups of rats were treated with CGRP(8 - 37), SR140333, SR48968 or SR142801, respectively. Prostaglandins involvement was tested with indomethacin treatment. To inhibit nitric oxide synthase (NOS) activity or specific neuronal NOS, rats were treated with N(G)-nitro-L-arginine or 7-nitroindazole, respectively. 3. PIV was found in rats, as in humans. PIV was abolished by neonatal treatment with capsaicin and by administration of CGRP(8 - 37) but remained unchanged with SR140333, SR48968 and SR142801 treatments. Prostaglandin inhibition resulted in a significant decrease in PIV. Inhibition of NOS abolished PIV, whereas inhibition of neuronal NOS caused a diminution of PIV. 4. These data suggest that PIV depends on capsaicin-sensitive fibres in rats, as in humans. It appears that CGRP plays a major role in the PIV, whereas neurokinins have no role. Furthermore, PIV involves a contribution from prostaglandins and depends on endothelial NO, whereas neuronal NO has a smaller role.     

Assignment of the human gene for muscle-type phosphofructokinase (PFKM) to chromosome 1 (region cen→q32) using somatic cell hybrids and monoclonal anti-M antibody

Human phosphofructokinase (PFK; EC 2.7.1.11) is under the control of three structural loci which encode muscle-type (M), liver-type (L), and platelet-type (P) subunits; human diploid fibroblasts and leukocytes express all three loci. In order to assign human PFKMlocus to a specific chromosome we have analyzed human × Chinese hamster somatic cell hybrids for the expression of human M subunits, using an anti-human M subunit-specific mouse monoclonal antibody. In 18 of 19 hybrids studied, the expression of the PFKMlocus segregated concordantly with the presence of chromosome 1 (discordancy rate 0.05) as indicated by chromosome and isozyme marker analysis. The discordancy rates for all the other chromosomes were 0.32 or greater, indicating that the PFKMlocus is on chromosome 1. For the regional mapping of PFKM,eight hybrids were studied that contained one of five distinct regions of chromosome 1. These results further localize the human PFKMlocus to region cenq32 of chromosome 1.     

The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B lymphocytes, involves blood, bone marrow, and secondary lymphoid organs such as the lymph nodes (LN). A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations, but its contribution in vivo remains ill-defined. To elucidate the effects of tumor-host interactions in vivo, we purified tumor cells from 24 treatment-naive patients. Samples were obtained concurrently from blood, bone marrow, and/or LN and analyzed by gene expression profiling. We identified the LN as a key site in CLL pathogenesis. CLL cells in the LN showed up-regulation of gene signatures, indicating B-cell receptor (BCR) and nuclear factor-κB activation. Consistent with antigen-dependent BCR signaling and canonical nuclear factor-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL, indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation, quantified by the expression of the E2F and c-MYC target genes and verified with Ki67 staining by flow cytometry, was highest in the LN and was correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and the inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.     

Comparing Patients’ Opinions on the Hospital Discharge Process Collected With a Self-Reported Questionnaire Completed Via the Internet or Through a Telephone Survey: An Ancillary Study of the SENTIPAT Randomized Controlled Trial

Background

Hospital discharge, a critical stage in the hospital-to-home transition of patient care, is a complex process with potential dysfunctions having an impact on patients’ health on their return home. No study has yet reported the feasibility and usefulness of an information system that would directly collect and transmit, via the Internet, volunteer patients’ opinions on their satisfaction concerning the organization of hospital discharge.

Objective

Our primary objective was to compare patients’ opinions on the discharge process collected with 2 different methods: self-questionnaire completed on a dedicated website versus a telephone interview. The secondary goal was to estimate patient satisfaction.

Methods

We created a questionnaire to examine hospital discharge according to 3 dimensions: discharge logistics organization, preplanned posthospital continuity-of-care organization, and patients’ impressions at the time of discharge. A satisfaction score (between 0 and 1) for each of those dimensions and an associated total score were calculated. Taking advantage of the randomized SENTIPAT trial that questioned patients recruited at hospital discharge about the evolution of their health after returning home and randomly assigned them to complete a self-questionnaire directly online or during a telephone interview, we conducted an ancillary study comparing satisfaction with the organization of hospital discharge for these 2 patient groups. The questionnaire was proposed to 1141 patients included in the trial who were hospitalized for ≥2 days, among whom 867 eligible patients had access to the Internet at home and were randomized to the Internet or telephone group.

Results

Of the 1141 patients included, 755 (66.17%) completed the questionnaire. The response rates for the Internet (39.1%, 168/430) and telephone groups (87.2%, 381/437) differed significantly (P<.001), but their total satisfaction scores did not (P=.08) nor did the satisfaction subscores (P=.58 for discharge logistics organization, P=.12 for preplanned posthospital continuity-of-care organization, and P=.35 for patients’ impressions at the time of discharge). The total satisfaction score (median 0.83, IQR 0.72-0.92) indicated the patients’ high satisfaction.

Conclusions

The direct transmission of personal health data via the Internet requires patients’ active participation and those planning surveys in the domain explored in this study should anticipate a lower response rate than that issued from a similar survey conducted by telephone interviews. Nevertheless, collecting patients’ opinions on their hospital discharge via the Internet proved operational; study results indicate that conducting such surveys via the Internet yields similar estimates to those obtained via a telephone survey. The results support the establishment of a permanent dedicated website that could also be used to obtain users’ opinions on other aspects of their hospital stay and follow-up.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01769261","term_id":"NCT01769261"}}NCT01769261; http://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT01769261","term_id":"NCT01769261"}}NCT01769261 (Archived by WebCite at http://www.webcitation.org/6ZDF5bdQb).     

Long-term response to rituximab and fludarabine combination in IgM anti-myelin-associated glycoprotein neuropathy

We report the clinical response and biological effects of treatment with rituximab and fludarabine (RF) in five patients with IgM anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. Between November 2006 and October 2009, four men and one woman aged 52-85 years received intravenous rituximab at 375 mg/m(2) on day 1 and oral fludarabine at 40 mg/m(2) /day from days 1 to 5, in a treatment cycle that was repeated every month for up to 6 months. Two patients had IgM monoclonal gammopathy of undetermined significance and three low tumor mass Waldenstrom's macroglobulinemia. Four patients showed a major hematological response with a decrease in anti-MAG titer in three and clearing in one. One patient did not respond. For the responding patients, symptoms and electrophysiological parameters improved significantly. No patient relapsed at post-RF treatment follow-up (12-45 months), and no toxicity was reported. The combination of RF induced significant responses in IgM anti-MAG demyelinating neuropathies, without toxicity. Clinical improvements were correlated to hematological and immunological results.     

Effect of isoflurane on skin-pressure-induced vasodilation

Since general anesthesia has been shown to attenuate endothelium-dependent vasodilation, it was of interest to verify whether general anesthesia would modify skin vasodilation in response to local pressure application, which is endothelium dependent. To study the effect of general anesthesia on pressure-induced vasodilation development, we examined the effects of low- and high-dose isoflurane. Skin blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in locally applied pressure in anesthetized rats treated with low or high doses of isoflurane. Following the administration of low doses of isoflurane, skin blood flow increased from baseline, with increasing local pressure application (+37 +/- 10% at 2.0 kPa). The increase in skin blood flow was absent in rats treated with high doses (-20 +/- 5% at 2.0 kPa), even when the anesthesia-induced hypotension was corrected by gelofusine infusion (-20 +/- 10% at 2.0 kPa). Whereas sodium-nitroprusside-induced vasodilation developed following low and high doses of isoflurane, acetylcholine-induced vasodilation was impaired with high doses compared to low doses. These data show that pressure-induced vasodilation is abolished with high doses of anesthetics. It is not the anesthesia-induced hypotension, but the depth of anesthesia, which can lead to the disappearance of pressure-induced vasodilation by an alteration in endothelial function.