Acquired hematopoietic stem cell defects determine B-cell repertoire changes associated with aging

Aging is associated with an inability to mount protective antibody responses to vaccines and infectious agents. This decline is associated with acquisition of defects in multiple cellular compartments, including B cells. While peripheral B-cell numbers do not decline with aging, the composition of the compartment appears to change, with loss of naïve follicular B cells, accumulation of antigen-experienced cells, and alteration of the antibody repertoire. The underlying cause of this change is unknown. We tested the hypothesis that aging-associated repertoire changes can be attributed directly to decreased B lymphopoiesis. Using an Ig transgenic model to report changes in the B-cell repertoire, we show that the reduced B-cell generative capacity of “aged” long-term reconstituting hematopoietic stem cells (LT-HSCs) alters the representation of antigen specificities in the peripheral B-cell repertoire. Further, we show that reconstitution using suboptimal numbers of fully functional LT-HSCs results in the generation of a similarly altered B-cell repertoire. This may be an important factor to consider when deciding the number of bone marrow cells to transplant in the clinical setting. In conclusion, when B lymphopoiesis is limited peripheral B-cell homeostasis is altered. This is reflected in reduced diversity of the B-cell repertoire, which likely reduces the protective quality of the immune response.     

Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics.

Idiopathic hypereosinophilic syndrome (HES) characterized by unexplained and persistent hypereosinophilia is heterogeneous and comprises several entities: a myeloproliferative form where myeloid lineages are involved with the interstitial chromosome 4q12 deletion leading to fusion between FIP1L1 and PDGFRA genes, the latter acquiring increased tyrosine kinase activity. And a lymphocytic variant, where hypereosinophilia is secondary to a primitive T lymphoid disorder demonstrated by the presence of a circulating T-cell clone. We performed molecular characterization of HES in 35 patients with normal karyotype by conventional cytogenetic analysis. TCRgamma gene rearrangements suggesting T clonality were seen in 11 (31%) patients, and FIP1L1-PDGFRA by RT-PCR in six (17%) of 35 patients, who showed no evidence of T-cell clonality. An elevated serum tryptase level was observed in FIP1L1-PDGFRA-positive patients responding to imatinib, whereas serum IL-5 levels were not elevated in T-cell associated hypereosinophilia. Sequencing FIP1L1-PDGFRA revealed scattered breakpoints in FIP1L1-exons (10-13), whereas breakpoints were restricted to exon 12 of PDGFRA. In the 29 patients without FIP1L1-PDGFRA, no activating mutation of PDGFRA/PDGFRB was detected; however; one patient responded to imatinib. FISH analysis of the 4q12 deletion was concordant with FIP1L1-PDGFRA RT-PCR data. Further investigation of the nature of FIP1L1-PDGFRA affected cells will improve the classification of HES.     

Differential expression of CYP1A1 and CYP1B1 in human breast epithelial cells and breast tumor cells

Human cytochromes P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) catalyze the metabolic activation of a number of procarcinogens and the hydroxylation of 17beta-estradiol (E2) at the C-2 and C-4 positions, respectively. The aromatic hydrocarbon receptor (AhR) agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) has a marked effect on estrogen metabolism in MCF-7 breast-tumor cells by induction of these two enzymes. To investigate whether induction of CYP1A1 and CYP1B1 by AhR agonists and the associated increase in E2 metabolism are common to all breast epithelial cells and breast-tumor cells, we determined the effects of TCDD on E2 metabolism, and CYP1A1 and CYP1B1 mRNA levels in a series of non-tumor-derived breast epithelial (184A1 and MCF-10A) and breast-tumor (MCF-7, T-47D, ZR-75-1, BT-20, MDA-MB-157, MDA-MB-231 and MDA-MB-436) cell lines. In 184A1 cells, which did not express detectable estrogen receptor (ER) alpha mRNA, CYP1A1 mRNA and activity were induced by TCDD, and enhanced E2 metabolism in TCDD-treated cells was predominantly E2 2-hydroxylation. In MCF-10A, MCF-7, T-47D, ZR-75-1 and BT-20 cells, which expressed varying levels of ER alpha mRNA, both CYP1A1 and CYP1B1 mRNA levels and rates of both E2 2- and 4- hydroxylation were highly elevated following exposure to TCDD. In MDA- MB-157, MDA-MB-231 and MDA-MB-436 cells, which did not express detectable ER alpha mRNA and generally displayed fibroblastic or mesenchymal rather than epithelial morphology, CYP1B1 induction was favored, and the rate of E2 4-hydroxylation exceeded that of 2- hydroxylation in TCDD-treated cells. These results show that breast epithelial cells and tumor cells vary widely with regard to AhR- mediated CYP1A1 and CYP1B1 induction, suggesting that factors in addition to the AhR regulate CYP1A1 and CYP1B1 gene expression. In these cell lines, significant CYP1A1 inducibility was restricted to cultures displaying epithelial morphology, whereas CYP1B1 inducibility was observed in cells of both epithelial and mesenchymal morphology.      

Vertebral artery dominance and hand preference: is there a correlation?

The two vertebral arteries are usually unequal in size, the left one being generally larger than the right one. It is not clear why this asymmetry exists. One of the hypotheses is that this asymmetry is related to the vascular requirements of the brain. To support this statement, we investigated the correlation between a dominant left vertebral artery and right-handedness and vice versa. No correlation between differences in vertebral artery diameter and hand dominance was found. Hence, the hypothesis that a dominant left vertebral artery is associated with right-handedness and vice versa cannot be confirmed.     

Differences in isometric neck muscle strength between healthy controls and women with chronic neck pain: the use of a reliable measurement

Cagnie B, Cools A, De Loose V, Cambier D, Danneels L. Differences in isometric neck muscle strength between healthy controls and women with chronic neck pain: the use of a reliable measurement.

Objectives

To determine the intra- and interrater reliability of the Biodex isokinetic dynamometer to measure the maximal isometric strength of the cervical flexors and extensors, to develop an age- and sex-based normative database in a healthy population, and to evaluate the differences in neck strength between women with chronic neck pain and healthy controls.

Design

Cross-sectional.

Setting

Physical and rehabilitation medicine department.

Participants

Ninety-six healthy volunteers (4 age groups: 20-29, 30-39, 40-49, 50-59y; each consisting of 12 men and 12 women) and 30 women with chronic neck pain.

Interventions

Not applicable.

Main Outcome Measures

Peak isometric strength of the cervical muscles was tested for flexion and extension by using the Biodex isokinetic dynamometer. The intra- and interrater reliability of the protocol was evaluated in 12 volunteers.

Results

The reliability for strength was high for both flexion and extension (intraclass correlation coefficient, .92-.96). The mean peak torque for flexion and extension was significantly higher in men (24Nm, 36.4Nm, respectively) compared with women (16.6Nm, 26.5Nm, respectively) (P<.001). Peak torque production for extension was significantly lower in the patient group (22.3Nm) compared with the healthy female control group (26.5Nm) (P=.003). No significant differences in flexion strength between patient and female control group were found.

Conclusions

Results show a high degree of intra- and interrater reliability in measuring isometric neck muscle strength when using the Biodex isokinetic dynamometer. The use of normative data for neck strength when evaluating patients with neck disorders needs to take sex into account. The current study has shown that women with chronic neck pain have lower neck muscle strength in extension than the healthy female group.     

Pain reduction by infrared light-emitting diode irradiation: a pilot study on experimentally induced delayed-onset muscle soreness in humans

The present pilot study investigated the analgesic efficacy of light-emitting diode (LED). In view of a standardised and controlled pain reduction study design, this in vivo trial was conducted on experimentally induced delayed-onset muscle soreness (DOMS). Thirty-two eligible human volunteers were randomly assigned to either an experimental (n=16) or placebo group (n=16). Immediately following the induction of muscle soreness, perceived pain was measured by means of a visual analog scale (VAS), followed by a more objective mechanical pain threshold (MPT) measurement and finally an eccentric/concentric isokinetic peak torque (IPT) assessment. The experimental group was treated with infrared LED at one of both arms, the other arm served as control. Irradiation lasted 6 min at a continuous power output of 160 mW, resulting in an energy density of 3.2 J/cm². The subjects of the placebo group received sham irradiation at both sides. In post-treatment, a second daily assessment of MPT and VAS took place. The treatment and assessment procedure (MPT, VAS and IPT) was performed during 4 consecutive days. Statistical analysis (a general linear model followed by post hoc least significant difference) revealed no apparent significant analgesic effects of LED at the above-described light parameters and treatment procedure for none of the three outcome measures. However, as the means of all VAS and MPT variables disclose a general analgesic effect of LED irradiation in favour of the experimental group, precaution should be taken in view of any clinical decision on LED. Future research should therefore focus on the investigation of the mechanisms of LED action and on the exploration of the analgesic effects of LED in a larger randomised clinical trial and eventually in more clinical settings.     

The effect of exercise regimens on reflex response time of the vasti muscles in patients with anterior knee pain: a prospective randomized intervention study

The purpose of this prospective randomized intervention study was to evaluate the effect of two exercise protocols on reflex response time of vastus medialis obliquus (VMO), vastus lateralis (VL), in patients with anterior knee pain. Sixty patients were randomized into a 5-week treatment program, which consisted of only open kinetic chain tonification exercises (group I) (n = 30), or only closed kinetic chain tonification exercises (group II) (n = 30). Assessment of an aspect of neuromotor control was obtained by measuring the reflex response times of VMO and VL at the time of initial clinical examination, at the end of the exercise period (five weeks), and three months after the completion of the exercise period. At these evaluation occasions, the intensity and the number of times that the patients experienced anterior knee pain during daily life was recorded on a Visual Analog Scale (VAS). No alterations in reflex response times of VMO and VL were observed in either group. Changes of anterior knee pain over time were statistically significant in both groups. Only small and not statistically supported differences in anterior knee pain were found between the two groups. These results suggest that the reflex response times of the two vasti muscles can not be altered after a five week open or closed kinetic chain exercise program. In contrast, knee pain decreased significantly in both groups.