Polymorphisms in FcgammaRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenstr?m's macroglobulinemia.

PURPOSE: Rituximab is an important therapeutic for Waldenstrom's macroglobulinemia (WM). Polymorphisms in FcgammaRIIIA (CD16) receptor expression modulate human immunoglobulin G1 binding and antibody-dependent cell-mediated cytotoxicity, and may therefore influence responses to rituximab. PATIENTS AND METHODS: Sequence analysis of the entire coding region of FcgammaRIIIA was undertaken in 58 patients with WM whose outcomes after rituximab were known. RESULTS: Variations in five codons of FcgammaRIIIA were identified. Two were commonly observed (FcgammaRIIIA-48 and FcgammaRIIIA-158) and predicted for amino acid polymorphisms at FcgammaRIIIA-48: leucine/leucine (L/L), leucine/arginine (L/R), and leucine/histidine (L/H). Polymorphisms at FcgammaRIIIA-158 were phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V), and valine/valine (V/V). A clear linkage between these polymorphisms was detected and all patients with FcgammaRIIIA-158F/F were always FcgammaRIIIA-48L/L, and patients with either FcgammaRIIIA-L/R or -L/H always expressed at least one valine at FcgammaRIIIA-158 (P < or = .001). The response trend was higher for patients with FcgammaRIIIA-48L/H (38.5%) versus -48L/R (25.0%) and LL (22.0%), and was significantly higher for patients with FcgammaRIIIA-158V/V (40.0%) and -V/F (35%) versus -158F/F (9.0%; P = .030). Responses for patients with FcgammaRIIIA-48L/L were higher when at least one valine was present at FcgammaRIIIA-158 (P = .057), thereby supporting a primary role for FcgammaRIIIA-158 polymorphisms in predicting rituximab responses. With a median follow-up of 13 months, no significant differences in the median time to progression and progression-free survival were observed when patients were grouped according to their FcgammaRIIIA-48 and -158 polymorphisms. CONCLUSION: The results of these studies therefore support a predictive role for FcgammaRIIIA-158 polymorphisms and responses to rituximab in WM.     

Shoulder activity level in the preoperative assessment of patients with rotator cuff tears

The purpose of this study was to investigate shoulder activity level in preoperative assessment of shoulder function and health-related quality of life (QoL) for patients with rotator cuff tears. One hundred and six patients with rotator cuff tears were prospectively evaluated using the following outcome instruments: the Shoulder Activity scale, the Constant scale, the Simple Shoulder Test, and the Short Form-36v2 (SF-36v2). Clinical and structural data, including patients’ demographics, comorbidities, duration of symptoms, shoulder contracture, and tear size, were collected and analyzed. We determined that the shoulder activity level was associated with gender, medical comorbidities, and age. Females had lower activity level, worse scores for health-related QoL, and longer duration of symptoms than males. Patients who had severe comorbidities had lower shoulder activity scores and worse SF-36v2 scores compared to patients who did not have such comorbidities. The patient age correlated with the shoulder activity level, but did not have significant correlation with the duration of symptoms and shoulder function. The shoulder activity level was related to patient gender, general health status and age; therefore, further investigation is warranted to determine if the activity level can be used as a prognostic variable relating to outcome in the treatment of rotator cuff tears.     

The Time-Course of Voluntary and Electrically Evoked Muscle Performance During and After Stretch-Shortening Exercise is Different

The aim of the study was to establish the dynamics of maximal voluntary contraction force (MVCF), height of drop jump (DJ) and electrically evoked quadriceps muscle force at different stimulation frequencies during and after 100 DJs (stretch-shortening exercise, SSE). Healthy untrained men (n = 11; age = 21.8 ± 1.7 years) participated in the study. DJs were performed with 30 s intervals between jumps from the height of 0.5 m with counter-movement to 90 degrees angle in the knee and immediate maximal rebound. The force of the quadriceps muscle, evoked by electrical stimulation at 1 Hz (Pt), 20 Hz (P20) and 100 Hz (P100) frequencies (electrically evoked performance, EEP), MVCF and height of DJ (voluntary evoked performance, VEP) were established during SSE (after 10, 50, 100 DJ) as well as at 1, 4, 8, 24, 48 and 72 h after SSE. Time-course of P20 and P100 during and after SSE was time (ANOVA: p < 0.001) and frequency dependent (ANOVA: p < 0.001) The Pt, P20 and P100 decreased significantly (p < 0.01) more than MVCF and H of DJ during SSE. At the beginning of SSE (during 1-10 DJs) P20 and P100 decreased significantly (p < 0.001) more than during 11-50 and 51-100 DJs. There was a significant (p < 0.05) increase in Pt, P20 and P100 from 8 h to 48 h, whereas height of DJ and MVCF significantly decreased at that time. In conclusion, the differences in time course of VEP and EEP are most evident at beginning of SSE, where VEP does not change as EEP decreases, and within 8-48 hours after SSE, where VEP decreases as EEP increases.

Key points

• There was no change in voluntary muscle performance while electrically evoked performance decreased significantly during first 10 drop jumps.
• There was a significant increase in electrically evoked muscle performance from 8 h to 48 h after 100 drop jumps, whereas voluntary contraction force, decreased significantly.
• The secondary decrease in the height of drop jump as well as in maximal voluntary contraction force correlated significantly with muscle soreness within 24-48 h after exercise.

Key words: Drop jump, muscle damage, electrical stimulation, low frequency fatigue     

A domain substitution procedure and its use to analyze voltage dependence of homotypic gap junctions formed by connexins 26 and 32.

We have developed a procedure for the replacement of defined domains with specified domains from other proteins that we used to examine the molecular basis for the differences in voltage-dependent gating between connexins 26 (Cx26) and 32 (Cx32). This technique does not depend on sequence homology between the domains to be exchanged or the presence of restriction endonuclease sites. Rather, it makes use of a PCR strategy to create an adhesive "band-aid" that directs the annealing of the amplified sequence to the correct location in the recipient clone. With this technique we created a series of chimeras involving the replacement of topologically defined protein domains of Cx32 with the corresponding sequences of Cx26. We focused on domains that are predicted to line the gap junction channel as we expect that a component of the voltage-sensing mechanism resides there. Differences between Cx26 and Cx32 in the sequences of their first and second extracellular loops, the cytoplasmic loop, and the third transmembrane domain did not account for the difference in their calculated gating charges. Shifts along the voltage axis in the steady-state conductance-voltage relations of the chimeric connexins were produced by replacement of the first extracellular loop or the cytoplasmic loop and the amino-terminal half of the third transmembrane domain. These data suggest that the voltage-sensing mechanism arises from the interaction of domains lining the aqueous channel and domains deeper in the channel wall.     

Do nurses feel stressed? A perspective from primary health care

This study describes nurses' experiences of stress in primary healthcare settings, and examines correlations between stress and personal factors. There were 187 nurses from 18 public primary care centers participating, drawn from one county of Lithuania. The Expanded Nursing Stress Scale was used to evaluate the study data. The study indicates that in primary healthcare centers, nurses working with adult patients experienced less stress than those working with younger patients. The most frequently reported stressors were those related to death and dying, and conflicts with physicians and patients and their families. In particular, older nurses more frequently experienced stress related to death and dying. The intensity of nurses' stress in conflict situations with physicians was related to age, however, the depth of work experience in the healthcare setting was more influential. Findings indicate that more detailed research is needed regarding stress experiences in primary health care, and especially the related impact of the social contexts involved in the setting.     

CD4+ T cell activation in multiple sclerosis

Interleukin-2 (IL-2) production by CD4-enriched T cells from multiple sclerosis (MS) patients and normal individuals stimulated with concanavalin A (conA) and/or autologous and allogeneic B lymphoid cell lines (B-LCL) was evaluated 24, 48 and 96 h after stimulation. ConA-stimulated CD4+ cells from MS patients did not produce significantly more IL-2 than normal CD4+ cells. In contrast, autologous B-LCL-induced IL-2 production by MS CD4+ cells significantly (P = 0.026) exceeded that produced by normal CD4+ cells identically stimulated after 24 h in culture. Differences in IL-2 production by CD4+ cells from MS patients reached highest significance using allogeneic B-LCL, whose stimulatory capacity was similar, whether established from normal individuals or MS patients. This increased IL-2 production in response to B-LCL may represent a supranormal response of CD4+ cells from MS patients to class II major histocompatibility (MHC)-associated stimuli. It suggests that the deficiency of suppressor T cell functions postulated to play a role in MS does not arise from a lack of IL-2 induction and might indicate that bursts of IL-2 production could play a role in MS.     

Expression of matrix metalloproteinases, their tissue inhibitors, and osteopontin in the wall of thoracic and abdominal aortas with dilatative pathology

Matrix metalloproteinases (MMPs) degrade extracellular matrix and may play a central role in the pathogenesis of aortic aneurysms. We studied 2 groups of patients: 15 with dilatative pathology of the ascending thoracic aorta and 17 with aneurysm of the abdominal aortic wall (AAA). We compared the expression of MMPs, tissue inhibitors of matrix metalloproteinases (TIMPs), and osteopontin in the wall of thoracic and abdominal aneurysms. In AAA, MMP-9 and TIMP-1 expression in inflammatory cells was higher than in smooth muscle cells (SMCs) (median score: 3.5 versus 1, P < .0001; 2 versus 1, P < .04, respectively), whereas MMP-2 demonstrated higher expression in SMCs than in inflammatory cells (median score: 0 versus 4, P < .0001). In ATA, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-3, and osteopontin expression in SMCs was higher than in inflammatory cells (median score: 3 versus 0, P < .0001; 4 versus 1, P < .0005; 2 versus 0, P < .001; 5 versus 2, P < .0001; 2 versus 0, P < .005; and 5 versus 1.5, P < .0001, respectively), when both inflammatory cells of the media and the adventitia were considered together. The cellular expression of MMP-9 and their tissue inhibitors TIMP-1, TIMP-2, and TIMP-3 differs in the dilatative pathology of abdominal and thoracic aortas, so the hypothetical model of morphogenesis of AAA cannot completely explain the formation of dilatative pathology of the ascending thoracic aorta.