Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire.

The study of immunoglobulin genes in multiple myeloma over the last decade has provided important information regarding biology, ontogenetic assignment, disease evolution, pathogenic consequences and tumor-specific therapeutic intervention. Detailed analysis of VH genes has revealed the clonal relationship between switch variants expressed by the bone marrow plasma cell and myeloma progenitors in the marrow and peripheral blood. Regarding VH usage, a bias was found against the V4-34 gene encoding antibodies with cold agglutinin specificity (anti-I/i), thus explaining in part the absence of autoimmune phenomena in myeloma compared to other B cell lymphoproliferative disorders. However, in some studies a substantial number of cases analyzed were carrying the rearranged Humkappav325 Vkapppa gene, known to be over utilized by B cell chronic lymphocytic leukemia clones and possessing autoantibody binding activity. VH genes accumulate somatic hypermutations following a distribution compatible with antigen selection, but with no intraclonal heterogeneity. The analysis of Vkappa genes indicates a bias in usage of Vkappa family members; somatic hypermutation, in line with antigen selection, of the expressed Vkappa genes is higher than any other B cell lymphoid disorder. Similar conclusions were reached for Vlambda genes; in this case, the analysis raises the controversial issue of N nucleotide insertion at Vlambda-Jlambda junctions, apparently as a result of TdT activity. A complementary imprint of antigen selection as evidenced by somatic hypermutation of either the VH or VL clonogenic genes has been observed. The absence of ongoing somatic mutations in either VH or VL genes gives rise to the notion that the cell of origin in myeloma is a post-germinal center memory B cell.     

Pressure support ventilation in adult respiratory distress syndrome: Short-term effects of a servocontrolled mode

: To assess the short-term effects of pressure support ventilation in adult respiratory distress syndrome (ARDS), we studied 17 patients with moderate to severe ARDS using mandatory rate ventilation (MRV), a servocontrolled mode of PSV having respiratory rate as the targeted parameter.: Based on the duration of ARDS, the patients were divided into two groups: Group 1, early ARDS (duration up to 1 week), 10 patients; Group 2, intermediate ARDS (duration between 1 and 2 weeks). The patients were initially ventilated with assisted mechanical ventilation then with MRV, and finally with controlled mechanical ventilation. After a 20-minute period allowed for stabilization in each mode, ventilatory variables, gas exchange, hemodynamics, and patient's inspiratory effort were evaluated.: During MRV blood gases, airway pressures and hemodynamic variables remained within acceptable limits in all patients. Compared with assisted mechanical ventilation, during MRV, patients of group 1 decreased their Vt and V? (from 0.64 ± 0.04 to 0.42 ± 0.03 L/sec) and increased their Ti/Tt (from 0.39 ± 0.03 to 0.52 ± 0.03). f did not change. PAO₂ - PaO₂ and Q?s/Q?t decreased (from 306 ± 16 to 269 ± 15 mm Hg, and from 20.2 ± 1.4 to 17.5 ± 1.1, respectively), while PaCO₂ increased (from 44 ± 3 to 50 ± 3 mm Hg). On the contrary, patients of group 2 increased their Vt (from 0.69 ± 0.02 to 0.92 ± 0.09 L), decreased their f (from 22.3 ± 0.5 to 19.3 ± 0.3 b/min), although they did not change their V? and Ti/Tt. PAO₂ - PaO₂ and Q?s/Q?t remained stable. PaCO₂ diminished (from 39 ± 3 to 34 ± 3 mm Hg). Pressure support level was higher in group 2 than in group 1 (29.4 ± 3.0 v 19.8 ± 2.9 cm H₂O).: We conclude that (1) PSV delivered by MRV may adequately ventilate patients with moderate to severe ARDS, preserving gas exchange and hemodynamics, at least for the short period tested; (2) early and intermediate ARDS respond in a different manner to MRV in terms of breathing pattern, gas exchange, and level of pressure assistance; and (3) patients with early ARDS are those who have an improvement in intrapulmonary oxygenation probably due, at least in part, to alveolar recruitment augmented by active diaphragmatic contraction.     

The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations

A pathogenic GAA repeat expansion in the first intron of the fibroblast growth factor 14 gene (FGF14) has been recently identified as the cause of spinocerebellar ataxia 27B (SCA27B). We herein screened 160 Greek index cases with late-onset cerebellar ataxia (LOCA) for FGF14 repeat expansions using a combination of long-range PCR and bidirectional repeat-primed PCRs. We identified 19 index cases (12%) carrying a pathogenic FGF14 GAA expansion, a diagnostic yield higher than that of previously screened repeat-expansion ataxias in Greek LOCA patients. The age at onset of SCA27B patients was 60.5 ± 12.3 years (range, 34–80). Episodic onset (37%), downbeat nystagmus (32%) and vertigo (26%) were significantly more frequent in FGF14 expansion-positive cases compared to expansion-negative cases. Beyond typical cerebellar signs, SCA27B patients often displayed hyperreflexia (47%) and reduced vibration sense in the lower extremities (42%). The frequency and phenotypic profile of SCA27B in Greek patients was similar to most other previously studied populations. We conclude that FGF14 GAA repeat expansions are the commonest known genetic cause of LOCA in the Greek population and recommend prioritizing testing for FGF14 expansions in the diagnostic algorithm of patients with LOCA.     

The impact of different fluence rates on pain and clinical outcome in patients with actinic keratoses treated with photodynamic therapy

Background/purpose: Literature data suggest that lower fluence rates are preferable in terms of clinical response and tolerability for treating patients with actinic keratoses (AKs). We aimed to clarify the impact of different fluence rates on pain during photodynamic therapy (PDT) for AKs, as well as on treatment outcome. Methods: Individuals with at least three discrete AKs were recruited. Each lesion was randomly allocated to 25, 50 or 75 mW/cm² of topical 5‐aminolevulinic acid (5‐ALA) PDT, using non‐coherent light source. Primary end point was pain during illumination, evaluated using a visual analogue scale (VAS). Secondary end points were clinical outcome and adverse events. Results: Fifty adults, with 150 AKs lesions were recruited in the study. Mean VAS score did not significantly differ between the groups of 25 and 50 mW/cm² (P=0.714). However, mean VAS was significantly higher at the group of 75 mW/cm² in comparison to the former ones (P=0.000). With respect to the clinical outcome and adverse events during the first year of follow‐up, no differences were observed between the three groups. Comparison between the 25 and the 50 mW/cm² (P=0.749), as well as between the former and the 75 mW/cm², did not show a dependence of complete response rate on fluence (P=0.749 and P=1.000, respectively). Conclusions: According to our observations a fluence rate between 25 and 50 mW/cm² is effective and better tolerated by patients treated with topical 5‐ALA PDT for AKs.     

Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma.

In this study, we analyzed the targeting of the somatic hypermutation (SHM) mechanism at specific hotspot sequence motifs in the V(H) and Vkappa genes of 10 follicular lymphoma (FL) cases and the Vkappa and Vlambda genes of 11 kappa- and six lamda-light chain expressing multiple myeloma (MM) cases. These sequences were analyzed for targeting of specific motifs, ie certain highly mutable trinucleotides (3-NTPs), the tetranucleotide (4-NTP) RGYW and its complementary, WRCY (where R = purine, Y = pyrimidine and W = A or T). Comparisons were carried out between mutation frequencies in RGYW vs WRCY and the incidence of mutations in complementarity determining region (CDR)-1 vs CDR2 vs CDR3. Statistically significant differences were obtained when comparing: (1) the ratio of mutations in 4-NTPs (RGYW, WRCY, RGYW+WRCY)/mutations in the whole V sequence in MM-Vkappa vs MM-Vlamda; (2) the total number of mutated 4-NTPs in MM-Vkappa vs FL-Vkappa; (3) the number of mutated RGYW 4-NTPs in MM-Vkappa vs FL-Vkappa and FL-V(H) vs FL-Vkappa; (4) the number of mutated WRCY 4-NTPs in MM-Vkappa vs FL-Vkappa (P= 0.006) and FL-V(H) vs FL-Vkappa; (5) the targeting of RGYW vs WRCY in the CDRs of FL-V(H) genes. Similar results (regarding statistical significance) were obtained when undertaking intergroup comparisons for 3-NTPs. These findings conform well with relevant data derived from normal peripheral B cells. The differences observed in favor of 4-NTP (RGYW and WRCY) targeting in FL-V(H) vs FL-Vkappa and MM-Vkappa vs FL-Vkappa may implicate differences in the evolution of SHM coupled with selection in different stages of B cell ontogeny. Several explanations can be offered for the fact that hotspot sequences were not always targeted by SHM in FL and MM: (1) other unrecognized motifs may be targets of SHM; (2) 'inappropriately' introduced mutations were fixed and propagated by the neoplastic process; (3) certain FL and MM cases might have lost their ability to correct mutations introduced in classic hotspots due to deficient mismatch-repair (MMR) mechanisms; conversely, in other cases with intact MMR function, the hotspot to non-hotspot targeting of somatic hypermutation is balanced.     

Performance of QuantiFERON®-TB Gold In-Tube assay in children receiving disease modifying anti-rheumatic drugs

Background

To evaluate the performance of the Quantiferon^®-TB Gold In-Tube (QFT-IT) interferon (IFN)-γ assay for the detection of latent tuberculosis infection (LTBI) in children receiving anti-rheumatic treatment in a tertiary referral hospital of Northern Greece.

Methods

A total of 79 consecutive children receiving anti-rheumatic treatment [of which 18 screened prior to antitumor necrosis factor (TNF)-α treatment] were tested using Mantoux tuberculin skin test (TST) and QFT-IT. Association of both tests with risk factors for latent tuberculosis and Bacillus Calmette-Guerin immunization was determined. Influence of age, TNF-α inhibitors, systemic corticosteroids, conventional disease modifying anti-rheumatic drugs (DMARDs) and total duration of therapy on the QFT-IT mitogen-induced response was evaluated.

Results

Agreement between TST and QFT-IT results was moderate (k=0.38). Frequency of QFT-IT indeterminate results was low (2.5%). In patients with risk factors for LTBI, the odds of a positive IFN-γ assay was increased by a factor of 27.6 (P=0.002), whereas there was no positive TST. There was a significant difference in the mitogen-induced IFN-γ secretion among various treatments (P=0.038). TNF-α inhibitors were associated with increased mitogen-induced IFN-γ secretion compared to monotherapy with conventional DMARDs (P=0.008). All children screened prior to anti-TNF-α treatment exhibited a negative QFT-IT and no active TB disease was detected during a 2-year follow-up.

Conclusions

QFT-IT may be a more reliable test than TST for detection of LTBI in children with rheumatic diseases receiving anti-rheumatic treatment. Drug regimen might influence the mitogen-induced IFN-γ secretion and the effect of TNF-α inhibitors might vary according to the specific agent administered.

     

Measurement equivalence of the Birth Satisfaction Scale-Revised (BSS-R): further evidence of construct validity

Objective and background: The 10-item Birth Satisfaction Scale-Revised (BSS-R) is being increasingly used internationally, including the development of translated versions of the tool. However, to date, a direct comparison between the original version of the tool and a non-English language translated version has yet to be conducted. Recognising that measurement equivalence is critical in order to be able to meaningfully compare scores on the measure between different versions, the current study sought to evaluate the measurement invariance characteristics of the BSS-R within this context. Methods: A secondary analysis of two data sets. The study used a measurement invariance testing approach to determine the relative equivalence between the original UK English-language version and the Greek-translated version of the BSS-R. Participants were a convenience sample of UK (n = 228) and Greek (n = 162) postnatal women. Results: The BSS-R was found to offer an excellent model fit with pooled data, a robust configural model and metric-level invariance between English- and Greek-language versions. The BSS-R was also found to demonstrate partial scalar invariance, with 80% of item intercepts non-invariant between both versions. Two non-invariant items at the scalar level are likely to represent real differences between participant groups in terms of birth satisfaction as an artefact of service delivery type and relative difference in delivery mode. Conclusion: The BSS-R is both conceptually and statistically comparable between different versions of the tool suggesting the utility of the measure for international comparative studies.