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Our group previously demonstrated that M-protein light chain (LC) glycosylation can be detected on routine MASS-FIX testing. Glycosylation is increased in patients with immunoglobulin LC amyloidosis (AL) and rarely changes over the course of a patient’s lifetime. To determine the rates of progression to AL and other plasma cell disorders (PCDs), we used residual serum samples from the Olmsted monoclonal gammopathy of undetermined significance (MGUS) screening cohort. Four-hundred and fourteen patients with known MGUS were tested by MASS-FIX, and 25 (6%) were found to have glycosylated LCs. With a median follow-up of surviving patients of 22.2 years, the 20-year progression rates to a malignant PCD were 67% (95% CI 29%, 84%) and 13% (95% CI 9%, 18%) for patients with and without glycosylated LCs, respectively. The risk of progression was independent of Mayo MGUS risk score. The respective rates of progression to AL at 20 years were 21% (95% CI 0.0%, 38%) and 3% (95% CI 0.6%, 5.5%). In summary, monoclonal LC glycosylation is a potent risk factor for progression to AL, myeloma, and other PCDs, an observation which could lead to earlier diagnoses and potentially reduced morbidity and mortality.

Smoldering multiple myeloma (SMM) carries a 50% risk of progression to multiple myeloma (MM) or related malignancy within the first 5 years following diagnosis. The goal of this study was to determine if high levels of circulating plasma cells (PCs) are predictive of SMM transformation within the first 2–3 years from diagnosis. Ninety-one patients diagnosed with SMM at Mayo Clinic from January 1994 through January 2007, who had testing for circulating PCs using an immunofluorescent assay and adequate follow-up to ascertain disease progression, were studied. High level of circulating PCs was defined as absolute peripheral blood PCs >5 × 10 6 /l and/or >5% PCs per 100 cytoplasmic immunoglobulin (Ig)-positive peripheral blood mononuclear cells. Patients with high circulating PCs (14 of 91 patients, 15%) were significantly more likely to progress to active disease within 2 years compared with patients without high circulating PCs, 71% versus 24%, respectively, P =0.001. Corresponding rates for progression within 3 years were 86% versus 34%, respectively, P <0.001. Overall survival (OS) after both SMM diagnosis and MM diagnosis was also significantly different. High levels of circulating PCs identify SMM patients with an elevated risk of progression within the first 2–3 years following diagnosis.

To determine if the serum free light chain (FLC) ratio has prognostic value in patients with symptomatic multiple myeloma (MM), baseline serum samples from a well-characterized cohort of 790 newly diagnosed MM patients were tested with the FLC assay. FLC ratio was calculated as κ/λ (reference range 0.26–1.65). On the basis of the distribution of values, a cutpoint κ/λ FLC ratio of <0.03 or >32 was chosen for further analysis. Overall survival was significantly inferior in patients with an abnormal FLC ratio of <0.03 or >32 ( n =479) compared with those with an FLC ratio between 0.03 and 32 ( n =311), with median survival of 30 versus 39 months, respectively. We incorporated abnormal FLC ratio with the International Staging System (ISS) risk factors (that is, albumin <3.5 g/dl and serum β 2 -microglobulin ⩾3.5 g/l), to create a risk stratification model with improved prognostic capabilities. Patients with 0, 1, 2 or 3 adverse risk factors had significantly different overall survival, with median survival times of 51, 39, 30 and 22 months, respectively ( P <0.001). These findings suggest that the serum FLC ratio at initial diagnosis is an important predictor of prognosis in myeloma, and can be incorporated into the ISS for improved risk stratification.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5–3.7; P <0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1–3.00; P =0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

The purpose of this study was to determine if there is an increased risk of acute leukemia and myelodysplastic syndromes (MDS) in persons with monoclonal gammopathy of undetermined significance (MGUS). We used a large population-based cohort of individuals systematically screened for the presence or absence of MGUS. MGUS status was then linked to the diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and MDS. A total of 17 315 patients age 50 and older (605 MGUS and 16 710 controls) with a cumulative 435 021 person-years of follow-up were studied. MGUS patients had a significantly higher risk of developing MDS compared with controls, hazard ratio 2.4 (95% CI 1.08, 5.32), P =0.031. There was no statistically significant increase in the risk of AML (RR 1.36 P =0.675), and no increased risk of developing ALL.

Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information ( n =337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population ( P <0.001). In multivariable analysis, survival for the entire study cohort ( n =1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9–27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7–15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ⩾15 × 10 9 /l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.

Many clinical musculoskeletal pain conditions are characterized by chronic inflammation that sensitizes nociceptors. An unresolved issue is whether inflammation affects all nociceptors in a similar manner. Exercise-induced muscle damage (EIMD) has been proposed as a model for simulating clinical inflammatory pain in healthy samples. We sought to test the effect of EIMD on various painful stimuli (pressure and thermal), central pain processing (via the nociceptive flexion reflex) and endogenous pain modulation via conditioned pain modulation and exercise-induced hypoalgesia. Eighteen participants (9F, age: 24.6 ± 3.3) were recruited for repeated measures testing and each completed pain sensitivity testing prior to and 48 hours after an eccentric exercise protocol. The participants performed a minimum of 6 rounds of 10 eccentric knee extension exercises to induce muscle damage and localized inflammation in the right quadriceps. Force decrements, knee range-of-motion, and delayed onset muscle soreness (DOMS) were used to quantify EIMD. There was a significant main effect of time for pressure pain (%diff; -58.9 ± 23.1; p = 0.02, ηp2 = 0.28) but no significant main effect was observed for limb (%diff; -15.5 ± 23.9; p = 0.53, ηp2 = 0.02). In contrast, there was a significant interaction between time and limb (p < 0.001, ηp2 = 0.47) whereby participants had lower pressure pain sensitivity in the right leg only after the damage protocol (%diff; -105.9 ± 29.2; p = 0.002). Individuals with chronic inflammatory pain usually have an increased sensitivity to pressure, thermal, and electrical stimuli, however, our sample, following muscle damage to induce acute inflammation only had sensitivity to mechanical pain. Exercise induced inflammation may reflect a peripheral sensitivity localized to the damaged muscle rather than a global sensitivity like those with chronic pain display.

In this population-based descriptive study covering the 65-year period, 1928-92, there was a 5-fold increase in hip fracture prevalence among Rochester, Minnesota residents between 1928-42 and 1973-82, from 135.8 to 675.8 per 100,000. This change was dictated almost entirely by an increase in the incidence of first hip fractures due to moderate trauma (n = 2058) that was observed among Rochester women through 1950, and among men through 1980, that affected all age groups. Declining incidence rates thereafter led to a 9% fall in hip fracture prevalence from 1973-82 to 1983-92 to a rate of 612.7 per 100,000. A 13.7-year increase in age at first hip fracture over the study period was accounted for by aging of the underlying population, and a comparable 13.9-year increase in the age at death following hip fracture appeared to result from improved survival in the population generally. Thus, trends in hip fracture prevalence were mainly determined by changes in incidence rather than relative changes in age at onset and death following hip fracture.

Sex differences exist in pain sensitivity, however, the underlying mechanism(s) that explain these differences are not fully understood. Pain sensitivity has been shown to be influenced by body mass index, but limited data exist on the role of body composition on pain sensitivity. The purpose was to examine the influence of body composition on pain sensitivity in males and females. This cross-sectional study design used pressure pain thresholds (PPT) of 87 participants (45 female) who were assessed in the vastus lateralis (leg PPT) and brachioradialis (arm PPT) using a pressure algometer. Fat and lean tissue were assessed via dual-energy X-ray absorptiometry (DXA). A two group by two limb, repeated measured ANOVA was used to assess differences between limbs and sex. Spearman correlations and hierarchical regression analyses were employed to determine the association between body composition and PPT. Males had higher PPTs then females ( <0.05) and had higher DXA assessed lean and lower levels fat mass ( <0.05). Total body and limb specific lean mass was associated with PPTs (r≥0.34; <0.05). Hierarchical regression analysis revealed lean mass was a significant predictor of 8% of the variance in arm PPT ( <0.006) and 18% of the variance in leg PPT ( <0.001). However, lean mass was not found to statistically mediate the observed sex differences in PPT. This finding suggests lean mass may play a previously unknown role in sex differences in pressure pain sensitivity. Future studies are needed to confirm this finding and a larger sample size is likely required to have sufficient power to perform the mediation analysis.

This controlled trial was designed to investigate the influence of osteoporosis-related kyphosis (O-K) on falls. Twelve community-dwelling women with O-K (Cobb angle, 50-65 degrees measured from spine radiographs) and 13 healthy women serving as controls were enrolled. Mean age of the O-K group was 76 years (+/-5.1), height 158 cm (+/-5), and weight 61 kg (+/-7.9), and mean age of the control group was 71 years (+/-4.6), height 161 cm (+/-3.8), and weight 66 kg (+/-11.7). Quantitative isometric strength data were collected. Gait was monitored during unobstructed level walking and during stepping over an obstacle of four different heights randomly assigned (2.5%, 5%, 10%, and 15% of the subject's height). Balance was objectively assessed with computerized dynamic posturography consisting of the sensory organization test. Back extensor strength, grip strength, and all lower extremity muscle groups were significantly weaker in the O-K group than the control group (P <0.05), except right ankle plantar flexors (P =0.09). There was a significant difference in the anteroposterior and mediolateral displacements and velocities. The O-K subjects had less anteroposterior displacement, greater mediolateral displacement, reduced anteroposterior velocity, and increased mediolateral velocity compared with controls for all conditions of unobstructed and obstructed level walking. Obstacle height had a significant effect on all center-of-mass variables. The O-K subjects had significantly greater balance abnormalities on computerized dynamic posturography than the control group (P =0.002). Data show that thoracic hyperkyphosis on a background of reduced muscle strength plays an important role in increasing body sway, gait unsteadiness, and risk of falls in osteoporosis.