The impact of hypermobility spectrum disorders on musculoskeletal tissue stiffness: an exploration using strain elastography

Clinical Rheumatology - Hypermobility spectrum disorders (HSDs) are conditions associated with chronic joint pain and laxity. HSD’s diagnostic approach is highly subjective, its validity is...     

Relaxin increases secretion of tissue inhibitor of matrix metalloproteinase-1 and -2 during uterine and cervical growth and remodeling in the pig.

Remodeling of reproductive organs during pregnancy requires degradation and resynthesis of structural barriers to cell invasion. Matrix metalloproteinases (MMPs) are enzymes that break down components of the extracellular matrix (ECM) and are essential for tissue remodeling processes. Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of MMP activity. In the pig, relaxin stimulates growth and remodeling of the uterus and cervix during pregnancy, effects that include the ability to alter elements of the ECM. Therefore, the objective of this study was to determine whether relaxin alters the production and/or activity of TIMP-1 and TIMP-2 in the porcine uterus or cervix. The growth-promoting effects of relaxin were elicited by administering relaxin to prepubertal gilts every 6 h for 54 h. Expression of TIMP-1 and TIMP-2 was characterized by immunoblotting. Total enzyme activity was measured using an MMP-specific fluorescent substrate assay. TIMP-1 and TIMP-2 proteins were present in the uterus and cervix of control and relaxin-treated pigs, and both proteins were increased by relaxin in the uterine flushes and tissues (P < 0.05). Inhibitor activity in uterine tissue extracts and uterine flushes from relaxin-treated animals was greater than that in controls; however, this activity was restricted to inhibition of MMP-2. In the uterine cervix, relaxin enhanced expression of TIMP-1 and TIMP-2 (P < 0.05), whereas expression of both TIMP proteins was similar in the vaginal cervix of control and relaxin-treated animals. Likewise, inhibitor activity against MMP-2 in the uterine cervix was enhanced in response to relaxin (P < 0.05). In contrast, inhibitor activity was attenuated in extracts from the vaginal cervix (P < 0.05). This study highlights the complex nature of MMP/TIMP regulation during reproductive tissue growth and suggests that TIMP-1 and TIMP-2 may be involved in other aspects of the growth process. These data support a role for relaxin in regulating the activity of TIMPs during growth and remodeling of reproductive connective tissue.     

Declining beta-cell function in type 2 diabetes: 5-year follow-up and immunologic studies of the population of Wadena, MN

The aim of the study was to describe 5-year changes in meal-stimulated pancreatic insulin reserve in adults with normal and impaired glucose tolerance (NGT, IGT) and diabetes, with or without islet-related antibodies. This was a 5-year follow-up of 270 residents of Wadena, MN, of northern European origin, with good kidney function, defined as creatinine clearance greater than 60 mL/min/1.73 m(2). The subjects comprised a population-based sample originally studied in 1986 to 1987. Urine C-peptide (CP), in a 260-minute collection, was the integrated measure of insulin secretion; Ensure-Plus (Ross, Columbus, OH) was the liquid meal. Islet cytoplasmic antibodies (ICA), insulin autoantibodies (IAA), and glutamate decarboxylase antibodies (GAD65ab) were measured. In 182 subjects with NGT, there was no mean within-subject change in urine CP over 5 years (P =.34). In 41 subjects with impaired GT (IGT), there was a moderate, but nonsignificant, increase in mean CP, and 6 (15%) subjects increased. In 37 type 2 diabetic subjects not taking insulin (type 2-No Ins), who had a mean diabetes duration at the 5-year examination of 9.6 +/- 6.3 years, there was a 21% decrease in mean urine CP (P =.012), attributable mostly to a major drop in 8 of the 37 subjects (22%). Islet-related antibody tests were mostly negative; GAD65ab positivity was related to CP decline only among insulin-taking subjects. In summary, in Wadena adults, meal-stimulated urine CP was stable or increased over 5 years in subjects with NGT and IGT, but CP decreased significantly in about one fifth of type 2-No Ins subjects, with no relation to antibody test results.     

Outcome of lung transplantation in patients with mycetomas.

BACKGROUND: Lung transplantation has become an acceptable treatment option for many end-stage lung diseases. Pulmonary mycetomas are found in patients with end-stage lung diseases, especially sarcoidosis. The clinical course and long-term outcome of these patients after transplantation remains unknown. METHODS: We reviewed retrospectively the pathology reports of the explanted lungs from all lung and heart-lung transplantations performed at our institution between January 20, 1992, and June 26, 2000. Patients were included in our study if mycetomas were present on the specimens. Information on transplant date and type, diagnosis, information on antifungal therapy and fungal infections pretransplant and posttransplant, and clinical course after transplantation was recorded. RESULTS: Mycetomas were present in 3.0% of transplant recipients (9 of 303 patients). The underlying pulmonary diagnoses were sarcoidosis (six patients), and emphysema, idiopathic pulmonary fibrosis, and pneumoconiosis (one patient each). Seven patients received bilateral lung transplants, one patient received a heart/lung transplant, and one patient received a single lung transplant. Aspergillus was isolated from culture in five patients pretransplant and from five patients posttransplant. Six patients received treatment with itraconazole, or IV or inhaled amphotericin B prior to transplantation. All patients who survived transplantation received posttransplant antifungal therapy. Four patients died in the first month after transplantation. Two patients died at 17 months and 24 months posttransplant, respectively; one patient received a second transplant 30 months later; and two patients are alive and free from fungal infections 17 months and 18 months, respectively, after transplantation. All of the medium-term survivors received lengthy therapy with inhaled and systemic amphotericin B and itraconazole before and after transplantation. CONCLUSIONS: Lung transplant recipients with mycetomas have significantly reduced posttransplant survival. Careful selection of patients and aggressive antifungal therapies before and after transplantation have led to improved outcomes in patients with mycetomas. Additional research is needed to define the best therapeutic strategy for these patients during transplantation.     

Candidate loci for insulin sensitivity and disposition index from a genome-wide association analysis of Hispanic participants in the Insulin Resistance Atherosclerosis (IRAS) Family Study

Aims/hypothesis

The majority of type 2 diabetes genome-wide association studies (GWAS) to date have been performed in European-derived populations and have identified few variants that mediate their effect through insulin resistance. The aim of this study was to evaluate two quantitative, directly assessed measures of insulin resistance, namely insulin sensitivity index (S_I) and insulin disposition index (DI), in Hispanic-American participants using an agnostic, high-density single nucleotide polymorphism (SNP) scan, and to validate these findings in additional samples.

Methods

A two-stage GWAS was performed in Hispanic-American samples from the Insulin Resistance Atherosclerosis Family Study. In Stage 1, 317,000 SNPs were assessed using 229 DNA samples. SNPs with evidence of association with glucose homeostasis and adiposity traits were then genotyped on the entire set of Hispanic-American samples (n?=?1,190). This report focuses on the glucose homeostasis traits: S_I and DI.

Results

Although evidence of association did not reach genome-wide significance (p?=?5?×?10^?7), in the combined analysis SNPs had admixture-adjusted p values of p _ADD?=?0.00010–0.0020 with 8 to 41% differences in genotypic means for S_I and DI.

Conclusions/interpretation

Several candidate loci were identified that are nominally associated with S_I and/or DI in Hispanic-American participants. Replication of these findings in independent cohorts and additional focused analysis of these loci is warranted.     

Human African trypanosomiasis in endemic focus of Abraka,Nigeria

ObjectiveTo investigated the prevalence of human African trypanosomiasis (HAT), a neglected tropical disease caused by Trypanosoma brucei gambiens in an endemic focus of Nigeria, as it relates to age, sex and occupational differences.MethodsA total of 474 human subjects were screened using card agglutination test for trypanosomiasis kit. Positive samples were further investigated for parasite positivity in blood/serum and cerebrospinal fluid (CSF).ResultsOf the 474 screened, 44(9.3%) were seropositive with seroprevalence of 22(9.6%) in Urhouka, 14(9.5%) in Umeghe and 8(7.9%) for Ugonu. The number of seropositives, observed for weakly, moderately and strongly positives for the three communities were 4, 7 and 11 in Urhouka, 4, 5 and 5 in Umeghe and 3, 2 and 3 in Ugonu respectively. Among the 16 volunteers with detected parasite in their blood, 4 of them were weakly positive, 5 of them were moderately positive and 7 of them strongly positive. 4 volunteers from Urhouka community were found parasites in their CSF and they were all strongly positive. The difference between the seroprevalence of males and females was not statistically significant (OR=1.14, 95% CI=0.37–3.4, P>0.05). The prevalence difference between age group 21–30 years old and the youngest and oldest age groups was statistically significant (OR=3.5, 95% CI=1.08–12.57, P<0.05) but not significant for other age categories (P>0.05). It was observed that farmers had significantly higher prevalence of HAT infection as well as greater risk of Trypanosoma brucei gambiense infection than inhabitants with other occupations (OR=3.25, 95% CI=0.99–11.79, P<0.05).ConclusionsHuman activities such as farming and visits to the river have been identified as major risk factors to HAT. Also the breakdown of HAT control program has been advanced for the rise in HAT in Abraka, an endemic focus in Nigeria.     

Effect of forward and reverse selection for ethanol-induced locomotor response on other measures of ethanol sensitivity

BACKGROUND: Ethanol sensitivity may be a predictor of genetic predisposition to ethanol abuse. To examine ethanol sensitivity in rodents, two lines of mice were bred in replicate for high (FAST-1 and -2) and low (SLOW-1 and -2) locomotor stimulant responses to ethanol. After large differences between the lines developed and further response to selection seemed to have arrested, reverse selection was initiated by breeding the slowest FAST mice with each other and the fastest SLOW mice with each other. The reverse-selected lines, named r-FAST and r-SLOW, were virtually equally sensitive to the stimulant effects of the selection dose of ethanol after 16 generations of reverse selection. METHODS: These experiments used this unique genetic model to examine two responses, putatively genetically correlated with sensitivity to ethanol stimulation: handling-induced convulsions during chronic ethanol withdrawal, and ethanol-induced hypothermia. Ethanol clearance, for which a small difference was previously found between the FAST and SLOW lines, was also examined. RESULTS: Handling-induced convulsions during chronic ethanol withdrawal were significantly greater in both FAST lines compared with both SLOW lines. Reverse selection eliminated the difference between the replicate 1 lines but did not alter the difference between the replicate 2 lines. Ethanol-induced hypothermia was greater in both SLOW lines compared with the FAST lines. This difference was significantly reduced by reverse selection in r-SLOW mice only. Ethanol clearance rates were similar among all lines and replicates. CONCLUSIONS: These data demonstrate the usefulness of reverse-selected lines for examining putatively genetically correlated traits. Changes in the correlated traits demonstrated the existence of persistent trait-relevant genetic heterogeneity and some genetic overlap between the correlated traits and the selection trait. Absence of a change after reverse selection suggests that trait-relevant genetic heterogeneity was eliminated by forward selection or, alternatively, that the trait was not influenced by genes associated with successful reverse selection.     

Heterogeneity in older people: examining physiologic failure,age, and comorbidity

OBJECTIVES: To derive a clinically relevant age-independent physiologic failure scoring system and to use this system to examine aspects of the association of physiologic failure, age, and comorbidity with inpatient mortality. DESIGN: Retrospective, secondary analysis of a derivation and validation cohort selected from the Cleveland Health Quality Choice Coalition data set. SETTING: Thirty hospitals in greater Cleveland. PARTICIPANTS: Thirty-one thousand nine hundred seventy-six inpatients aged 50 and older discharged in 1993 with a diagnosis of congestive heart failure, pneumonia, or stroke. MEASUREMENTS: The Inpatient Physiologic Failure Score (IPFS) was developed and used to calculate physiologic failure. Forty-four candidate variables were examined for their association with inpatient mortality, and 12 were selected. A point value (2, 3, 4, or 6) based on adjusted odds ratio was assigned for an abnormal result for each of the 12 common physiologic variables. Each patient's abnormal physiology points were summed to produce a physiologic failure score (range 0-39). Comorbidity was quantified using the Patient Management Category Severity Scale. The association between mortality and increasing physiologic failure, increasing age and comorbidity, and distribution of physiologic failure with increasing age and comorbidity were examined. A threshold age was sought. Models for predicting inpatient mortality were developed. RESULTS: Twelve physiologic variables constitute the IPFS. Increasing physiologic failure, age, and comorbidity were associated with increasing mortality. Increasing physiologic failure was not associated with increasing age or comorbidity. We did not find a threshold age. The area under the receiver operating characteristic (ROC) curve for predicting inpatient mortality for IPFS was 0.730, and for comorbidity was 0.741 (not significant). The area under the ROC curve for a mortality prediction model based on age was significantly less (0.603). Accounting for patient age did not significantly improve the predictive ability of the IPFS model (area = 0.752, P <.05). The complete model best predicted mortality (0.829). CONCLUSIONS: The IPFS represents a clinically relevant method for scoring physiologic failure. Physiologic failure, age, and comorbidity are independently and differently associated with inpatient mortality. Physiology fails independent of age and comorbidity.