Isolated calf deep vein thrombosis in the community setting: the Worcester Venous Thromboembolism study

The prevalence of isolated calf deep vein thrombosis (DVT) in the community setting is relatively unexplored. Confusion remains with regards to its management and contemporary natural history. The purpose of this investigation was to describe the number of cases of calf DVT in the community, use of early management strategies, and rates of venous thromboembolism (VTE) recurrence and major bleeding. The medical records of residents of the Worcester (MA) metropolitan area with ICD-9 codes consistent with potential VTE during 4 study years (1999/2001/2003/2005) were validated by trained nurses. Patient demographic/clinical characteristics, treatment practices, and outcomes were evaluated. Isolated calf DVT was diagnosed in 166 (11.1%) of 1,495 patients with lower extremity DVT. Patients with calf DVT were less likely to be discharged on anticoagulants or with an IVC filter than patients with proximal DVT (84.1 vs. 92.3%). The rates of VTE recurrence and pulmonary embolism did not differ significantly between patients with calf DVT and proximal DVT at 6 months (11.0 vs. 8.7%, 2.6 vs. 1.8%, respectively). Patients with calf DVT had higher adjusted risk of early (14-day) VTE recurrence/extension (OR 2.34, 95% CI 1.01–5.44). Patients with calf DVT had lower rates of major bleeding at 6 months compared to patients with proximal DVT (5.2 vs. 9.3%, P = 0.04). Rates of recurrent VTE and major bleeding following calf DVT in the community are much higher than in randomized clinical trials of patients with proximal or calf DVT. Further study of management strategies for isolated calf DVT is needed.     

Diversification of complex butterfly wing patterns by repeated regulatory evolution of a Wnt ligand

Although animals display a rich variety of shapes and patterns, the genetic changes that explain how complex forms arise are still unclear. Here we take advantage of the extensive diversity of Heliconius butterflies to identify a gene that causes adaptive variation of black wing patterns within and between species. Linkage mapping in two species groups, gene-expression analysis in seven species, and pharmacological treatments all indicate that cis-regulatory evolution of the WntA ligand underpins discrete changes in color pattern features across the Heliconius genus. These results illustrate how the direct modulation of morphogen sources can generate a wide array of unique morphologies, thus providing a link between natural genetic variation, pattern formation, and adaptation.     

Mental health of displaced and refugee children resettled in low-income and middle-income countries: risk and protective factors

Children and adolescents who are forcibly displaced represent almost half the world's internally displaced and refugee populations. We undertook a two-part systematic search and review of the evidence-base for individual, family, community, and societal risk and protective factors for the mental health outcomes of children and adolescents. Here we review data for displacement to low-income and middle-income settings. We draw together the main findings from reports to identify important issues and establish recommendations for future work. We draw attention to exposure to violence as a well established risk factor for poor mental health. We note the paucity of research into predictor variables other than those in the individual domain and the neglect of other variables for the assessment of causal associations, including potential mediators and moderators identifiable in longitudinal work. We conclude with research and policy recommendations to guide the development and assessment of effective interventions.     

Impact of a psychoeducational intervention on caregiver response to behavioral problems

BACKGROUND: Eighty percent of persons with Alzheimer's disease and related disorders are cared for by family members who often lack adequate support and training for this all-consuming job. OBJECTIVE: To evaluate the efficacy of a longitudinal, multisite, community-based intervention designed to teach home caregivers to manage behavioral problems in persons with Alzheimer's disease. METHODS: Usable data were analyzed from 237 caregiver/care recipient dyads (n = 132 Experimental; n = 105 Comparison). The experimental group received a psychoeducational nursing intervention that was conceptually grounded in the Progressively Lowered Stress Threshold model (Hall & Buckwalter, 1987). The comparison group received routine information and referrals for case management, community-based services, and support groups. Although a variety of psychosocial outcomes were compared between caregivers in the two groups, this article focuses on frequency and response to behavioral problems and functional decline. RESULTS: The Progressively Lowered Stress Threshold intervention had a statistically significant effect on spousal response to memory/behavioral problems (p <.01) for all caregivers and on response to activities of daily living problems (p <.01) for spousal caregivers. In addition, nonspouses in the experimental group reported a reduction in the frequency of memory/behavioral problems (p <.01). No intervention effect on reports of activities of daily living frequencies was found for either spouses or nonspouses. CONCLUSIONS: This Progressively Lowered Stress Threshold-based intervention had a positive impact on both the frequency of and response to problem behaviors among spousal caregivers.     

Extrahepatic metastases occur in a minority of hepatocellular carcinoma patients treated with locoregional therapies: analyzing patterns of progression in 285 patients

Although most cancers are considered predominantly systemic processes, this may not hold true for hepatocellular carcinoma (HCC). The literature regarding patterns of progression of HCC (local versus systemic) has been relatively sparse. Our objectives were to: (1) analyze patterns of progression in HCC patients presenting with intrahepatic disease from initial treatment until death, and (2) identify clinically relevant risk factors for the development of metastases. Over a 9-year period, 285 patients treated with transarterial locoregional therapies underwent scheduled imaging follow-up from treatment until death and were categorized by pattern of progression: (i) intrahepatic (increased tumor enhancement/size, development/progression of vascular invasion, new hepatic lesions) progression or (ii) extrahepatic (adrenal/bone/lung/lymph node) metastases. Uni/multivariate analyses assessing the risk factors for the development of metastases were performed. The median time from last scan to death was 2.4 months (interquartile range: 1.3-4.8 months). The time to development of metastases, vascular invasion, and/or new lesions was 13.8 months (confidence interval: 11.3-17.7 months). Of the 209 patients followed until death, only 50 developed extrahepatic metastases (24%). Multivariate analyses identified age <65 years (P = 0.038), alpha-fetoprotein >200 ng/mL (P = 0.04), and vascular invasion (P = 0.017) as significant predictors of metastases development. CONCLUSION: Knowledge of the risk factors associated with the development of metastases may help guide assessment of patient prognosis. Because 76% of patients presenting with local disease treated with locoregional therapies die without developing extrahepatic metastases, the notion of HCC as a systemic disease, as detected by imaging, may be reconsidered.     

The prion model for [URE3] of yeast: Spontaneous generation and requirements for propagation

The genetic properties of the non-Mendelian element, [URE3], suggest that it is a prion (infectious protein) form of Ure2p, a mediator of nitrogen regulation in Saccharomyces cerevisiae. Into a ure2Δ strain (necessarily lacking [URE3]), we introduced a plasmid overproducing Ure2p. This induced the frequent “spontaneous generation” of [URE3], with properties identical to the original [URE3]. Altering the translational frame only in the prion-inducing domain of URE2 shows that it is Ure2 protein (and not URE2 RNA) that induces appearance of [URE3]. The proteinase K-resistance of Ure2p is unique to [URE3] strains and is not seen in nitrogen regulation of normal strains. The prion-inducing domain of Ure2p (residues 1–65) can propagate [URE3] in the absence of the C-terminal part of the molecule. In contrast, the C-terminal part of Ure2p cannot be converted to the prion (inactive) form without the prion-inducing domain covalently attached. These experiments support the prion model for [URE3] and extend our understanding of its propagation.     

The Bcl-2/Bax ratio of lymphocytes from human systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease. It has recently been suggested that a failure of apoptosis wherein autoreactive lymphocytes continue to survive is a major factor in the pathogenesis of SLE. Fas antigen is increased on peripheral blood lymphocytes from human SLE patients while Bcl-2 protein, which inhibits apoptosis, is highly expressed in peripheral T lymphocytes of SLE patients. The Bcl-2 family includes homologs that are believed to be related to regulation of apoptosis. Of these, Bax is capable of forming heterodimers with Bcl-2, thereby counteracting the action of Bcl-2. The present study examines the ratio of Bcl-2 to Bax in relation to the activity of SLE, with implications relating to the survival or death of lymphocytes. The ratio of Bcl-2 to Bax in active SLE was significantly higher than in inactive SLE and in normal controls. Although the exact role of apoptosis in SLE is still unclear, a high ratio of Bcl-2 to Bax in active SLE patients might support the survival of autoreactive cells.     

The contribution of activated factor XIII to fibrinolytic resistance in experimental pulmonary embolism

BACKGROUND: The resistance of thrombi to fibrinolysis induced by plasminogen activators remains a major impediment to the successful treatment of thrombotic diseases. This study examines the contribution of activated factor XIII (factor XIIIa) to fibrinolytic resistance in experimental pulmonary embolism. METHODS AND RESULTS: The fibrinolytic effects of specific inhibitors of factor XIIIa-mediated fibrin-fibrin cross-linking and alpha2-antiplasmin-fibrin cross-linking were measured in anesthetized ferrets with pulmonary emboli. Five experimental groups were treated with heparin (100 U/kg) and/or tissue plasminogen activator (TPA, 1 mg/kg) and the percent (mean+/-SD) lysis of emboli was determined: (1) control, normal factor XIIIa activity (14.1+/-4. 8% lysis); (2) inhibited factor XIIIa activity (42.7+/-7.4%); (3) normal factor XIIIa activity+TPA (32.3+/-7.7%); (4) inhibited factor XIIIa activity+TPA (76.0+/-11.9%); and (5) inhibited alpha2-antiplasmin-fibrin cross-linking+TPA (54.7+/-3.9%). Inhibition of factor XIIIa activity increased endogenous lysis markedly (group 1 versus 2; P<0.0001), to a level comparable to that achieved with TPA (group 2 versus 3; P<0.05). Among groups receiving TPA, selective inhibition of factor XIII-mediated alpha2-antiplasmin-fibrin cross-linking enhanced lysis (group 3 versus 5; P<0.0005). Complete inhibition of factor XIIIa also amplified lysis (group 3 versus 4; P<0.0001) and had greater effects than inhibition of alpha2-antiplasmin cross-linking alone (group 4 versus 5; P<0.0005). No significant fibrinogen degradation occurred in any group. CONCLUSIONS: Factor XIIIa-mediated fibrin-fibrin and alpha2-antiplasmin-fibrin cross-linking both caused experimental pulmonary emboli to resist endogenous and TPA-induced fibrinolysis. This suggests that factor XIIIa may play a critical role in regulating fibrinolysis in human thrombosis.     

Mapping a gene defect in absorptive hypercalciuria to chromosome 1q23.3-q24

Absorptive hypercalciuria (AH), a common cause of kidney stones, is due to intestinal hyperabsorption of calcium. The presence of a family history of nephrolithiasis, in about half of the affected individuals studied indicates that an inherited genetic defect is one likely cause of AH. Although it is known that intestinal calcium absorption is regulated by a number of factors, the molecular biological basis for the increased calcium absorption in AH is unknown. This study was designed to determine the chromosomal locus of the gene defect linked to the AH phenotype in three families with a severe form of AH. Three kindreds were evaluated in a systematic autosomal genome-wide linkage analysis study. The AH phenotype, characterized by hyperabsorption of calcium and hypercalciuria, was linked to only one chromosomal locus, 1q23.3-q24. A 2-point logarithm of odds score of 3.3 was obtained with markers D1S318 and D1S196 at a recombination frequency of theta = 0. Nonparametric multipoint linkage analysis yielded a peak nonparametric linkage Z(all)-score of 12.7, P = 6 x 10(-6) Analysis of key recombinants within the families studied localized the gene to a 4.3-megabase region between markers D1S2681 (centromere) and D1S2815. A trait associated with intestinal hyperabsorption of calcium in a severe form of absorptive hypercalciuria has been mapped to chromosome 1q23.3-q24.     

Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient

Clotting factor activities and coagulation screening tests in 36 massively transfused patients were measured after every 12 units of blood and whenever diffuse microvascular bleeding (MVB) developed. Moderate deficiencies in clotting factors were common, but they were not associated with MVB. MVB was associated with severe abnormalities of coagulation, i.e. a fibrinogen level less than 0.5 g/l or clotting factor levels less than 20%. The quantitative relationship between the prothrombin (PT) and partial thromboplastin (PTT) times and underlying clotting factor levels was explored by multiple linear regression. Clotting factor levels accounted for only 65-85% of the variability in these tests. However, clotting factor activities less than 20% were reliably reflected by marked prolongations of the PT and PTT (values greater than 1.8 times control). Our data suggest that commonly used replacement formulas are not likely to prevent MVB, since consumption of platelets and/or clotting factors, rather than simple dilution, is a major cause of the deficiencies leading to MVB. Modified whole blood alone was sufficient replacement therapy for most patients. Guidelines for transfusion of supplemental components during massive transfusion are given.