Iron homeostasis in beta-thalassemic mice

To explore the pathogenesis of nontransfusional iron overload in iron- loading anemia, we examined features of external iron exchange, internal iron kinetics, and tissue iron burden in adult mice with inherited gene-deletion beta-thalassemia. Mice homozygous for beta- thalassemia display moderate anemia, reticulocytosis, and shortened red cell survival, whereas heterozygous carriers appear hematologically normal. Quantitative iron determination revealed that iron content and concentration in liver, spleen, and kidney, but not heart, were far higher (P less than .01) in 15-to 35-week old homozygous thalassemic mice than in age-matched normal and heterozygous controls; of these tissues, iron content increased with age only in kidneys (P = .01) of homozygous affected mice. Although plasma iron levels were only minimally elevated in homozygotes, plasma iron turnover was threefold greater (P less than .001) than that seen in heterozygote controls. Nevertheless hyperabsorption of enteric radioiron, discernible among homozygous thalassemic mice as late as 6 to 8 weeks after birth, was not observed in older mice, additionally, thalassemic and control mice at 18 to 34 weeks showed comparable iron excretion after intravenous radioiron. We conclude that adult mice with beta-thalassemia regain balanced external iron exchange, despite substantial tissue iron excess and accelerated internal iron transit.     

Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus

We recently discovered the Kaposi's sarcoma-associated herpes virus (KSHV/HHV-8) in an uncommon and unusual subset of AIDS-related lymphomas that grow mainly in the body cavities as lymphomatous effusions without an identifiable contiguous tumor mass. The consistent presence of KSHV and certain other distinctive features of these body cavity-based lymphomas suggest that they represent a distinct entity. We tested this hypothesis by investigating 19 malignant lymphomatous effusions occurring in the absence of a contiguous tumor mass for their clinical, morphologic, immunophenotypic, viral, and molecular characteristics, KSHV was present in 15 of 19 lymphomas. All four KSHV- negative lymphomatous effusions exhibited Burkitt or Burkitt-like morphology and c-myc gene rearrangements and, therefore, appeared to be Burkitt-type lymphomas occurring in the body cavities. In contrast, all 15 KSHV-positive lymphomatous effusions exhibited a distinctive morphology bridging large-cell immunoblastic lymphoma and anaplastic large-cell lymphoma, and all 12 cases studied lacked c-myc gene rearrangements. In addition, these lymphomas occurred in men (15/15), frequently but not exclusively in association with HIV infection (13/15), in which homosexuality was a risk factor (13/13), presented initially as a lymphomatous effusion (14/15), remained localized to the body cavity of origin (13/15), expressed CD45 (15/15) and one or more activation-associated antigens (9/10) in the frequent absence of B-cell- associated antigens (11/15), exhibited clonal immunoglobulin gene rearrangements (13/13), contained Epstein-Barr virus (14/15), and lacked bcl-2, bcl-6, ras and p53 gene alterations (13/15). These findings strongly suggest that the KSHV-positive malignant lymphomatous effusions represent a distinct clinicopathologic and biologic entity and should be distinguished from other malignant lymphomas occurring in the body cavities. Therefore, we recommend that these malignant lymphomas be designated primary effusion lymphomas (PEL), rather than body cavity-based lymphomas, since this term describes them more accurately and avoids their confusion with other malignant lymphomas that occur in the body cavities. We further recommend that these PEL be considered for inclusion as a new entity in the Revised European- American Lymphoma Classification.     

Cryptic structural lesions in refractory partial epilepsy: MR imaging and CT studies

Results of contrast material-enhanced computed tomography (CT) and T2-weighted spin-echo magnetic resonance (MR) imaging were correlated with pathologic findings in 25 patients treated surgically for refractory partial epilepsy. Of 12 lesions present, ten (83%) were detected by MR imaging and seven (58%) by CT scanning. Of nine low-grade gliomas, eight were detected by MR imaging and four by CT scanning. One posttraumatic scar and one case of temporal lobe atrophy were better demonstrated by MR imaging. A small, thrombosed arteriovenous malformation was the only lesion detected by CT scanning but not by MR imaging. No lesions were detected in 13 patients with mild gliosis and one patient with a 1.2-cm grade 1 astrocytoma. Although more sensitive than CT for detection of structural lesions in patients with refractory partial epilepsy, MR imaging resulted in a 25% false-negative diagnostic rate when a repetition time of 2,000 msec and echo time of 60 msec were used. Multi-echo imaging with at least one long echo time may be needed to increase the sensitivity of MR imaging in these patients.     

Encapsidated adenovirus mini-chromosome-mediated delivery of genes to the retina: application to the rescue of photoreceptor degeneration

First (DeltaE1/E3) and second (DeltaE1+DeltaE2/E3/E4) generation adenovirus (Ad) vectors have been shown previously to be of limited use in the treatment of human genetic diseases due to the induction of a host cytotoxic T-cell mediated immune response against virally expressed genes. In addition, a limited cloning capacity of approximately 8 kb does not cater for the incorporation of large upstream sequences essential for regulated tissue-specific expression or inclusion of multiple gene-expression cassettes. In this study we have exploited our recently developed Ad-based vector, the encapsidated adenovirus mini-chromosome (EAM) from which all of the viral genes have been deleted. EAMs contain only the inverted terminal repeats required for replication and five cis -acting Ad encapsidation signals necessary for packaging. We have shown previously that EAMs can efficiently transduce a variety of cell types in vitro. In this study we demonstrate that EAMs can transduce and rescue cells from the neurosensory retina in vivo. EAM-mediated delivery of the beta subunit of cyclic GMP phosphodiesterase (PDE) cDNA to mice affected with retinal degeneration (rd) allows prolonged transgene expression and rescue of rod photoreceptor cells. RT-PCR analysis from the injected retina indicates that transgene products are present for at least 18 weeks post-injection. Both the alpha and beta subunits of PDE could be detected up to 90 days postnatal in EAM-injected rd retina by western analysis. A maximal PDE activity of 150 nm/min/mg was detected at 33 days postnatal. Examination of outer nuclear thickness showed significant differences up to 12 weeks post-injection. These results demonstrate an improved level of rescue over first-generation adenoviral vectors and suggest the possibility of successful EAM- mediated treatment of some retinal diseases in humans.      

The role of health insurance characteristics in utilization of bariatric surgery

BackgroundBariatric surgery is underutilized in the United States.ObjectiveTo examine temporal changes in patient characteristics and insurer type mix among adult bariatric surgery patients in southeastern Pennsylvania and to investigate the associations between payor type, insurance plan type, cost-sharing arrangements (among traditional Medicare beneficiaries), and bariatric surgery utilization.SettingPennsylvania Health Care Cost Containment Council’s databases in southeastern Pennsylvania during 2014–2018.MethodsAll adult patients who underwent the most common types of bariatric surgery and a 1:1 matched sample of surgery patients and those who were eligible for surgery but did not undergo surgery were identified. Contingency tables, Pearson χ² tests, and logistic regression were used for statistical analysis.ResultsOver the 5 years, there was an increase in the proportion of Black individuals (37.1% in 2014 versus 43.0% in 2018), Hispanics (5.4% versus 8.0%), and Medicaid beneficiaries (19.2% in 2014 versus 28.5% in 2018) who underwent surgery. The odds of undergoing bariatric surgery based on payor type only between Medicare beneficiaries were statistically different (22% smaller odds) compared with privately insured individuals. There were significantly different odds of undergoing surgery based on insurance plan type within Medicare and private insurance payor categories. Individuals with traditional Medicare plans with no supplementary insurance and those with dual eligibility had smaller odds of undergoing surgery (42% and 32%, respectively) compared with those with private secondary insurance.ConclusionsInsurance plan design may be as important in determining the utilization of bariatric surgery as the general payor type after controlling for confounding socio-demographic factors.     

Changes in symptom scores as a potential clinical endpoint for studies of cystic fibrosis pulmonary exacerbation treatment

Introduction: Symptom improvement was assessed as changes in the Chronic Respiratory Infection Symptom Score (CRISS) during intravenous antimicrobial exacerbation treatments among subjects from study NCT02109822.Methods: Median daily CRISS reduction (i.e., improvement) and covariates associated with CRISS reduction by Day 14 were assessed by logistic regression.Results: Among 173 subjects, median baseline CRISS was 49 [IQR 41, 56]; 93.6% had a CRISS reduction of ≥11 (minimal clinically important difference); median time to –11 reduction was 2 days [95% CI 2, 3]. The greatest median CRISS difference from baseline, on Day 17, was –26 [–29, –23]. Odds of –26 CRISS change by Day 14 were greater in subjects with higher baseline CRISS (P=.006) and younger ages (P=.041).Conclusions: CRISS response has good dynamic range and may be a useful efficacy endpoint for PEx interventional trials. The optimal use of CRISS change as an endpoint remains uncharacterized.     

Increased plasma thyroid stimulating hormone in treated congenital hypothyroidism: relation to severity of hypothyroidism, plasma thyroid hormone status, and daily dose of thyroxine

Plasma thyroid stimulating hormone (TSH) concentrations obtained during the first four years of treatment in 418 children with congenital hypothyroidism, identified by neonatal screening, were examined in relation to paired measurements of plasma thyroxine (n = 1945), free thyroxine (n = 836), triiodothyronine (n = 480), and free triiodothyronine (n = 231), and estimated daily dose of thyroxine at the time of blood sampling. Overall, plasma TSH was above 7 mU/l in 1280 out of 2960 samples (43%); the percentage was not related to severity of hypothyroidism at diagnosis. Mean values for thyroxine and free thyroxine, and to a lesser extent free triiodothyronine, were consistently lower in samples with TSH concentrations over 7 mU/l and this was the case in patients with either severe or less severe hypothyroidism. Raised TSH concentrations were also associated with lower mean doses of thyroxine (micrograms/kg/day) but here the mean doses of thyroxine in children with severe hypothyroidism were higher than in the children with less severe hypothyroidism. The mean dose of thyroxine associated with low/normal TSH values was highest in the first 6 months and fell progressively. Thyroxine dose was significantly related to thyroxine and free thyroxine concentrations but not to triiodothyronine and free triiodothyronine and the latter appeared to be of limited value as measures of plasma thyroid hormone status during treatment.     

瞬时性受体电位通道香草酸受体5、6与骨代谢的关系

目的:探讨瞬时性受体电位通道香草酸受体5、6与骨代谢的关系。资料来源:应用计算机检索PubMed数据库1999-01/2006-07相关瞬时性受体电位通道方面的文献,检索词“TRPV”,限定文献语言种类为English。资料选择:对资料进行初审,选取包括瞬时性受体电位通道香草酸受体5、6的文献,开始查找全文。纳入标准:对两者及瞬时性受体电位通道家族进行研究的文章。排除标准:研究内容局限于瞬时性受体电位通道香草酸受体1～4的文章。资料提炼:共检索到106篇关于瞬时性受体电位通道香草酸受体的文献,最终纳入30篇符合标准的文献。资料综合:瞬时性受体电位通道香草酸受体5、6是瞬时性受体电位通道超家族中的成员,是专门的上皮样钙离子通道。目前研究已经证明它们在肠道和肾脏等组织中有表达,并对跨细胞钙离子转运起着关键性调控作用。但在骨组织中表达情况相关报道较少,在骨代谢机制上的研究更少,本文针对目前两者与骨代谢的关系进行综述。结论:深入研究瞬时性受体电位通道香草酸受体5、6钙离子通道在骨代谢中的作用,对于那些与骨代谢相关疾病的治疗将能从分子水平上找到解决的方法。     

创伤与复苏:治疗创伤性凝血病需要特殊血液制品

民用创伤中心和部队战斗支持医院正在收治越来越多的严重损伤,他们常规挽救那些在二十年前无法医治的病人。最重要的进展是发展了“紧急”外科学———由于发生凝血病阻碍了正常解剖的恢复,这项技术的发展超越了常规的血库支持治疗。失控的凝血紊乱性出血是创伤后可预防的导致死亡的主要原因。在美国每年大约有1/10的人由于创伤需要医疗处理,其中1/100的人住院,大约1/1000由于创伤后紧急处理而输注了血液制品。2000年,美国马里兰的大学创伤性休克中心(UMSTC),5649人中8%的受伤病人入院后直接根据创伤情况输注红细胞,5%的输注血浆,3%的输注…     

Prevalence and risk factors for hepatitis C antibodies in volunteer blood donors in Brazil

BACKGROUND: Little is known about the prevalence, risk factors, and transmission of hepatitis C virus (HCV) in a nontransfused population, particularly in developing countries. STUDY DESIGN AND METHODS: To investigate the association between HCV seropositivity and some demographic variables, a case-control study was conducted on 138 seropositive donors among 4762 consecutive volunteer blood donors and 1101 seronegative controls in Rio de Janeiro, Brazil. Donors were initially screened by interview for male homosexuality, use of illicit drugs, tattoos, previous transfusions, venereal diseases, and jaundice. Eligible donors were then tested for HCV antibodies by enzyme-linked immunosorbent assay. A multivariate analysis was performed on age, ethnic group, gender, and prior donation. RESULTS: The overall prevalence of HCV seropositivity was 2.89 percent. An increased risk of seropositivity was demonstrated for nonwhite donors at an odds ratio of 2.11 (95% CI, 1.43-3.13), for males at 2.39 (95% CI, 1.01-5.7), and for prior donors at 1.66 (95% CI, 1.09-2.52). The risk of anti-HCV positivity increased markedly with age. Those at highest risk were the group 40 to 49 years old, with an odds ratio of 4.37 (95% CI, 2.39- 7.99) versus the group 20 to 29 years old. The group under 20 years old showed an odds ratio of 0.50 (95% CI, 0.06-3.87) compared to the group 20 to 29 years old. These findings were equally significant in a univariate analysis. CONCLUSION: Our results suggest that HCV seropositivity is strongly associated with male sex, nonwhite ethnicity, and greater age. A significant number of seropositive donors were not detected by screening interview.