Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Antigenic and immunogenic properties of recombinants from Salmonella typhimurium and Salmonella minnesota rough mutants expressing in their lipopolysaccharide a genus-specific chlamydial epitope.

Rough mutants from Salmonella typhimurium and Salmonella minnesota were transformed with a plasmid containing a 6.5-kilobase insert of DNA from Chlamydia trachomatis assumed to encode a glycosyltransferase. Transformation resulted in the expression of a genus-specific chlamydial epitope on the lipopolysaccharide (LPS) of the recombinant strains. Proteinase K-digested whole-cell lysates of the recombinants and of controls were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining or Western blot analysis. Two LPS populations were detected in the recombinants, the parent LPS and a faster-migrating component. The latter stained with monoclonal antibody against the genus-specific chlamydial epitope and was not seen in the controls. LPS was extracted and purified from recombinants of S. minnesota R595 and R4 and characterized by the passive hemolysis and passive hemolysis inhibition assays and by hydrolysis kinetics. Different antigenic determinants could be distinguished from each other by the passive hemolysis inhibition test with monospecific antigen-antibody reactions. Rabbits were immunized with heat-killed recombinant bacteria to study the immunogenic properties of the recombinants. In all animals, antibodies were raised against the parent core specificity and against the chlamydia-specific epitope. The data show that the recombinant bacteria are useful as immunogens to prepare polyclonal antisera against chlamydiae and that LPS isolated from them exhibits the same antigenic determinants as chlamydial LPS and may thus be used as a substitute for chlamydial LPS in serological assays.     

Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.      

Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia.

CONTEXT: Human papillomavirus (HPV) infection is believed to be the central cause of cervical cancer, although most of the epidemiological evidence has come from retrospective, case-control studies, which do not provide information on the dynamics of cumulative or persistent exposure to HPV infection. OBJECTIVE: To assess the risks of cervical neoplasia related to prior persistent HPV infections. DESIGN AND SETTING: Longitudinal study of the natural history of HPV infection and cervical neoplasia in women residing in the city of S?o Paulo, Brazil, which was conducted between November 1993 and March 1997 and involved repeated measurements of HPV and lesions with follow-up until June 2000. PARTICIPANTS: A total of 1611 women with no cytological lesions at enrollment and HPV test results available from the first 2 visits. MAIN OUTCOME MEASURE: Cervical specimens taken for Papanicolaou cytology and HPV testing every 4 months in the first year and twice yearly thereafter. Incident cervical cancer precursor lesions ascertained by expert review of all cytology smears. RESULTS: The incidence rate of squamous intraepithelial lesions (SILs) was 0.73 per 1000 women-months (95% confidence interval [CI], 0.5-0.9) among women free of HPV at the 2 initial visits and 8.68 (95% CI, 2.3-15.1) among women with HPV type 16 or 18 infections persisting over both visits. Relative to those negative for HPV oncogenic types at both initial visits, the relative risk (RR) of incident SIL was 10.19 (95% CI, 5.9-17.6) for persistent infections with any known oncogenic HPV types. The equivalent RR of incident high-grade SIL was 11.67 (95% CI, 4.1-33.3). The RRs of lesions were considerably higher for persistent infections with HPV type 16 or 18. CONCLUSION: A strong relationship exists between persistent HPV infections and SIL incidence, particularly for HPV types 16 and 18.     

Interaction between tobacco and alcohol consumption and the risk of cancers of the upper aero-digestive tract in Brazil

The authors investigated the joint effects of tobacco and alcohol consumption on the risk of squamous cell carcinomas of the upper aero-digestive tract (UADT) using data from a hospital-based case-control study conducted in southern Brazil, 1986-1989. A total of 784 cases of cancers of the mouth, pharynx, and larynx and 1,578 non-cancer controls matched on age, sex, hospital catchment area, and period of admission were interviewed about their smoking and drinking habits and other characteristics. Using logistic regression, evidence was found for interaction between the cumulative exposures for smoking and alcohol on UADT cancer risk. The joint effects for pharyngeal cancers exceeded the levels expected under a multiplicative model for moderate smokers (p = 0.007). There was little statistical evidence, however, for interaction on cancers of the mouth (p = 0.28) or larynx (p = 0.95). Among never smokers, heavy drinkers had 9.2 times (95% confidence interval 1.7, 48.5) greater risk of cancers of mouth, pharynx, and supraglottis than never drinkers, with a dose-response trend (p = 0.013) with cumulative consumption. The authors conclude that the interaction occurring in the pharynx between smoking and alcohol on UADT cancers is not uniform, with varying effects depending on the level of smoking exposure. Alcohol may act as both a promoter for tobacco and as an independent risk factor.     

Early relationships and marriage in conflict and post-conflict settings: vulnerability of youth in Uganda

While there is increased attention to child marriage, defined as marriage before 18 years of age, in countries where the practice is especially prevalent, less attention has been directed at understanding the factors affecting relationships, marriage and cohabitation among adolescents affected by conflict and displacement. This article presents factors which contribute to early relationships and informal marriages in conflict and post-conflict settings, based on qualitative research undertaken among two distinct populations in Uganda: internally displaced persons in Mucwini transit camp in northern Uganda and Congolese refugees in the Nakivale refugee settlement in southwestern Uganda. Themes were examined through a social–ecological framework. Findings indicate that fundamental shifts in economies, family relationships, and communication combined with structural changes encountered in settlements resulted in changed relationships and marriage patterns. Participants reported that poverty, splintering of family, and lack of education – which they believed to be exacerbated by conflict in both settings – had profoundly affected the views, perceptions and behaviours of youth around relationships and marriage. We identify interventions applicable to humanitarian settings that would offer refugee and internally displaced adolescents greater and more meaningful opportunities for development.     

Quantitative comparison of the microscopic anatomy of the human ACL femoral and tibial entheses

The femoral enthesis of the human anterior cruciate ligament (ACL) is known to be more susceptible to injury than the tibial enthesis. To determine whether anatomic differences might help explain this difference, we quantified the microscopic appearance of both entheses in 15 unembalmed knee specimens using light microscopy, toluidine blue stain and image analysis. The amount of calcified fibrocartilage and uncalcified fibrocartilage, and the ligament entheseal attachment angle were then compared between the femoral and tibial entheses via linear mixed‐effects models. The results showed marked differences in anatomy between the two entheses. The femoral enthesis exhibited a 3.9‐fold more acute ligament attachment angle than the tibial enthesis (p < 0.001), a 43% greater calcified fibrocartilage tissue area (p < 0.001), and a 226% greater uncalcified fibrocartilage depth (p < 0.001), with the latter differences being particularly pronounced in the central region. We conclude that the ACL femoral enthesis has more fibrocartilage and a more acute ligament attachment angle than the tibial enthesis, which provides insight into why it is more vulnerable to failure. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1811–1817, 2015.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

Evidence that Meningeal Mast Cells Can Worsen Stroke Pathology in Mice

Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cells in modulating brain pathology. Although different immune cells traffic through meningeal vessels en route to the brain, mature mast cells do not circulate but are resident in the meninges. With the use of genetic and cell transfer approaches in mice, we identified evidence that meningeal mast cells can importantly contribute to the key features of stroke pathology, including infiltration of granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two mast cell-derived products, interleukin-6 and, to a lesser extent, chemokine (C-C motif) ligand 7, can contribute to stroke pathology. These findings indicate a novel role for mast cells in the meninges, the membranes that envelop the brain, as potential gatekeepers for modulating brain inflammation and pathology after stroke.Stroke, the leading cause of adult disability and the fourth most common cause of death in the Unites States,^1,2 occurs when there is insufficient blood flow to the brain, and the resultant injury initiates a cascade of inflammatory events, including immune cell infiltration into the brain.^3–5 This post-stroke inflammation is a critical determinant of damage and recovery after stroke; understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention.^4–7 However, successfully exploiting this therapeutic potential requires a detailed understanding of the interplay between the immune system and the brain after stroke.⁴An understudied but important aspect of this interplay is the role of meningeal-located immune cells in modulating brain pathology. The meninges have long been recognized as an anatomical barrier that protects the central nervous system (CNS). However, accumulating evidence suggests that the meninges are important for communication between the CNS and immune system during health and disease.^8–10 All blood vessels pass through the meningeal subarachnoid space before entering the brain, and this vascular connection and the close proximity of the meninges to the underlying parenchymal nervous tissue make them ideally located to act as a gatekeeper to modulate immune cell trafficking to the CNS. To support this gatekeeper function is evidence that the meninges modulate brain infiltration of T cells, neutrophils, and monocytes during meningitis and autoimmune conditions,^11–14 with immune cells observed in some instances accumulating in the meninges before they infiltrate into the parenchyma.^11,13Emerging evidence suggests that the actions of immune cells resident in the meninges are important for this gatekeeper function.^11,12,15 Mast cells (MCs), best known as proinflammatory effector cells, can play critical roles in the development of inflammation in many disease settings.^16–18 MCs reside in high numbers within the meninges, but their function in this site has not been fully investigated in stroke pathology. Unlike most immune cells, mature MCs do not circulate in the blood but are long-term residents of tissues, often in perivascular locations, and can rapidly perform their functions in situ. CNS MCs are found in the brain parenchyma and the meninges of rodents and humans.¹⁸ It has been proposed that brain parenchymal MCs can enhance brain neutrophil numbers after stroke and can exacerbate stroke pathology.^19–24 However, much of the evidence to support such conclusions is indirect. For example, some of the studies that implicate MCs in stroke pathology used pharmacologic approaches to interfere with MC activation,^19,20,22 but such drugs can have effects on other cell types.²⁵ Moreover, the role of the meningeal MCs in modulating post-stroke inflammation and pathology is unknown. Finally, little is understood about which among the many MC-derived mediators may be important in stroke pathology.^17,26To address these questions, we used genetic and cell transfer approaches to study the role of MCs in the pathology of ischemic stroke in mice. Specifically, we tested a c-kit–mutant mouse model (ie, WBB6F₁-Kit^W/W-v mice) which is profoundly MC deficient and can be repaired of this deficiency by engraftment of in vitro-derived MCs from wild-type (WT) mice. This MC knock-in approach enables the MC-dependent effects in the mutant mice to be separated from effects due to other abnormalities associated with their mutation,^11,17,26,27 because only the MC deficiency is repaired by MC engraftment. Furthermore, one can investigate the mechanisms by which MCs influence stroke pathology by engrafting MCs from transgenic mice that lack specific MC-associated products. We also tested our newly described Cpa3-Cre; Mcl-1^fl/fl mice, in which MC (and basophil) numbers are reduced constitutively via Cre-mediated depletion of the anti-apoptotic factor, myeloid cell leukemia sequence 1 (Mcl-1), in the affected lineages.²⁸ Cpa3-Cre; Mcl-1^fl/fl mice lack the other abnormalities associated with the c-kit mutations in WBB6F₁-Kit^W/W-v mice.²⁸With the use of these in vivo models, we identified meningeal MCs as important contributors to key features of stroke pathology, including increased numbers of brain granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two potentially proinflammatory MC-derived products, IL-6 and, to a lesser extent, chemokine (C-C motif) ligand 7 (CCL7), can contribute to pathology in this setting.