Serum concentrations of DDE, PCBs, and other persistent organic pollutants and mammographic breast density in Triana, Alabama, a highly exposed population.

INTRODUCTION: Although some persistent organic pollutants (POPs) are considered human carcinogens, results from studies evaluating exposures and breast cancer risk have been inconsistent, potentially related to varying ages at exposure. Additionally, few studies evaluated the association between POPs exposure and mammographic breast density (MBD), an intermediate biomarker of breast cancer risk. We carried out a cross-sectional study to investigate associations between serum POPs concentrations and MBD measured in 1998 in female residents of Triana, Alabama, in a predominately African American population with high POPs exposures, particularly to p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane). METHODS: We measured lipid-adjusted serum concentrations (ng/g lipid) of p,p'-DDT and its main metabolite p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), polychlorinated biphenyls (PCBs), ß-hexachlorocyclohexane (ß-HCCH), heptachlor epoxide, oxychlordane, trans-nonachlor, mirex, and aldrin for each woman in our study (n = 210). We also measured two MBD metrics, percent MBD (%MBD) and area of MBD (aMBD). Using adjusted Spearman correlation coefficients (rs) we evaluated correlations between %MBD and aMBD with individual POPs in the overall population and by age group (19-40, 41-54, and 55-91 years) and also estimated adjusted mean measures of MBD with 95% confidence intervals across tertiles of analytes using generalized linear models (GLM). We calculated p-values for multiplicative interaction by age group using GLM. Additional analyses excluded women with current hormone replacement therapy (HRT) use and evaluated early-life exposure (prior to age 18) during the heaviest contamination period in Triana (1947-90). RESULTS: Among all women, we found no correlation between p,p'-DDE and %MBD, but after age stratification and exclusion of HRT users, there was a suggestion of a difference by age group, with younger women having a weak positive correlation (rs = 0.12, p = 0.37) and older women having a weak negative correlation (rs = -0.12, p = 0.43); pinteraction = 0.06. In contrast, PCBs were weakly positively correlated with %MBD among all women, with the correlation magnitudes increasing after excluding current HRT users (rs-total PCBs = 0.17, p = 0.03). After age stratification and exclusion of HRT users, correlations for PCBs were higher among younger and middle-age women, with only a handful of these correlations being statistically significant. For ß-HCCH, the strongest finding was a negative correlation among older women (rs = -0.26, p = 0.07). Correlations were positive predominantly in the younger age group for heptachlor epoxide (rs = 0.27, p = 0.04), oxychlordane (rs = 0.35, p = 0.006), and trans-nonachlor (rs = 0.37, p = 0.003), and largely null for the middle and older age groups; pinteraction range: 0.03-0.05. Similar patterns were found in GLM analyses using tertiles of exposure and aMBD as the metric for MBD. Women exposed during the heaviest chemical contamination period in Triana prior to age 18 had positive correlations between %MBD and PCBs, heptachlor epoxide, mirex, oxychlordane, and trans-nonachlor. CONCLUSIONS: In this population, despite high exposures to p,p'-DDT and thus high serum concentrations of its main metabolite, p,p'-DDE, we did not find strong evidence of a positive association with MBD. In fact, there was some evidence of a negative association among older women for p,p'-DDE; a similar pattern was found for ß-HCCH. However, younger women with higher serum levels of PCBs, heptachlor epoxide, oxychlordane, and trans-nonachlor, who were likely exposed in early life, had higher MBD. These findings should be replicated in larger studies.

Outcomes following laparoscopic transhiatal esophagectomy for esophageal cancer.

BACKGROUND: Most published minimally invasive esophagectomy techniques involve a multiple field approach, including laparoscopic and thoracoscopic esophageal mobilization. Laparoscopic transhiatal esophagectomy (LTE) should potentially reduce the complications associated with thoracotomy. This study aims to compare outcomes of LTE with open transhiatal esophagectomy (OTE) and en-bloc esophagectomy (EBE). METHODS: Retrospective chart review was performed on all patients who had an LTE for cancer between July 2008 and July 2012 at our institution. Data was compared with an historic cohort of patients who underwent OTE and EBE at the same institution from July 2002 to July 2008. RESULTS: There were 33 patients with LTE, compared with 60 patients with OTE and 139 with EBE. The presence of minor operative complications was similar (p = 0.36), but major complications were significantly less common in the LTE group (12, 23 and 33 %, respectively; p = 0.04). The median number of blood transfusions during hospitalization was significantly lower in the LTE group (0, 2.5 and 3, respectively; p = 0.005). Median tumor size was significantly smaller (1.5, 2.2, and 3 cm, respectively; p = 0.03), but the LTE group had a significantly higher percentage of patients with neoadjuvant treatment (39, 14 and 29 %, respectively; p = 0.008). Median lymph node yield for LTE was lower (24, 36 and 48, respectively; p < 0.0001), but the percentage of patients with positive nodes was similar (33, 33 and 39 %, respectively; p = 0.69). Mortality was equivalent among the groups (0, 2 and 4 %, respectively; p = 0.38). The median LOS for the LTE group was significantly lower (10, 13 and 15 days, respectively; p < 0.0001). Overall survival was not different between the three groups (p = 0.65), with median survival at 24 months of 70, 65 and 65 %, respectively. CONCLUSION: LTE can be performed safely with less major complications and shorter hospital stay than open esophagectomy. The reduced lymph-node harvest did not impact overall survival.

Pancreatic acinar cell-specific overexpression of group 1B phospholipase A2 exacerbates diet-induced obesity and insulin resistance in mice.

Genome-wide association studies have identified significant association between polymorphisms of the Group 1B phospholipase A(2) (PLA2G1B) gene and central obesity in humans. Previous studies have shown that Pla2g1b inactivation decreases post-prandial lysophospholipid absorption, and as a consequence increases hepatic fatty acid oxidation and protects against diet-induced obesity and glucose intolerance in mice. The present study showed that transgenic mice with pancreatic acinar cell-specific overexpression of the human PLA2G1B gene gained significantly more weight and displayed elevated insulin resistance characteristics, such as impaired glucose tolerance, compared with wild-type (WT) mice, when challenged with a high-fat/carbohydrate diet. Pre- and post-prandial plasma ß-hydroxybutyrate levels were also lower, indicative of decreased hepatic fatty acid oxidation, in the hypercaloric diet-fed PLA2G1B transgenic mice. These, along with earlier observations of Pla2g1b-null mice, document that Pla2g1b expression level is an important determinant of susceptibility to diet-induced obesity and diabetes, suggesting that the relationship between PLA2G1B polymorphisms and obesity may be due to differences in PLA2G1B expression levels between these individuals. The ability of pancreas-specific overexpression of PLA2G1B to promote obesity and glucose intolerance suggests that target phospholipase activity in the digestive tract with non-absorbable inhibitors should be considered as a therapeutic option for metabolic disease therapy.

Comparing cortico-motor hotspot identification methods in the lower extremities post-stroke: MEP amplitude vs. latency.

Transcranial magnetic stimulation (TMS) is a technique used to probe and measure cortico-motor responses of the nervous system. However, lower extremity (LE) specific methodology has been slow to develop. In this retrospective analysis, we investigated what motor evoked potential metric, amplitude (MEPamp) or latency (MEPlat), best distinguished the motor-cortical target, i.e. hotspot, of the tibialis anterior and soleus post-stroke. Twenty-three participants with stroke were included in this investigation. Neuronavigation was used to map hotspots, derived via MEPamp and MEPlat, over a 3cm × 5cm grid. Distances between points with the greatest response within a session and between days were compared. Both criterion, amplitude and latency, provided poor identification of locations between trials within a session, and between multiple visits. Identified hotspots were similar only 15 % and 8% of the time between two assessments within the same session, for amplitude and latency respectively. However, MEPamp was more consistent in identifying hotspots, evidenced by locations being less spatially distant from each other (Amplitude: 1.4 cm (SD 0.10) Latency: 1.7 (SD 1.04), P = 0.008) within a session and between days (Amplitude: 1.3 cm (SD 0.95), Latency 1.9 cm (SD 1.14), P = 0.004). While more work is needed to develop LE specific methodology for TMS, especially as it applies to investigating gait impairments, MEPamp appears to be a more consistent criterion for hotspot identification when compared to MEPlat. It is recommended that future works continue to use MEPamp when identifying tibialis anterior and soleus hotspots using neuronavigation.

MRI-Derived Sarcopenia Associated with Increased Mortality Following Yttrium-90 Radioembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate the influence of sarcopenia on survival in patients with hepatocellular carcinoma (HCC) treated with 90Y radioembolization. MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 82 consecutive patients (65 men and 17 women, mean age 65 years, range 31-83 years) with HCC treated with 90Y radioembolization between December 2013 and December 2017. Sarcopenia was assessed on pre-procedure MRI performed within 100 days prior to 90Y radioembolization by segmenting the paraspinal musculature at the level of the superior mesenteric artery origin and subtracting fat-intensity pixels to yield fat-free muscle area (FFMA). Sarcopenia was defined as FFMA ≤31.97 cm2 for men and ≤28.95 cm2 for women. Survival at 90 days, 180 days, 1 year, and 3 years following initial treatment was assessed using medical and public obituary records. RESULTS: Sarcopenia was identified in 30% (25/82) of patients. Death was reported for 49% (32/65) of males and 71% (8/17) of females (mean follow-up 19.6 months, range 21 days-58 months). Patients with sarcopenia were found to have increased mortality at 180 days (31.8% vs. 8.9%) and 1 year (68.2% vs. 21.2%). Sarcopenia was an independent predictor of mortality adjusted for BCLC stage and sub-analysis demonstrated that sarcopenia independently predicted increased mortality for patients with BCLC stage B disease. CONCLUSION: Sarcopenia was associated with increased 180-day and 1-year mortality in HCC patients undergoing 90Y radioembolization. Sarcopenia was an independent predictor of survival adjusted for BCLC stage with significant deviation in the survival curves of BCLC stage B patients with and without sarcopenia.

Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice.

Previous studies have shown that group 1B phospholipase A2-mediated absorption of lysophospholipids inhibits hepatic fatty acid ß-oxidation and contributes directly to postprandial hyperglycemia and hyperlipidemia, leading to increased risk of cardiometabolic disease. The current study tested the possibility that increased expression of lysophosphatidylcholine acyltransferase-3 (LPCAT3), an enzyme that converts lysophosphatidylcholine to phosphatidylcholine in the liver, may alleviate the adverse effects of lysophospholipids absorbed after a lipid-glucose mixed meal. The injection of an adenovirus vector harboring the human LPCAT3 gene into C57BL/6 mice increased hepatic LPCAT3 expression fivefold compared with mice injected with a control LacZ adenovirus. Postprandial glucose tolerance tests after feeding these animals with a bolus lipid-glucose mixed meal revealed that LPCAT3 overexpression improved postprandial hyperglycemia and glucose tolerance compared with control mice with LacZ adenovirus injection. Mice with LPCAT3 overexpression also showed reduced very low density lipoprotein production and displayed elevated levels of the metabolic- and cardiovascular-protective large apoE-rich high density lipoproteins in plasma. The mechanism underlying the metabolic benefits of LPCAT3 overexpression was shown to be due to the alleviation of lysophospholipid inhibition of fatty acid ß-oxidation in hepatocytes. Taken together, these results suggest that specific LPCAT3 induction in the liver may be a viable strategy for cardiometabolic disease intervention.

The isolation and characterisation of a platelet-specific beta-globulin (beta-thromboglobulin) and the detection of antiurokinase and antiplasmin released from thrombin-aggregated washed human platelets.

A protein fraction was isolated from the supernatant of thrombin-aggregated washed human platelets and was shown, by immunodiffusion techniques, to contain a platelet-specific beta-globulin (beta-thromboglobulin) as the major component. A molecular weight of 35 800 was determined for beta-thromboglobin from the measured sedimentation coefficient of3.0 S and Stokes radius of 2.85 nm. Beta-Thromboglobin was detected in the serum from whole blood and the supernatant of 48-h-old platelet-rich plasma and 28-day-old citrated whole blood, but not in platelet-poor plasma. The fraction containing beta-thromboglobulin was shown to possess an antiurokinase activity but was devoid of antiplasmin activity. A further fraction of approximate molecular weight 70 000 was also isolated which contained an antiplasmin but was devoid of antiurokinase activity.

Platelet antiheparin activity. The isolation and characterisation of platelet factor 4 released from thrombin-aggregated washed human platelets and its dissociation into subunits and the isolation of membrane-bound antiheparin activity.

Platelet factor 4 was isolated by gel filtration from the soluble release products of thrombin-aggregated washed human platelets as a proteoglycan-platelet factor 4 complex of molecular weight 358 000, Stokes radius (r-s) of 14.0 nm, sedimentation coefficient (s) of 7.1 S and frictional ratio (f/f-o) of 3.04. The complex was dissociated at high ionic strength (I equals 0.75) and the proteoglycan separated from platelet factor 4 by gel filtration. Platelet factor 4 had a molecular weight of 27 100, r-s of 2.52 nm, s of 2.4 S and f/f-o of 1.26, was insoluble under physiological conditions but readily soluble at pH 3. Under these conditions platelet factor 4 dissociated into four subunits with a molecular weight of 6900, r-s of 1.92 nm, s of 0.8 S, and f/f-o of 1.52. Qualitative N-terminal amino acid analysis showed the presence of glutamic acid or glutamine as the major end group. Platelet factor 4 was compared with protamine sulphate, which has similar biological properties, by electrophoresis at pH 2.2, in which both migrated as single bands but with differing mobility, and by amino acid analysis which showed a more normal distribution of residues than occurred in protamine sulphate. Of the basic amino acids platelet factor 4 (molecular weight 27 100) contained 5.97% arginine, 3.18% histidine, and 12.31% lysine compared to protamine sulphate with 64.2% arginine, 0.6% lysine and no histidine. A partial specific volume (v) of 0.747 was calculated for platelet factor 4 from its amino acid analysis. A membrane fraction with antiheparin activity, an isopycnic density of 1.090-1.110 and r-s of 15-35 nm, was also isolated by sucrose density gradient centrifugation from the ultrasonicated insoluble platelet residue remaining after thrombin-induced aggregation of washed human platelets. Trypsin treatment of the membrane fraction neither solubilised nor destroyed the activity.

Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole.

PURPOSE: Trimethoprim/sulfamethoxazole (TMP/SMX) is the drug of choice for Pneumocystis carinii pneumonia (PCP) prophylaxis in immunocompromised patients. In children with malignancy, TMP/SMX is well tolerated, but adverse reactions that necessitate discontinuation can occur. We evaluated the safety and efficacy of aerosolized pentamidine (AP) as an alternative prophylaxis modality in children with malignancy who are intolerant of or allergic to TMP/SMX. PATIENTS AND METHODS: AP (200 mg/m2 every 4 weeks) was administered to 60 children with malignancy receiving chemotherapy who had experienced severe adverse reactions to TMP/SMX. Seven hundred twenty doses of AP have been administered during a 3 1/2-year period (21,600 patient-days), with 30 patients treated for > or = 12 months (range, 12 to 25). RESULTS: Adverse reactions occurred during 79 (10%) of the 720 treatments and included bronchospasm in 23, cough in 40, vomiting in 10, and nausea in six. Only two patients had severe bronchospasm. AP was discontinued due to toxicity in three patients (5%). None of the patients (upper 95% confidence limit, 0.049) have developed PCP. CONCLUSION: AP appears to be well tolerated and effective in the prevention of PCP in children with malignancy.

Plasma beta-thromboglobulin in diabetes mellitus.

The plasma beta-thromboglobulin (betaTG) content was measured in 56 diabetic patients with known complications of this disease, including neuropathy, retinopathy, and ischemic skin lesions. Although two patients were found to have elevated levels beyond the normal range, there was no significant difference between the diabetic group as a whole and the group of 35 controls. The significance of these findings with regard to the proposed contribution of small-vessel platelet sequestration in the pathogenesis of late complications of diabetes mellitus is discussed.

The anemia of chronic disease: spectrum of associated diseases in a series of unselected hospitalized patients.

PURPOSE: Previous studies of the anemia of chronic disease (ACD) have generally begun with patients afflicted with one of the classical underlying diseases such as rheumatoid arthritis. The clinical spectrum of ACD has not been thoroughly examined. We hypothesized that many patients have an anemia with the characteristics of ACD but do not have one of the infectious, inflammatory, or neoplastic disorders usually associated with ACD. We therefore evaluated a series of consecutive, unselected, anemic patients admitted to a county hospital. PATIENTS AND METHODS: All patients admitted to the medicine ward service of a county hospital were screened for anemia (hematocrit less than 40% in men, less than 37% in women). Additional laboratory data were collected on all anemic patients, except those with active gastrointestinal bleeding, hemolytic disease, or leukemia or multiple myeloma. The patients were divided into three groups on the basis of serum values indicating iron distribution: iron deficiency (serum ferritin less than 10 ng/mL), ACD (serum iron less than 60 micrograms/dL and serum ferritin more than 50 ng/mL), and all others (non-ACD). The hospital records of the patients in the latter two groups were reviewed and their diagnoses recorded. RESULTS: Seven patients with iron deficiency were not considered further. Ninety patients with ACD were compared with 75 patients with non-ACD. The anemia in ACD patients was more severe than most authors describe. The mean hematocrit was 31%, and 20% of patients had hematocrits below 25%. The anemia was usually normocytic (mean red cell volume [MCV] 86 fL), but 21% had an MCV less than 80 fL. The level of saturation of serum iron-binding capacity was quite low in ACD (mean 15%) and was normal in non-ACD (mean 31%). Renal insufficiency was common in both groups; serum creatinine values were more than 2 mg/dL in 31% of patients with ACD and 20% of non-ACD patients. Sixty percent of patients with ACD had a principal diagnosis that fell into the infectious, inflammatory, and neoplastic categories commonly associated with ACD. Renal insufficiency was the major diagnosis in 16%, and the principal diagnosis in 24% was a disease not commonly considered to be associated with ACD. In non-ACD patients, the principal diagnosis was an infectious, inflammatory, or neoplastic disease in 55%, renal insufficiency in 9%, and another disease in 36%. CONCLUSIONS: When ACD was defined by the abnormalities of iron distribution, which are its most consistent and widely accepted characteristics, the spectrum of associated diseases was much broader than the traditional categories of infectious, inflammatory, and neoplastic disorders, and the overlap with non-ACD was large. Until the etiologic and pathogenetic mechanisms of ACD are better understood, a flexible and inclusive view of this disorder seems appropriate.

103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma.

PURPOSE: To summarize biochemical failure rates and morbidity of external beam irradiation (EBRT) combined with palladium (103Pd) boost for clinically localized high-risk prostate carcinoma. METHODS AND MATERIALS: Seventy-three consecutive patients with stage T2a-T3 prostatic carcinoma were treated from 1991 through 1994. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (71 patients), Gleason score 7-10 (40 patients), prostate specific antigen (PSA) > 15 (32 patients), or elevated prostatic acid phosphatase (PAP) (17 patients). Patients received 41 Gy EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose: 80 Gy). Biochemical failure was defined as a PSA greater than 1.0 ng/ml (normal < 4.0 ng/ml). Patients whose PSA was still decreasing at the last follow-up were censored at that time. Patients whose PSA plateaued at a value greater than 1.0 were scored as failures at the time the PSA first plateaued. RESULTS: The overall, actuarial freedom from biochemical failure at 3 years after treatment was 79%. In Cox proportional hazard multivariate analysis, the strongest predictor of failure was elevated acid phosphatase (p = 0.04), followed by PSA (p = 0.17), Stage (p = 0.23), and Gleason score (p = 0.6). Treatment-related morbidity was usually limited to temporary, RTOG Grade 1-2 urinary symptoms. One patient, who had both a transurethral incision of the prostate (TUIP) and a transurethral resection of the prostate (TURP), developed low-volume urinary incontinence. The actuarial potency rate at 3 years after implantation was 77% for 46 patients who were sexually potent prior to implant. CONCLUSION: Biochemical freedom from failure rates following combined EBRT and 103Pd brachytherapy for clinically localized, high-risk prostate cancer compare favorably with that reported after conventional dose EBRT alone. Morbidity has been acceptable.

Prognostic role of serum prostatic acid phosphatase for 103Pd-based radiation for prostatic carcinoma.

PURPOSE: To establish the prognostic role of serum enzymatic prostatic acid phosphatase (PAP) in patients treated with palladium (103Pd) and supplemental external beam irradiation (EBRT) for clinically localized, high-risk prostate carcinoma. METHODS AND MATERIALS: One hundred twenty-four consecutive patients with Stage T2a-T3 prostatic carcinoma were treated from 1992 through 1995. Each patient had at least one of the following risk factors for extracapsular disease extension: Stage T2b or greater (100 patients), Gleason score 7-10 (40 patients), pretreatment prostate specific antigen (PSA) >15 ng/ml (32 patients), or elevated serum PAP (25 patients). Patients received 41 Gy conformal EBRT to a limited pelvic field, followed 4 weeks later by a 103Pd boost (prescription dose 80 Gy). Biochemical failure was defined as a PSA greater than 1 ng/ml (normal <4 ng/ml). RESULTS: The overall, actuarial freedom from biochemical failure at 4 years after treatment was 79%. In Cox-proportional hazard multivariate analysis, the strongest predictor of failure was elevated pretreatment acid phosphatase (p = 0.02), followed by Gleason score (p = 0.1), and PSA (p = 0.14). CONCLUSION: PAP was the strongest predictor of long-term biochemical failure. It may be a more accurate indicator of micrometastatic disease than PSA, and as such, we suggest that it be reconsidered for general use in radiation-treated patients.

Placental chorioangioma: presentation of a case with electron-microscopic and immunochemical studies.

A case of placental chorioangioma in an infant who experienced transient congestive heart failure is presented. The mechanism for this heart failure was probably due to excessive left to right shunting of blood across the tumor. Electron-microscopic examination revealed the tumor to be composed of endothelial cells and vascular structures of different types. Immunochemistry revealed the lack of normal placental antigens indicating that these tumors are not composed of trophoblastic tissue.

The origin of the autoimmune disease-resistant LER rat: an outcross between the buffalo and autoimmune disease-prone Lewis inbred rat strains.

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear. We report the analysis of 19 simple dinucleotide repeat polymorphisms in 13 rat strains including the LEW/N and LER/N rat strains. The LEW/N and LER/N alleles were the same in only 42% of cases. For all of the other polymorphisms, the LER/N and Buffalo (BUF/N) rat strain alleles were identical. These data provide evidence that the LER strain did not arise as a spontaneous mutation in the LEW strain but is the result of an outcross between the LEW and BUF rat strains. The LER rat strain is now a recombinant inbred rat strain. This information should facilitate the genetic analysis of the loci responsible for resistance to experimental autoimmune disease in the LER rat.

The different forms of antithrombin II in serum.

Antithrombin III (AT III) complexes were isolated from human serum by affinity chromatography and gel filtration. In the first step of the preparation, using heparin-agarose chromatography, we observed that the complexed form of AT III bound less strongly to the gel than the free form and that about half of the AT III was free. With further purification a 2.5 X 10(5) molecular weight complex was isolated. Using 125I labelled human thrombin, this complex was radioactive indicating the presence of thrombin. Only in a synthetic thrombin-AT III system was a 9 X 10(4) molecular weight complex detected, but not in serum. These facts suggest that in serum AT III complexes may exist in a polymeric form. Also, an AT III antigen derived from the original AT III molecule, but not complexed, was isolated which may be a degradation product.

beta-thromboglobulin and deep vein thrombosis.

The measurement of plasma beta-thromboglobulin as a potential diagnostic test for venous thrombosis has been investigated in 16 normal volunteers, 24 patients presenting with deep vein thrombosis (DVT) or pulmonary embolism and 46 patients screened by 125I fibrinogen test (IFT) for post-operative DVT. The normal mean was 33 ng/ml (range 15-117 ng/ml). Of the 24 patients with clinical thrombotic disease 22 presented with DVT confirmed by phlebogram or IFT and 2 presented with embolism confirmed by lung scan. At the time of first presentation 12 out of 24 had betaTG values greater than 70 ng/ml. All except 3 of this group of 24 patients had values of greater than 70 ng/ml at some stage during a subsequent week of daily sampling. DVT was detected in 13 out of 46 screened post-operative patients. There was a rise om betaTG observed within 24 hr of the IFT becoming positive but the mean rise did not reach significance at the 5% level. An association between DVT and high betaTG values has been confirmed. However, its clinical value cannot yet be fully elucidated until factors, probably related to blood sampling and clearance, are further investigated.

Value of C-reactive protein determination in the initial diagnostic evaluation of the febrile, neutropenic child with cancer.

We studied prospectively the value of administration C-reactive protein (CRP) in the diagnostic evaluation of the child with cancer hospitalized for fever and neutropenia. During a 7-month period 74 patients with malignant disease had 122 hospital admissions because of fever and neutropenia. All patients had a serum CRP obtained 8 to 24 hours after the onset of fever as part of their initial evaluation. There was a borderline correlation between serum CRP concentration and temperature at admission (P = 0.06). Patients with fever without an identifiable source had significantly lower CRP concentrations compared with those having focal or microbiologically documented infection (34.9 +/- 6 vs. 70.2 +/- 12 mg/liter; P = 0.0005). Twelve patients had positive blood cultures, 5 of which were coagulase-negative staphylococci considered to be central venous catheter-related infection or colonization. CRP concentrations were significantly lower in these 5 patients compared with the 7 patients with septicemia caused by other organisms (21 +/- 9 vs. 113 +/- 23 mg/liter; P = 0.01). In distinguishing between septicemic and nonsepticemic children, serum CRP was found to have excellent sensitivity and negative predictive value at concentration limits of 20, 50 and 100 mg/liter. However, both specificity and positive predictive value were low at these respective levels, thus limiting the overall utility of serum CRP in the initial empiric management of the febrile, neutropenic child with cancer.