Mapping urinary chemokines in human lupus nephritis: Potentially redundant pathways recruit CD4+ and CD8+ T cells and macrophages

Renal infiltration of inflammatory cells contributes to the pathogenesis of lupus nephritis (LN). Current knowledge on the recruitment mechanisms relies mainly on findings in rodent models. Here, we assess various chemokine pathways in human LN by comparing urinary chemokine concentrations (in 25 patients with acute LN and in 78 lupus patients without active LN) with the expression of corresponding chemokine receptors on urinary leukocytes (in ten acute LN patients). Nine urinary chemokines were significantly elevated in LN patients and correlated with renal disease activity and urinary cell counts; however, their concentrations displayed considerable interindividual heterogeneity. Analysis of the corresponding receptors revealed abundance of urinary CD8⁺ T cells for CCR5 and CXCR3, while CD4⁺ T cells were additionally enriched for CCR1, CCR6 and CXCR6. Urinary Treg showed similar CCR expression, and urinary CD14⁺ macrophages were enriched for CCR5 expressing cells. In conclusion, cell specific recruitment patterns seem to involve CCR5 and CXCR3 in all cells studied, while CD4⁺ T‐cell subset recruitment is probably much more varied. However, urinary chemokine abundance in active LN is individually variable in our cohort and does not offer a singular chemokine usable as universal biomarker or potential future treatment target.     

Oxidative stress‐dependent increase in ICAM‐1 expression promotes adhesion of colorectal and pancreatic cancers to the senescent peritoneal mesothelium

Intercellular adhesion molecule‐1 (ICAM‐1) has been implicated in adhesion of colorectal and pancreatic cancer cells (of the SW480 and PSN‐1 line, respectively) to the peritoneal mesothelium. It has been demonstrated that ICAM‐1 expression increases with senescence in some cell types, however, the significance of this phenomenon in the context of malignant dissemination remains elusive. In this report we show that the adherence of SW480 and PSN‐1 cells to senescent human omentum‐derived mesothelial cells (HOMCs) in vitro is greater than to early‐passage cells and that the effect is mediated by ICAM‐1. Senescent HOMCs display increased expression of ICAM‐1 mRNA and cell surface protein. The development of this phenotype is related to increased oxidative stress in senescent cells. The augmented ICAM‐1 expression in HOMCs can be reduced by culturing cells with antioxidants; in contrast, exposure of HOMCs to an oxidant, t‐BHP, leads to cellular senescence and increased ICAM‐1 expression. The effect is partly mediated by activation of p38 MAPK and AP‐1 signaling pathways. Finally, culture of HOMCs in the presence of a strong antioxidant, PBN, significantly reduces the senescence‐associated increase in SW480 and PSN‐1 cancer cell binding. These results indicate that increased oxidative stress and increased expression of ICAM‐1 in senescent HOMCs may facilitate peritoneal adhesion of selected colorectal and pancreatic cancers.     

Decreased Catecholamine Degradation Associates with Shock and Kidney Injury after Cardiac Surgery

Enzymatic pathways involving catechol-O-methyltransferase (COMT) catabolize circulating catecholamines. A G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid substitution at codon 158, which leads to thermolability and low (“L”), as opposed to high (“H”), enzymatic activity. We enrolled 260 patients postbypass surgery to test the hypothesis that COMT gene variants impair circulating catecholamine metabolism, predisposing to shock and acute kidney injury (AKI) after cardiac surgery. In accordance with the Hardy-Weinberg equilibrium, we identified 64 (24.6%) homozygous (LL), 123 (47.3%) heterozygous (HL), and 73 (28.1%) homozygous (HH) patients. Postoperative catecholamines were higher in homozygous LL patients compared with heterozygous HL and homozygous HH patients (P < 0.01). During their intensive care stay, LL patients had both a significantly greater frequency of vasodilatory shock (LL: 69%, HL: 57%, HH: 47%; P = 0.033) and a significantly longer median duration of shock (LL: 18.5 h, HL: 14.0 h, HH: 11.0 h; P = 0.013). LL patients also had a greater frequency of AKI (LL: 31%, HL: 19.5%, HH: 13.7%; P = 0.038) and their AKI was more severe as defined by a need for renal replacement therapy (LL: 7.8%, HL: 2.4%, HH: 0%; P = 0.026). The LL genotype associated with intensive care and hospital length of stay (P < 0.001 and P = 0.002, respectively), and we observed a trend for higher mortality. Cross-validation analysis revealed a similar graded relationship of adverse outcomes by genotype. In summary, this study identifies COMT LL homozygosity as an independent risk factor for shock, AKI, and hospital stay after cardiac surgery. (ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT00334009","term_id":"NCT00334009"}}NCT00334009)Shock and acute kidney injury (AKI) are associated with increased mortality after cardiac surgery.^1,2 Cardiopulmonary bypass represents a common clinical setting of sympathetic nervous system activation and cardiovascular instability. Postoperative hypotension and vasodilation with increased requirements for catecholamines occur despite adequate intravascular filling, cardiac output, and increased plasma catecholamine concentrations.^1,3 High circulating catecholamine levels may contribute to persistent vasodilatation via α-adrenoceptor downregulation and desensitization,⁴ depression of vasopressin synthesis, and adenosine triphosphate-sensitive potassium channel activation in vascular smooth muscle cells.⁵ Circulating catecholamines are primarily catabolized through enzymatic pathways involving the enzyme catechol-O-methyltransferase (COMT).⁶ A functional G-to-A polymorphism in the fourth exon of the COMT gene results in a valine-to-methionine amino acid transition at codon 158 (COMT Val158Met polymorphism), leading to thermolability and lower (L), compared with higher (H) activity of the enzyme.^7,8 Genetically determined COMT activity, among others,^9,10 influences outcomes in patients with ischemic heart disease.^11,12 In the kidney, COMT is essential for catecholamine degradation along the distal parts of proximal tubules and thick ascending limb of loop of Henle.¹³ We hypothesized that the COMT LL genotype coding for low enzyme activity would shift metabolism toward increased plasma catecholamine concentrations and predispose to increased duration of vasodilatory shock and higher AKI incidence after cardiac surgery. To test this notion, we conducted a prospective observational cohort study in cardiac surgery patients.     

Psammoma bodies in cervicovaginal cytology specimens: a clinicopathological analysis of 31 cases

BACKGROUND: Psammoma bodies in cervicovaginal cytology specimens are associated with malignant and benign conditions. Few studies have evaluated which features distinguish patients with underlying malignancy from those with benign conditions. METHODS: Pathology files were searched for cervicovaginal specimens having psammoma bodies. The cytology specimen was assessed for the background, glandular atypia, squamous atypia, and presence of non-psammomatous calcifications. Clinical data was obtained from chart review. RESULTS: Nineteen women (mean age 42.7 years) had benign outcomes. None had signs or symptoms suggesting malignancy. None had highly atypical or malignant appearing glandular cells. Twelve women had malignant neoplasms (mean age 56 years), including 6 with recurrent disease. Four women without prior malignancy had worrisome signs including bleeding or mass. All six women with prior malignancy had signs of recurrent disease. All specimens contained highly atypical or malignant glandular cells. CONCLUSIONS: The only cytologic feature predictive of outcome was the presence of highly atypical glandular cells in the specimen (P = 0.001), but these cells may be few. Women with underlying malignancy were older than those with benign outcome (P = 0.014) and more likely to be postmenopausal (P = 0.05). Women with malignancy had signs that warranted additional investigation whereas those with benign outcome were usually asymptomatic (P = 0.001).     

Canine CNGB3 mutations establish cone degeneration as orthologous to the human achromatopsia locus ACHM3

Cone degeneration (cd ) is an autosomal recessive canine disease that occurs naturally in the Alaskan Malamute and German Shorthaired Pointer breeds. It is phenotypically similar to human achromatopsia, a heterogeneous autosomal recessive disorder associated with three distinct loci. Both the canine disease and its human counterparts are characterized by day-blindness and absence of retinal cone function in adults. We report linkage of the canine cd locus to marker C29.002 on canine chromosome 29 at recombination fraction theta = 0.0 with a maximum LOD score of 24.68 in a series of informative outbred pedigrees derived from cd-affected Alaskan Malamutes. Conserved gene order between CFA29 and the long arm of human chromosome 8 argued for homology between the cd locus and the human achromatopsia locus, ACHM3, at 8q21-22. The canine homolog of the cyclic nucleotide-gated channel beta-subunit gene (CNGB3), responsible for the human ACHM3 disease phenotype, was mapped within the zero-recombination interval for the cd locus. A deletion removing all exons of canine CNGB3 was identified in cd-affected Alaskan Malamute-derived dogs. A missense mutation in exon 6 (D262N, nucleotide 784) within a conserved region of the same gene was detected in German Shorthaired Pointers affected with an allelic disorder. Identification of these canine disorders as homologs of human ACHM3 underscores the power of recent developments in canine genomics, and provides a valuable system for exploring disease mechanisms and evaluating potential therapeutic measures in disorders of cone photoreceptors.     

Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix

OBJECTIVE: Patients with early-stage neuroendocrine cervical carcinoma (NECC) have a high mortality rate despite aggressive therapy. The rarity of this tumor precludes initiation of a randomized, prospective trial. We reviewed our experience in early stage disease and performed a meta-analysis of the literature to identify prognostic factors and determine optimal multimodality therapy. METHODS: Eleven women with International Federation of Gynecology and Obstetrics (FIGO) early stage (IB--IIA) NECC were treated with surgery and chemotherapy at our institutions between 1978 and 1998. Administration of radiation therapy was recorded, but not required for inclusion in this study. A gynecologic pathologist reviewed all histopathologic sections. Medical records were retrospectively reviewed and clinical data obtained. Twenty-three early-stage NECC patients who were similarly treated during the study interval were identified by a Medline search of the English literature and included in the analysis. The Kaplan--Meier method and log-rank test were used for survival analysis. RESULTS: The overall 2-year survival rate for the 34 patients was 38%. The median age was 37 years (range, 20--75 years). Median cervical tumor diameter was 3.2 cm (range 0.5--11.0 cm). Lymphovascular space invasion was present in 21 (78%) of 27 patients (7 unknown). Fifteen (52%) of twenty-nine had lymph node metastases (5 unknown). Fifteen patients received postoperative platinum/etoposide (PE), seven received vincristine/adriamycin/cyclophosphamide (VAC), two received alternating cycles of VAC and PE, and ten received other chemotherapy regimens. Twenty women were treated with radiation therapy. The presence of lymph node metastases was a poor prognostic factor (P < 0.001). PE and VAC chemotherapy was associated with increased survival (P < 0.01). CONCLUSION: NECC is a highly lethal variant of cervical cancer. The presence of lymph node metastases is the most important prognostic variable. Postoperative VAC or PE appears most likely to improve chances for survival.     

The role of cytoreductive surgery in the management of stage IV uterine papillary serous carcinoma

OBJECTIVE: The aim of this study was to evaluate the survival impact of cytoreductive surgery and other prognostic determinants in patients with Stage IV uterine papillary serous carcinoma (UPSC). METHODS: All patients with FIGO Stage IV UPSC diagnosed between January 1, 1989 and December 31, 1998 were identified from tumor registry databases. Individual patient data were collected retrospectively. Survival analysis and comparisons were performed using the method of Kaplan and Meier, the log-rank test, and the Cox proportional hazards regression model. Predictors of surgical outcome were evaluated using the log-rank test. RESULTS: Thirty-one patients underwent primary cytoreductive surgery for Stage IV UPSC (median age, 65 years). The median survival for all patients was 14.4 months. Optimal cytoreduction was defined as residual disease < or =1 cm in maximal diameter. The only significant predictor of a suboptimal surgical outcome was the presence of disease in three or more anatomic regions. Overall, 16 of 31 patients (51.6%) completed primary surgery with optimal disease status. Optimal cytoreduction was associated with a median survival of 26.2 months, compared with 9.6 months for patients left with suboptimal residual disease (P < 0.001). At 24 months, 57.1% of optimally cytoreduced patients were still alive, compared with just 6.7% of patients left with suboptimal disease. Furthermore, patients with only microscopic residual tumor had a significantly longer median survival (30.4 months) than both patients with 0.1- to 1.0-cm residual disease (20.5 months) and those left with suboptimal disease (P = 0.004). Postoperative platinum-based chemotherapy was associated with a median survival of 17.1 months, compared with 9.5 months without such therapy (P = 0.018). Patients receiving the combination of platinum + paclitaxel had a median survival rate of 29.1 months versus 14.4 months for patients receiving platinum + cyclophosphamide +/- doxorubicin (P = 0.054). On multivariate analysis, the only statistically significant predictor of survival was the cytoreductive surgical outcome. CONCLUSIONS: The strongest predictor of overall survival for patients with Stage IV UPSC was the amount of residual disease following surgery. Recommended management for this group of patients should consist of maximal surgical cytoreduction followed by platinum-based chemotherapy, preferably in combination with paclitaxel.     

Endometrial cancer in women 40 years old or younger

OBJECTIVE: The aim of this study was to characterize endometrial cancer in women 40 years of age and younger, with special attention toward body-mass index (BMI). METHODS: A retrospective review of women age 40 and under with endometrial cancer was performed. Patients were identified via tumor registry data as well as a search of pathology department diagnoses over the dates 1980-1998. Data were abstracted regarding tumor grade and histology, stage, treatment, smoking, use of oral contraceptives, BMI, medical and family history, parity, and survival. Data were also collected with regard to uterine conservation and pregnancies following endometrial cancer diagnoses. RESULTS: Ninety-five patients were identified. The age range was 24-40 years (median 37) with BMI ranging from 17.5 to 63.6 (median 28.4). Forty-eight patients (52%) were not obese, with BMI < 30. Seventy-six patients (80%) had stage I disease and 60 patients (63%) had grade 1 disease. All but 4 patients had endometrioid histology. Women with BMI < 25 were more likely to have advanced disease (P = 0.04) and more likely to have high-risk histology (P = 0.02). Of the 4 patients with high-risk histology (clear cell or serous papillary), all had BMI < 25. Twelve patients were treated medically rather than surgically, and 4 patients achieved pregnancy, with 5 live births. CONCLUSION: Women under 40 who are not obese are at higher risk of both advanced disease and high-risk histology. Further study at the molecular and genetic level is ongoing in our laboratory to determine whether the mechanism of disease is different in slender woman.