Nicotine induces the up-regulation of the α7-nicotinic receptor (α7-nAChR) in human squamous cell lung cancer cells via the Sp1/GATA protein pathway.

Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.

First-year outcomes of incident peritoneal dialysis patients in the United States.

BACKGROUND: Patterns of early outcomes in peritoneal dialysis (PD) are not well studied and dialysis providers need to establish a baseline of key outcomes for continuous quality improvement initiatives. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident PD patients from Fresenius Medical Care, North America from January 1 through December 31, 2009. FACTORS: Case-mix, comorbid illness, and baseline laboratory values. OUTCOMES: Death, hospitalization, peritonitis, and switch to hemodialysis (HD) within the first year on PD therapy. MEASUREMENTS: Event rates and outcome predictors. RESULTS: Of 1,677 incident PD patients, 1,313 started on PD therapy and 367 switched from HD therapy within the first 90 days. Normalized first-year event rates for mortality, switch to HD therapy, peritonitis, and hospitalization were 10, 27, 42, and 128 per 100 patient-years, respectively. 336 of 463 (72.6%) first peritonitis episodes and 637 of 939 (67.8%) first hospitalizations occurred within the first 6 months of PD treatment. Black race, higher body mass index, non-Hispanic ethnicity, peripheral vascular disease, and low weekly Kt/V associated with peritonitis risk. Dialysis vintage, female sex, diabetes, congestive heart failure, peripheral vascular disease, and history of limb amputation along with lower laboratory values for albumin, hemoglobin, and phosphorus and weekly Kt/V associated with hospitalization. Switchers to HD therapy (n=350) used central venous catheters 81.4% of the time as initial access (still 78.3% at 90 days later) because of lack of permanent access. LIMITATIONS: Residual confounding from unmeasured variables and exclusion of patients with a training day but who never started home PD therapy. CONCLUSIONS: Despite low first-year mortality, incident PD patients had high morbidity, particularly within the first 3-6 months. Increased focus to identify patients at greatest risk for peritonitis and hospitalization, as well as evaluation of care processes and implementation of preventive strategies, is required. Access planning for transition to HD therapy needs more attention, even during the first PD year.

The culture of education in a large dialysis organization: informing patient-centered decision making on treatment options for renal replacement therapy.

Challenged by the observation that newly admitted dialysis patients were often unaware of their treatment options, Fresenius Medical Care, North America developed a program to improve information delivered to chronic kidney disease (CKD) patients prior to their need for renal replacement therapy. Six years ago, the Treatment Options Program (TOPs) was established utilizing a standardized approach to educate individuals with CKD Stages 3 and 4. The program education focuses on modality and vascular access options. A key component includes follow-up at predetermined intervals, offering additional education and patient reminders to continue to work with their physician in selecting a preferred renal replacement modality. Since program inception, over 73,000 individuals have been educated through TOPs. Home therapy utilization as first treatment is higher in the patient population that received TOPs education. Similarly, participants had a higher rate of permanent vascular access with decreased use of hemodialysis catheters upon admission. Avoiding hemodialysis catheter use and expanding home therapy utilization both offer potential benefits to all stakeholders: patients, providers, and payors, particularly as we move toward accountable healthcare systems. The ability to expand the TOPs program relies on seeing patients early enough to allow each patient time to process the information and work with their physician to select the modality and access that best meets their healthcare and lifestyle needs. Educating our patients facilitates empowerment and active participation in their therapy, a much coveted component of patient-centered health care for the renal provider community as we look to the future.

Arsenic and chromium in drinking water promote tumorigenesis in a mouse colitis-associated colorectal cancer model and the potential mechanism is ROS-mediated Wnt/ß-catenin signaling pathway.

Exposure to carcinogenic metals, such as trivalent arsenic [As(III)] and hexavalent chromium [Cr(VI)], through drinking water is a major global public health problem and is associated with various cancers. However, the mechanism of their carcinogenicity remains unclear. In this study, we used azoxymethane/dextran sodium sulfate (AOM/DSS)-induced mouse colitis-associated colorectal cancer model to investigate their tumorigenesis. Our results demonstrate that exposure to As(III) or Cr(VI), alone or in combination, together with AOM/DSS pretreatment has a promotion effect, increasing the colorectal tumor incidence, multiplicity, size, and grade, as well as cell inflammatory response. Two-dimensional differential gel electrophoresis coupled with mass spectrometry revealed that As(III) or Cr(VI) treatment alone significantly changed the density of proteins. The expression of ß-catenin and phospho-GSK was increased by treatment of carcinogenic metals alone. Concomitantly, the expression of NADPH oxidase1 (NOX1) and the level of 8-OHdG were also increased by treatment of carcinogenic metals alone. Antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, were decreased. Similarly, in an in vitro system, exposure of CRL-1807 to carcinogenic metals increased reactive oxygen species (ROS) generation, the expression of ß-catenin, phospho-GSK, and NOX1. Inhibition of ROS generation by addition of SOD or catalase inhibited ß-catenin expression and activity. Our study provides a new animal model to study the carcinogenicity of As(III) and Cr(VI) and suggests that As(III) and Cr(VI) promote colorectal cancer tumorigenesis, at least partly, through ROS-mediated Wnt/ß-catenin signaling pathway.

Burkitt lymphoma in a child with atopic dermatitis and a 7-year history of regular topical tacrolimus use.

We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.

Effects of a nationwide predialysis educational program on modality choice, vascular access, and patient outcomes.

BACKGROUND: Patients' education about transplant, hemodialysis (HD), peritoneal dialysis (PD), and conservative care often is provided by nephrologists as needed and occurs as time allows. STUDY DESIGN: Quality improvement report. SETTING & PARTICIPANTS: Attendees of a national treatment options program (TOPs) who initiated long-term dialysis therapy (median, 3.4 months) at Fresenius Medical Care, North America facilities throughout 2008 were compared with period-prevalent incident patients receiving usual care. QUALITY IMPROVEMENT PLAN: Standardized predialysis treatment options education. OUTCOMES: Rates of opting for PD modality, arteriovenous HD access at initiation, and early (90-day) mortality risk. MEASUREMENTS: Logistic regression (for choice of PD and HD access type) and Cox models (for early mortality) were constructed, including a 1:1 matched cohort. A post hoc sensitivity analysis also compared a propensity score-matched cohort. RESULTS: 3,165 TOPs attendees (10.5% of 30,217 incident patients admitted between January 1 and December 31, 2008), were younger, more likely to be white, and had slightly larger body surface area. The unadjusted OR for TOPs attendees for selecting PD therapy was 8.45 (95% CI, 7.63-9.37) with a case-mix plus laboratory-adjusted OR of 5.13 (95% CI, 3.58-7.35). For patients who opted for in-center HD therapy, the OR was 2.14 (95% CI, 1.96-2.33) and adjusted OR was 2.06 (95% CI, 1.88-2.26) for starting with a fistula or graft. The unadjusted early mortality HR was 0.51 (95% CI, 0.43-0.60) and case-mix plus laboratory-adjusted adjusted HR was 0.61 (95% CI, 0.50-0.74) for TOPs attendees (all outcomes, P < 0.001). These results were consistent in the 1:1 matched analysis and propensity score-matched analysis. LIMITATIONS: It is possible that physicians who referred to these programs were more likely to prescribe PD therapy or place arteriovenous accesses. Motivated, treatment-adherent patients (who would have better outcomes) may have self-selected to attend education sessions. CONCLUSION: Attending an options class predialysis was associated with more frequent selection of home dialysis, fewer tunneled HD catheters, and lower mortality risk during the first 90 days of dialysis therapy.

Spontaneous resolution of a single lesion of myeloid leukemia cutis in an infant: case report and discussion.

Though infantile leukemia has a historically poor prognosis, there may be a subset of patients with cutaneous disease whose disease will resolve without therapy. The authors report a case of infantile leukemia cutis who presented with a single subcutaneous chloroma that spontaneously resolved over the course of several weeks and who remains without evidence of disease nearly two years later. After reviewing the literature of congenital leukemia cutis, the authors conclude that withholding chemotherapy in infants with cutaneous myeloid leukemia in the absence of known negative prognostic factors (MLL or BCR-ABL translocations) or progressive disease is clinically indicated.

FOXG1 is overexpressed in hepatoblastoma.

Bacterial artificial chromosome array comparative genomic hybridization analysis of hepatoblastomas reveals a deletion in the 14q12 locus in 12 of 16 cases. A high frequency of copy gain is seen on chromosomes 1q, 2, 5p, 8, and 20. Frequent deletions are also seen at 6q, 17q, and 1p with less frequent gains on 4p, 6p, and 19p. 14q12 deletion locus analyses using quantitative real-time polymerase chain reaction reveals copy number gain/amplification in the region immediately telomeric to the deleted locus, including copy number gain (2- to 4-fold) of FOXG1 in 13 out of 16 tumors. This is associated with up-regulation (approximately 87-fold) of FOXG1 gene transcripts and increased protein expression. Immunostaining reveals an inverse relationship between FOXG1 expression and p21cip1 expression in all histologic subtypes. However, FOXG1 transcript levels were significantly higher (approximately 75-fold) in tumors with embryonal and small cell components when compared with pure fetal hepatoblastomas. FOXG1 has been implicated in the repression of transforming growth factor beta-induced expression of p21cip1 and cytostasis. Our findings are consistent with such a role for FOXG1. We propose that FOXG1 overexpression may contribute to the maintenance of the undifferentiated state in hepatoblastomas and could be a potential target for molecular therapeutics. This is the first report of a possible role for FOXG1 in hepatoblastoma and pediatric neoplasia.

Genetic association of low density lipoprotein receptor and Alzheimer's disease.

The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) LDLR modulates the homeostasis of cholesterol, which itself appears associated with AD. Therefore, we evaluated whether LDLR haplotypes alter the odds of AD by performing an association study examining three LDLR single nucleotide polymorphisms (SNPs) in 118 AD patients and 133 non-AD subjects. LDLR genotypes were obtained by TaqMan allelic discrimination assays. Although individual LDLR SNPs were not associated with AD, analyses of unambiguous haplotypes suggested the hypothesis that the 211 LDLR haplotype was associated with reduced odds of AD. We then evaluated this hypothesis in a second study cohort, i.e., the Religious Orders Study. These results supported the hypothesis that the 211 LDLR haplotype is associated with reduced odds of AD. Moreover, these data suggested further associations between LDLR variants and AD. Thus, LDLR variants appear significantly associated with AD and merit additional study.

A multicenter, prospective, randomized, comparative evaluation of dual- versus triple-lumen catheters for hemodialysis and apheresis in 485 patients.

BACKGROUND: The purpose of this study is to compare a new temporary triple-lumen catheter (TLC) for dialysis that has a third lumen devoted to fluid and medication administration or blood sampling with a marketed dual-lumen catheter (DLC). METHODS: Four hundred eighty-five patients referred for acute hemodialysis or apheresis were randomly assigned to either a TLC or DLC in a multicenter, prospective, randomized trial. RESULTS: Analysis of blood flow rates was completed on 464 patients (228 patients, DLC; 236 patients, TLC) with a total of 1,681 hemodialysis (808 treatments, DLC; 873 treatments, TLC) and 82 apheresis treatments (37 treatments, DLC; 45 treatments, TLC). During hemodialysis, a median achieved flow rate (AFR) of 267 mL/min was realized for both groups (P = 0.58). During apheresis, a median AFR of 72.5 mL/min (range, 50 to 150 mL/min) was achieved in the DLC group, and 87 mL/min (range, 60 to 150 mL/min), in the TLC group (P = 0.14). Three hundred ninety-three patients (193 patients, DLC; 200 patients, TLC) had blood and catheter tip cultures performed on removal, and catheter-related bloodstream infection (CRBSI) status was determined. Thirty-one patients (7.9%) had a CRBSI: 16 patients (8.3%), DLC; and 15 patients (7.5%), TLC (P= 0.77). Incidence densities of CRBSI were 12.4/1,000 DLC-days and 10.2/1,000 TLC-days (P = 0.59). The CRBSI incidence of 18.2/1,000 catheter-days for femoral sites was significantly greater than the 7/1,000 catheter-days for jugular sites (P = 0.02) and 6.6/1,000 catheter-days for combined jugular and subclavian sites (P = 0.01). In multivariate analysis, antibiotic use was the only factor related to CRBSI (odds ratio, 0.30; 95% confidence interval, 0.12 to 0.76). There were no statistically significant differences in rates of other complications between the 2 catheters. CONCLUSION: Results show that the new TLC is similar to the marketed DLC.

Delayed tumor resection in a 5-year-old child with bilateral Wilms tumor.

We describe the case of a 5-year-old girl whose abdominal pain and distension were caused by Wilms tumor of the kidney. Because of the bilateral nature of her disease, she was spared biopsy or initial nephrectomy as part of her treatment course. Rather, she was treated presumptively for Wilms tumor based primarily on radiologic findings. Neoadjuvant chemotherapy consisting of vincristine, dactinomycin and doxorubicin was given to facilitate nephron-sparing surgery for tumor resection. Her initial chemotherapeutic course was complicated by tumor lysis syndrome manifested by elevated serum uric acid and was treated effectively with hyperhydration and alkalization of intravenous fluids. The patient's disease responded well to chemotherapy, and she underwent successful tumor excision after 12 weeks of chemotherapy. The resected tumor was identified as anaplastic Wilms tumor, illustrating that pathologic identification of Wilms tumor is possible even after multiple cycles of neoadjuvant chemotherapy and marked tumor shrinkage.

Peripheral T-Cell Lymphoma with Aberrant Expression of CD19, CD20, and CD79a: Case Report and Literature Review.

A case of lymphoma of T-cell derivation with aberrant expression of three B-cell lineage markers (CD19, CD20, and CD79a), which was diagnosed on a left axillary excision, is described. Immunohistochemical studies and flow cytometry analysis demonstrated neoplastic cells expressing CD3, CD19, CD20, and CD79a with absence of CD4, CD8, CD10, CD30, CD34, CD56, CD68, TDT, MPO, PAX-5, and surface immunoglobulin. Gene rearrangement studies performed on paraffin blocks demonstrated monoclonal T-cell receptor gamma chain rearrangement with no evidence of clonal heavy chain rearrangement. The neoplastic cells were negative for Epstein-Barr virus (EBV) or Human Herpes Virus 8 (HHV-8). At the time of diagnosis, the PET scan demonstrated hypermetabolic neoplastic cells involving the left axilla, bilateral internal jugular areas, mediastinum, right hilum, bilateral lungs, and spleen. However, bone marrow biopsy performed for hemolytic anemia revealed normocellular bone marrow with trilineage maturation. The patient had no evidence of immunodeficiency or infection with EBV or HHV-8. This is the first reported case of a mature T-cell lymphoma with aberrant expression of three B-cell lineage markers. The current report also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous neoplastic clones.

Increased polyclonal CD5+ B1a lymphocytes in a haploidentical stem cell transplant recipient.

BACKGROUND: Atypical lymphocyte populations may be seen in the peritransplant setting. In this case report, we describe an unusually high number of CD5+ B-cells (B1a cells) following transplant. METHODS: B1a cells identified during routine follow-up by immunophenotypic analysis in a middle-aged man who had a haploidentical stem cell transplant for acute myeloid leukemia were compared with a reference set of post-transplant samples. RESULTS: Increased but polyclonal B1a cells were identified with 100% donor chimerism. CONCLUSIONS: Our case demonstrates that a high absolute number of B1a cells may be seen post-transplant and should not be confused with an atypical CD5+ lymphoproliferative disorder. Furthermore, the population of polyclonal CD5+ B lymphocytes from the patient's donor is prominent 7 months post-transplant. This suggests that the maintenance of CD5+ B1 cells prior to conversion to adult-type CD5⁻ B2 cells is not hindered by the recipient adult stromal environment.

Home dialysis in the new USA bundled payment plan: implications and impact.

On 1 January 2011, a new payment system for Medicare patients will be implemented in the United States. This new system bundles services previously charged separately and under a "fee for service" environment. The authors discuss the implications of this approach. Over the next several pages is a response by American physicians and dialysis innovators to a federal initiative to change the way dialysis is paid for in the United States. Peter Blake, the Editor-in-Chief of Peritoneal Dialysis International, invited Thomas Golper to articulate physicians' concerns with this new payment scheme. After the government of the USA closed its comment period over the new payment methodology, called "bundling," Golper sought out colleagues from diverse backgrounds and compiled this collective view of the situation.