An improved set of electron-THFA cross sections refined through a neural network-based analysis of swarm data.

We review experimental and theoretical cross sections for electron transport in α-tetrahydrofurfuryl alcohol (THFA) and, in doing so, propose a plausible complete set. To assess the accuracy and self-consistency of our proposed set, we use the pulsed-Townsend technique to measure drift velocities, longitudinal diffusion coefficients, and effective Townsend first ionization coefficients for electron swarms in admixtures of THFA in argon, across a range of density-reduced electric fields from 1 to 450 Td. These measurements are then compared to simulated values derived from our proposed set using a multi-term solution of Boltzmann's equation. We observe discrepancies between the simulation and experiment, which we attempt to address by employing a neural network model that is trained to solve the inverse swarm problem of unfolding the cross sections underpinning our experimental swarm measurements. What results from our neural network-based analysis is a refined set of electron-THFA cross sections, which we confirm is of higher consistency with our swarm measurements than that which we initially proposed. We also use our database to calculate electron transport coefficients in pure THFA across a range of reduced electric fields from 0.001 to 10 000 Td.

Self-consistency of electron-THF cross sections using electron swarm techniques.

The drift velocity and first Townsend ionization coefficient of electrons in gaseous tetrahydrofuran are measured over the range of reduced electric fields 4-1000 Td using a pulsed-Townsend technique. The measured drift velocities and Townsend ionization coefficients are subsequently used, in conjunction with a multi-term Boltzmann equation analysis, as a further discriminative assessment on the accuracy and completeness of a recently proposed set of electron-THF vapor cross sections. In addition, the sensitivity of the transport coefficients to uncertainties in the existing cross sections is presented. As a result of that analysis, a refinement of the momentum transfer cross section for electron-THF scattering is presented, along with modifications to the neutral dissociation and dissociative electron attachment cross sections. With these changes to the cross section database, we find relatively good self-consistency between the measured and simulated drift velocities and Townsend coefficients.

A retrospective epidemiological analysis of risk factors for a primary necropsy diagnosis of bovine respiratory disease.

Bovine respiratory disease (BRD) is a multifactorial disease and the primary cause of both bovine morbidity and mortality in Ireland. The risk factors associated with a primary necropsy diagnosis of BRD among cattle in the traditional (non-feedlot) husbandry systems prevalent in Ireland have not been investigated previously. The aim of this case-control study was to investigate those risk factors among cattle of all ages over an 8 year period. A total of 3,090 BRD cases and 5,236 controls were matched by submitting veterinary practitioner. Univariable and multivariable analyses were performed to examine the association of selected animallevel, herd-level and environmental risk factors with case or control status using a conditional logistical regression model. Male cattle aged more than 31 days were significantly more likely to record a primary necropsy diagnosis of BRD than female cattle. Older cattle of both sexes were at increased odds of a BRD necropsy diagnosis than younger calves with the exception of female cattle aged greater than 165 days. The risk of a primary necropsy diagnosis of BRD increased with increasing herd size and decreased with increasing time in days since the last animal movement into the submitting herd. There were significantly reduced odds of a primary necropsy diagnosis of BRD in the summer (June to August) when compared with the autumn (September to November). These findings identify significant risk factors for a necropsy diagnosis of BRD under non-feedlot-type husbandry conditions.

Comparison of Utilization and Clinical Outcomes for Belatacept- and Tacrolimus-Based Immunosuppression in Renal Transplant Recipients.

The performance of belatacept in a real clinical setting has not been reported. A retrospective cohort study was conducted using registry data comparing 1-year clinical outcomes between belatacept- and tacrolimus-treated adult kidney transplant recipients (KTRs) from January 6, 2011, through January 12, 2014. Of 50 244 total patients, 417 received belatacept plus tacrolimus, 458 received belatacept alone, and 49 369 received tacrolimus alone at discharge. In the overall study cohort, belatacept alone was associated with a higher risk of 1-year acute rejection, with the highest rates associated with non-lymphocyte-depleting induction (adjusted hazard ratio 2.65, 95% confidence interval 1.90-3.70, p < 0.0001). There was no significant difference in rejection rates between belatacept plus tacrolimus and tacrolimus alone. In KTRs who met inclusion criteria for the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), 1-year kidney function was higher with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (mean estimated GFR 65.6, 60.4 and 54.3 mL/min per 1.73 m2 , respectively; p < 0.001). The incidence of new-onset diabetes after transplantation was significantly lower with belatacept plus tacrolimus and belatacept alone versus tacrolimus alone (1.7%, 2.2%, and 3.8%, respectively; p = 0.01). Despite improved graft function and metabolic complications with belatacept alone, it may be advisable to add short-term tacrolimus in the first year after transplant and to consider lymphocyte-depleting induction in patients with high rejection risk, as the risk-benefit ratio allows.

Transmission of Balamuthia mandrillaris through solid organ transplantation: utility of organ recipient serology to guide clinical management.

A liver, heart, iliac vessel and two kidneys were recovered from a 39-year-old man who died of traumatic head injury and were transplanted into five recipients. The liver recipient 18 days posttransplantation presented with headache, ataxia and fever, followed by rapid neurologic decline and death. Diagnosis of granulomatous amebic encephalitis was made on autopsy. Balamuthia mandrillaris infection was confirmed with immunohistochemical and polymerase chain reaction (PCR) assays. Donor and recipients' sera were tested for B. mandrillaris antibodies. Donor brain was negative for Balamuthia by immunohistochemistry and PCR; donor serum Balamuthia antibody titer was positive (1:64). Antibody titers in all recipients were positive (range, 1:64-1:512). Recipients received a four- to five-drug combination of miltefosine or pentamidine, azithromycin, albendazole, sulfadiazine and fluconazole. Nausea, vomiting, elevated liver transaminases and renal insufficiency were common. All other recipients survived and have remained asymptomatic 24 months posttransplant. This is the third donor-derived Balamuthia infection cluster described in solid organ transplant recipients in the United States. As Balamuthia serologic testing is only available through a national reference laboratory, it is not feasible for donor screening, but may be useful to determine exposure status in recipients and to help guide chemotherapy.

Hereditary ovarian and breast cancer: what have we learned?

An autosomal-dominant inherited trait predisposing women to both breast cancer (BC) and ovarian cancer (OC) was first described in 1971. Subsequent strides were made in identifying mutations in the eventually cloned genes BRCA1 and BRCA2 as being responsible for hereditary BC and OC (HBOC) in many women with early-onset HBOC. More recently, modifiers of BC risk have also been identified and are under study. The biological and molecular genetic pathways for malignant transformation in OC (ovarian epithelium and/or epithelium of the fallopian tube or, possibly, the endometrium and endocervix) remain elusive. The answer to the question 'What have we learned?' which is part of our chapter title unfortunately remains incomplete. However, intensive worldwide research indicates that its malignant transformation is the product of a multi-step process where there is an array of mutations which account for three or more classes of genes, inclusive of proto-oncogenes, tumor suppressor genes and mutator genes. This causal uncertainty heralds an enormous clinical-pathology dilemma, given the fact that epithelial OC, together with related Müllerian duct carcinoma, harbor the highest fatality rates of all gynecologic malignancies.

Current status of prophylactic surgery for hereditary breast and gynecologic cancers.

Given the limitations regarding the impact of screening and the uncertainties concerning chemoprevention for women with significant genetic susceptibilities to breast, endometrial and ovarian cancers, recent research and publications on prophylactic surgery for cancer prevention and improved long-term survival for women at hereditary risk have increasing importance.

Histology of prophylactically removed ovaries from BRCA1 and BRCA2 mutation carriers compared with noncarriers in hereditary breast ovarian cancer syndrome kindreds.

OBJECTIVE: The literature reports conflicting studies claiming premalignant histological features in benign ovaries from women who may have hereditary predilections for ovarian carcinoma. To test the veracity of these claims, this investigation studied ovaries prophylactically removed from members of hereditary breast ovarian cancer (HBOC) syndrome families who carry BRCA1 and BRCA2 mutations and compared these with the ovaries of mutation-negative women from the same HBOC syndrome kindred. METHODS: Sixty cases of women from HBOC syndrome families who had undergone prophylactic oophorectomies and whose BRCA1 and BRCA2 mutation status had been tested were selected from our database. Thirty had tested positive for BRCA1 mutations, 3 carried BRCA2 mutations, and 27 were negative for both BRCA1 and BRCA2 germline mutations. Histologic material from each case was examined by light microscopy blinded to the mutation status. Histologic features, previously reported to be possible precursor lesions for ovarian cancer, were quantified. Data from BRCA1 and BRCA2 mutation carriers were compared with those from mutation-negative cases in the direct line of genetic inheritance from the same HBOC syndrome families. RESULTS: Statistical analysis found that a more frequent occurrence of ovarian surface micropapillae in 87% of mutation carriers compared with just 55% of mutation-negative cases was the only histologic feature which was significantly different between the two groups (P = 0.39). Cortical clefts tended to be deeper in the ovaries of mutation carriers, but this did not reach significance (P = 0.051). There were no other significant histologic differences between the ovaries removed from mutation carriers and those from noncarriers. CONCLUSIONS: The results of our large and prospectively controlled, blinded study contrast with those reported from smaller, unblinded investigations. Except for the possible biological significance of surface micropapillae on ovaries from BRCA1 and BRCA2 mutation carriers, we found no histologic evidence for a genetically determined ovarian carcinoma precursor lesion.

Genetics and ovarian carcinoma.

Ovarian cancer is a disease that will affect approximately 1% of American women during their lifetime, and contributes to more than 14,000 deaths annually. If not detected early, this disease has a 5-year survival rate of less than 20%. Ovarian cancer develops predominantly from the malignant transformation of a single cell type, the surface epithelium. Although the biological mechanisms of transformation remain unclear, it is probably a multistep process requiring an accumulation of genetic lesions in a number of different gene classes. Several proto-oncogenes, such as AKT2 and Ki-RAS, are activated during ovarian cancer development, with putative oncogene-containing chromosomal regions showing imbalances and DNA amplifications. A number of chromosomal regions are also lost in ovarian tumors, indicating that the inactivation of tumor suppressor genes, such as TP53, may also contribute to cancer development. An important recent advancement in the field of ovarian cancer research is the identification of the breast/ovarian cancer susceptibility genes, BRCA1 and BRCA2. Mutations in these two tumor suppressor genes are responsible for the majority of heritable forms of epithelial ovarian cancers. A second class of genes involved in DNA mismatch repair (MMR) are responsible for most cases of hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC or Lynch II cancer syndrome patients are also at an increased risk for developing ovarian cancer. Individuals in cancer-prone kindreds are currently being screened for germline mutations in BRCA1, BRCA2, and several MMR genes (eg, MSH2, MLH1), and mutant allele carriers counseled for cancer risks. Issues related to counseling and management of women at high risk for developing ovarian cancer are discussed. Although BRCA1, BRCA2, and a number of MMR genes have been identified, many more genes involved in gynecologic malignancies remain to be discovered and the clinical significance of the cancer genes already known is still in its infancy.

Peritoneal dialysate fill-volumes and hernia development in a cohort of peritoneal dialysis patients.

A retrospective case control study was performed on a cohort of 244 peritoneal dialysis patients followed over 5 years to determine whether dialysate fill-volume was associated with hernia development. The laboratory and clinical parameters of patients who developed hernias during this time period were compared with those of patients who did not develop hernias. Information on 27 patients who developed hernias was compared with that on 217 patients who did not develop hernias. Dialysate fill-volume was similar between groups (2.2 +/- .3 L for patients with hernias vs. 2.2 +/- .3 L for controls). Three patients with fill-volumes of 1.5 L developed hernias, and no patients with fill-volumes of 3 L developed hernias. Age, duration of time on dialysis, and body surface area were also similar between groups. This investigation could not find a relationship between fill-volume and hernia formation. From this study it would appear that physicians should not hesitate to increase fill-volume based on concerns of hernia development.

IFN regulatory factor-1 gene transfer into an aggressive, nonimmunogenic sarcoma suppresses the malignant phenotype and enhances immunogenicity in syngeneic mice.

IFN-gamma has a direct antitumor effect on many tumor cell lines mediated through the IFN-gammaR. One effect of IFN-gamma is to induce the nuclear transcription factor IFN regulatory factor-1 (IRF-1), which may function as a tumor suppressor. In this study, mouse IRF-1 cDNA under a high constitutive expression promoter was transfected into the highly aggressive, nonimmunogenic MCA 101 murine sarcoma. Clones were obtained by G418 selection and screened for IRF-1 mRNA expression by reverse transcriptase-PCR (RT-PCR). High expression clones had high levels of two MHC class I proteins (H-2Kb and H-2Db) on the cell surface that correlated with increased levels of class I mRNA by RT-PCR. Furthermore, these clones also had increased levels of MHC class II protein (I-Ab), which correlated with increased levels of one subunit of class II mRNA by RT-PCR. IRF-1-expressing clones had markedly diminished cell growth in vitro and decreased anchorage-independent growth in a soft agar assay. These clones also demonstrated markedly prolonged tumor latency and slowed growth in syngeneic C57BL/6 mice. IRF-1 gene-transfected cells had shortened tumor latency and formed faster growing tumors in gamma-irradiated immunodeficient mice compared with results in immunocompetent mice. Mice immunized with IRF-1-transfected cells were protected against subsequent challenge with IRF-1 transfected cells and also demonstrated greater tumor latency and slower tumor growth against subsequent challenge with untransfected cells compared with mice immunized with empty vector-transfected cells. These studies demonstrate a tumor suppressor effect of IRF-1, which acts in vivo through both partial reversion of the malignant phenotype and enhanced immune recognition and may play a role in the antitumor effects of IFN-gamma.

In vivo murine tumor gene delivery and expression by systemic recombinant vaccinia virus encoding interleukin-1beta.

PURPOSE: This study investigates the feasibility of systemic gene delivery in a tumor-bearing host using a vaccinia virus-based in vivo gene delivery and expression system. METHODS: A recombinant vaccinia virus encoding human interleukin-1beta (hIL-1beta) was constructed with a strong synthetic vaccinia virus late promoter driving hIL-1beta gene expression. C57BL/6 mice bearing established subcutaneous pancreatic tumors were injected intravenously in a blinded, randomized fashion with different doses of either the recombinant vaccinia virus(vMJ601hIL-Ibeta), control vaccinia (wild-type or TK-deficient), or saline. Toxicity was assessed, serial tumor sizes were measured, and viral titers and the amount of hIL-1beta in tumor, liver, and spleen were determined. RESULTS: High viral titers (10(6) PFU/g) were detected in tumors for all three viruses on postinjection day 3, and tumor viral titers persisted at high levels until day 9. In contrast, viral titers were initially 104-fold lower in nontumor tissues and decreased to undetectable levels by day 9. vMJ60hIL-1beta was rapidly cleared from liver and spleen by day 3 (titer levels < 100 PFU/g), while tumor titer levels persisted at 8.5 x 10(6) PFU/g. hIL-1beta was measurable in three of three tumors from vMJ601hIL-1beta treated mice on postinjection day 3, one of three on day 6, and one of three on day 9; no hIL-1beta was detected in any other tumors or normal tissues. Wild-type vaccinia had no antitumor effects. Treatment with two different doses of vMJ601hIL-1beta resulted in a consistent and significant decrease in tumor size in repeatable experiments as compared to controls. Histologic analysis revealed tumor cell necrosis with a surrounding neutrophil infiltrate in the vMJ601hIL-1beta treated tumor. CONCLUSION: These data show that recombinant vaccinia virus encoding hIL-1beta given intravenously preferentially localizes and amplifies in tumor tissue, is rapidly cleared from liver and spleen, produces measurable hIL-1beta in tumor but not normal tissues, and inhibits growth of established solid tumors in mice. Recombinant vaccinia virus encoding therapeutic genes may be a practical, efficient vehicle for direct in vivo gene transfer and expression in the treatment of cancer.

Experience with positron emission tomography (PET) scans in patients with ovarian cancer.

Our first year of experience in the use of PET scanning in the management of nine patients with ovarian cancer leads us to conclude that this promising new technique may be more sensitive than either serum CA-125 determinations or computed tomography for the detection and demonstration of residual or recurrent abdominal and pelvic tumor. Seven of these patients underwent second-look laparotomy which confirmed our impressions from preoperative PET scans in six patients, and the one other scan showed a focus of metabolic uptake coinciding with residual tumor in our retrospective review. The clinical courses of two other patients who did not undergo laparotomy confirmed the impressions gained from PET scans.

A critical analysis of laparoscopic assisted vaginal hysterectomies compared with vaginal hysterectomies unassisted by laparoscopy and transabdominal hysterectomies.

The first 115 laparoscopically assisted vaginal hysterectomies (LAVH) done by our faculty surgeons were compared with 220 vaginal hysterectomies (VH) and 194 abdominal hysterectomies (AH) done in our affiliated hospitals over the same period of time. Logistic regression analysis indicates that LAVHs were done for cases that would significantly be more likely selected for AH than for VH (p less than 0.0001). Matched case control studies with 28 LAVH/VH and 34 LAVH/AH pairs and bivariate analyses demonstrated that LAVH can be accomplished with low morbidity, short lengths of stay, and little, if any, increase in operating times compared with VH and AH. The LAVH procedure can be expected to replace many AHs in the future.

Persistent trophoblastic implants after salpingostomy for ectopic pregnancy.

Laparoscopic management of ectopic pregnancies is the accepted method of treatment in most centers. This report describes a case of persistent trophoblastic implants to the peritoneum after laparoscopic linear salpingostomy for evacuation of an early ectopic pregnancy. Based on this experience, methods for follow up after such procedures, and recommendations for management of persistent trophoblastic implants are discussed.

Gynecologic cancer clues to Lynch syndrome II diagnosis: a family report.

Lynch syndrome II was diagnosed when two sisters manifested early-onset synchronous carcinomas of the ovary and endometrium and a third sister was found to have Duke's A carcinoma of the cecum. A detailed cancer family history indicated paternal transmission of the deleterious genotype. The pattern of carcinoma of the colorectum and extracolonic sites throughout the extended family was then found to be consonant with this hereditary cancer-prone disorder. Lynch syndrome II may be exceedingly difficult to diagnose due to an absence of premonitory clinical signs or biomarkers of genotypic susceptibility. Its recognition is therefore dependent on a detailed cancer family history (all anatomic sites), coupled with knowledge of the pattern of the cancer spectrum, distribution, and natural history, as manifested in this hereditary disorder. We describe the decision logic that was involved in the diagnosis of Lynch syndrome II in this family and indicate the important role of the gynecologists in this process.

Laparoscopy-assisted vaginal hysterectomy: report of seventy-five consecutive cases.

Patients who underwent laparoscopy-assisted vaginal hysterectomy with or without adnexectomy experienced less fever, required less postoperative analgesia, were able to tolerate a full diet within 24 hours of surgery, and had a faster recovery and shorter hospital stay than patients who had abdominal or traditional vaginal hysterectomy.