Retrieval of critically ill adults using extracorporeal membrane oxygenation: the nine-year experience in New South Wales.

In New South Wales, a coordinated extracorporeal membrane oxygenation (ECMO) retrieval program has been in operation since 2007. This study describes the characteristics and outcomes of patients transported by this service. We performed a retrospective observational study and included patients who were transported on ECMO to either of two adult tertiary referral hospitals in Sydney, New South Wales, between February 28, 2007 and February 29, 2016. One hundred and sixty-four ECMO-facilitated transports occurred, involving 160 patients. Of these, 118 patients (74%) were treated with veno-venous (VV) ECMO and 42 patients (26%) were treated with veno-arterial ECMO. The mean (standard deviation, SD) age was 40.4 (15.0) years. Seventy-seven transports (47%) occurred within metropolitan Sydney, 52 (32%) were from rural or regional areas within NSW, 17 (10%) were interstate transfers and 18 (11%) were international transfers. Transfers were by road (58%), fixed wing aircraft (27%) or helicopter (15%). No deaths occurred during transport. The median (interquartile range) duration of ECMO treatment was 8.9 (5.2-15.3) days. One hundred and nineteen patients (74%) were successfully weaned from ECMO and 109 (68%) survived to hospital discharge or transfer. In patients treated with VV ECMO, age, sequential organ failure assessment score, pre-existing immunosuppressive disease, pre-existing diabetes, renal failure requiring dialysis and failed prone positioning prior to ECMO were independently associated with increased mortality. ECMO-facilitated patient transport is feasible, safe, and results in acceptable short-term outcomes. The NSW ECMO Retrieval Service provides specialised support to patients with severe respiratory and cardiovascular illness, who may otherwise be too unstable to undergo inter-hospital transfer to access advanced cardiovascular and critical care services.

Antibodies against insulin measured by electrochemiluminescence predicts insulitis severity and disease onset in non-obese diabetic mice and can distinguish human type 1 diabetes status.

BACKGROUND: The detection of insulin autoantibodies (IAA) aids in the prediction of autoimmune diabetes development. However, the long-standing, gold standard 125I-insulin radiobinding assay (RBA) has low reproducibility between laboratories, long sample processing times and requires the use of newly synthesized radiolabeled insulin for each set of assays. Therefore, a rapid, non-radioactive, and reproducible assay is highly desirable. METHODS: We have developed electrochemiluminescence (ECL)-based assays that fulfill these criteria in the measurement of IAA and anti-insulin antibodies (IA) in non-obese diabetic (NOD) mice and in type 1 diabetic individuals, respectively. Using the murine IAA ECL assay, we examined the correlation between IAA, histopathological insulitis, and blood glucose in a cohort of female NOD mice from 4 up to 36 weeks of age. We developed a human IA ECL assay that we compared to conventional RBA and validated using samples from 34 diabetic and 59 non-diabetic individuals in three independent laboratories. RESULTS: Our ECL assays were rapid and sensitive with a broad dynamic range and low background. In the NOD mouse model, IAA levels measured by ECL were positively correlated with insulitis severity, and the values measured at 8-10 weeks of age were predictive of diabetes onset. Using human serum and plasma samples, our IA ECL assay yielded reproducible and accurate results with an average sensitivity of 84% at 95% specificity with no statistically significant difference between laboratories. CONCLUSIONS: These novel, non-radioactive ECL-based assays should facilitate reliable and fast detection of antibodies to insulin and its precursors sera and plasma in a standardized manner between laboratories in both research and clinical settings. Our next step is to evaluate the human IA assay in the detection of IAA in prediabetic subjects or those at risk of type 1 diabetes and to develop similar assays for other autoantibodies that together are predictive for the diagnosis of this common disorder, in order to improve prediction and facilitate future therapeutic trials.

An allele of IKZF1 (Ikaros) conferring susceptibility to childhood acute lymphoblastic leukemia protects against type 1 diabetes.

OBJECTIVE: IKZF1 encoding Ikaros, an essential regulator of lymphopoiesis and immune homeostasis, has been implicated in the development of childhood acute lymphoblastic leukemia (C-ALL). Because recent genome-wide association (GWA) studies have linked a region of the 3'-UTR of IKZF1 with C-ALL susceptibility, we tested whether IKZF1 is associated with the autoimmune disease type 1 diabetes. RESEARCH DESIGN AND METHODS: rs10272724 (T>C) near IKZF1 at 7p12 was genotyped in 8,333 individuals with type 1 diabetes, 9,947 control subjects, and 3,997 families of European ancestry. Association was tested using logistic regression in the case-control data and by the transmission disequilibrium test in the families. Expression data for IKZF1 by rs10272724 genotype were obtained using quantitative PCR of mRNA/cDNA generated from peripheral blood mononuclear cells from 88 individuals, whereas expression data for five other neighboring genes were obtained from the online Genevar dataset. RESULTS: The minor allele of rs10272724 (C) was found to be protective from type 1 diabetes (odds ratio 0.87 [95% CI 0.83-0.91]; P = 1.1 × 10(-11)). rs10272724 was not correlated with levels of two transcripts of IKZF1 in peripheral blood mononuclear cells. CONCLUSIONS: The major susceptibility genotype for C-ALL confers protection from type 1 diabetes. Our finding strengthens the link between autoimmunity and lymphoid cancers. Further investigation is warranted for the genetic effect marked by rs10272724, its impact on IKZF1, and the role of Ikaros and other family members, Ailios (IKZF3) and Eos (IKZF4), in autoimmunity.

Thermal ablation of tumor cells with antibody-functionalized single-walled carbon nanotubes.

Single-walled carbon nanotubes (CNTs) emit heat when they absorb energy from near-infrared (NIR) light. Tissue is relatively transparent to NIR, which suggests that targeting CNTs to tumor cells, followed by noninvasive exposure to NIR light, will ablate tumors within the range of NIR. In this study, we demonstrate the specific binding of antibody-coupled CNTs to tumor cells in vitro, followed by their highly specific ablation with NIR light. Biotinylated polar lipids were used to prepare stable, biocompatible, noncytotoxic CNT dispersions that were then attached to one of two different neutralite avidin-derivatized mAbs directed against either human CD22 or CD25. CD22(+)CD25(-) Daudi cells bound only CNTs coupled to the anti-CD22 mAb; CD22(-)CD25(+) activated peripheral blood mononuclear cells bound only to the CNTs coupled to the anti-CD25 mAb. Most importantly, only the specifically targeted cells were killed after exposure to NIR light.

Design, microfabrication, and analysis of micrometer-sized cylindrical ion trap arrays.

A description of the design and microfabrication of arrays of micrometer-scale cylindrical ion traps is offered. Electrical characterization and initial ion trapping experiments with a massively parallel array of 5 microm internal radius (r(0)) sized cylindrical ion traps (CITs) are also described. The ion trap, materials, and design are presented and shown to be critical in achieving minimal trapping potential while maintaining minimal power consumption. The ion traps, fabricated with metal electrodes, have inner radii of 1, 2, 5, and 10 microm and range from 5 to 24 microm in height. The electrical characteristics of packaged ion trap arrays were measured with a vector network analyzer. The testing focused on trapping toluene (C(7)H(8)), mass 91, 92, or 93 amu, in the 5 microm sized CITs. Ions were formed via electron impact ionization and were ejected by turning off the rf voltage applied to the ring electrode; a current signal was collected at this time. Optimum ionization and trapping conditions, such as a sufficient pseudopotential well and high ionization to ion loss rate ratio (as determined by simulation), proved to be difficult to establish due to the high device capacitance and the presence of exposed dielectric material in the trapping region. However, evidence was obtained suggesting the trapping of ions in 1%-15% of the traps in the array. These first tests on micrometer-scale CITs indicated the necessary materials and device design modifications for realizing ultrasmall and low power ion traps.

Diabetes-related end-stage renal disease in Missouri: trends and variations by age and race.

Diabetes-related end-stage renal disease (ESRD-DM) is a major source of morbidity and medical costs. The authors studied patterns of ESRD-DM in Missouri during the period 1985-1992. The incidence of ESRD-DM increased during this period, with the largest increase in older age groups. ESRD-DM is substantially more common among blacks than among whites. Enhanced efforts are needed to improve detection and control of diabetes and its complications, especially in high-risk populations.

Five years' experience with ChlVPP: effective low-toxicity combination chemotherapy for Hodgkin's disease.

Since 1975, 191 patients with Hodgkin's disease have been treated with a combination of chlorambucil, vinblastine, procarbazine and prednisolone (ChlVPP). Complete remission rates were 73% for previously untreated patients, 91% for patients previously treated with radiotherapy and 55% for patients previously treated with chemotherapy. In 59 patients with advanced disease who received no other treatment, a 5-year survival rate of 66% was comparable with that achieved by more toxic mustine-containing combinations. ChlVPP has few side effects, is easily given to outpatients, and can be combined with elective radiotherapy in selected patients.

Prognostic factors in clinical stage I non-seminomatous germ-cell tumours of the testis.

Prognostic factors have been studied in 59 men with clinical Stage I non-seminomatous germ-cell tumours of the testis (NSGCTT) seen at the Royal Marsden Hospital between 1973 and 1978. Fourteen of the patients relapsed, and 45 have remained continuously disease-free. Two factors were identified which showed a significant correlation with relapse following radiotherapy: local extent of the primary tumour, and rate of decline of serum alpha-foetoprotein (AFP) and beta-human chorionic gonadotrophin (hCG) levels following orchidectomy. High serum marker levels at the time of referral after orchidectomy were not prognostically significant per se. The presence of tissue-associated hCG in the primary tumour was not prognostically significant. The results were compared with histology and pathological stage of the primary tumour in patients presenting with lung metastases but no clinical evidence of lymph-node disease. Embryonal carcinoma was more commonly associated with a locally invasive primary tumour and with extralymphatic spread than was teratocarcinoma.

Three years' experience with Ch1VPP (a combination of drugs of low toxicity) for the treatment of Hodgkin's disease.

In 3 years, 118 patients with Hodgkin's disease have completed chemotherapy with chlorambucil, vinblastine, procarbazine and prednisolone (Ch1VPP). The complete remission rates were 90% for 29 patients previously treated with radiotherapy, 67% for 73 patients previously untreated and 44% for 16 patients with prior chemotherapy. The 3-year survival rates for the first 70 patients in the series were 83% for previously irradiated patients, 84% for previously untreated patients and 67% for those with prior chemotherapy. Forty-seven previously untreated or previously irradiated patients in this group achieved complete remission. The 3-year disease-free survival rates for these patients were 71% and 67% respectively. This regimen gives complete remission and survival rates comparable with results obtained with combinations including nitrogen mustard, while producing fewer side-effects.

A combination of chlorambucil, vinblastine, procarbazine and prednisolone for treatment of Hodgkin's disease.

Seventy patients with Hodgkin's disease have been treated with a combination of chlorambucil, vinblastine, procarbazine and prednisolone (Ch1VPP). The complete remission rate of 75-7% compares well with that produced by other combinations. The combination is non-toxic, easily administered and can be given safely to outpatients. Its main advantage is that it is far less upsetting to patients than combinations containing nitrogen mustard.

Hodgkin's disease in children.

Fifty-nine children with Hodgkin's disease were seen over a 34-year period. Compared with Hodgkin's disease in adults, there was an increased male incidence, especially in the younger children. This was associated with an increased male incidence of lymphocyte-predominant histology. Forty-six patients underwent lymphography as part of their staging, and 13 had staging laparotomies. The 5-year survival for the entire group was 85%, with a median survival of 10 years. Response to radiotherapy in children with Stages I-IIIA disease was: 12 children treated with involved-field radiotherapy after inadequate clinical staging had a 3-year remission rate of 13%, and a median length of remission of 18 months; 24 children treated with extended-field radiotherapy after adequate clinical staging, including lymphography, had a 3-year remission rate of 72%, and a median duration of remission not yet reached; 3 children treated with elective local radiotherapy for Stage IA disease after intensive clinical staging remain in complete remission for periods of up to 34 months. Eight out of 10 children with Stages IIIB-IV disease, treated with combination chemotherapy, achieved complete remission with a 3-year remission rate of 70%; 7 children treated with combination chemotherapy following relapse after radiotherapy all achieved complete remission with a 3-year complete remission rate of 66%. Thirteen children underwent laparotomy and splenectomy as a staging procedure. Five were found to have intra-abdominal disease, including 4 with splenic involvement. These results show that there is no place for involved-field radiotherapy after inadequate clinical staging, in the management of childhood Hodgkin's disease. Extended-field radiotherapy after adequate staging, and combination chemotherapy, produce results which are as good as those for adults, but the benefits of these treatments and of staging laparotomy must be balanced against the possible complications when they are used in children. These problems are discussed and a scheme of management is proposed.

Alcohol pain in Hodgkin's disease.

Thirty-five patients with Hodgkin's disease experienced alcohol pain. Nodular sclerosis was the predominant histological grade (77%). Alcohol pain was associated with other factors generally considered to indicate an unfavorable prognosis--systemic symptoms, Stage II disease with multiple site involvement, Stage III or IV disease. Enlargment and a rise in temperature of lymph nodes were both present at or appeared at the site of pain in the majority (86%) of patients with this symptom.

Reproductive and endocrine function in patients with Hodgkin's disease: effects of oophoropexy and irradiation.

Reproductive and endocrine function was investigated in 22 women with Hodgkin's disease who had bilateral mid-line oophoropexies performed at staging laparotomy. The operation was followed in 12 cases by "inverted Y" pelvic lymph node irradiation and in 4 cases by para-aortic lymph node irradiation. Pregnancies occurred after the operation in 4 of the 6 patients subsequently found not to require irradiation below the diaphragm. In the other 2 patients in this group the menstrual history was unaffected and normal gonadotrophin concentrations indicated intact ovarian function. In the group receiving para-aortic irradiation, in whom the ovarian irradiation dose was was small (about 150 rad to each ovary) menstrual function and gonadotrophin concentrations were normal at the time of review and one patient has subsequently become pregnant. In the group receiving inverted Y irradiation, in whom the ovaries were shielded from the radiation beam by a rectangular lead block, the ovarian dose was much higher (lowest dose 600 rad, highest dose 3500 rad). Nine of the 12 have persisting amenorrhoea with elevated levels of both gonadotrophins. One patient has since become pregnant and one patient has resumed menstrual cycles and has normal basal gonadotrophin concentrations. One patient who has resumed menstrual cycles has a monotrophic elevation of basal serum FSH concentrations. We conclude that bilateral mid-line oophoropexy does not impair ovarian function or gamete transport and should be performed at diagnositc laparotomy in women of child bearing age with Hodgkin's disease, even when it is uncertain whether pelvic node irradiation will be necessary. The results in the patients who received inverted Y irradiation indicate that the technique of pelvic shielding and ovarian transposition used were only partially successful in preserving fertility. Alternative techniques for preserving ovarian function are discussed.

The results of radiotherapy for Hodgkins' disease.

The results of radiation therapy in 212 patients with stages I and II Hodgkin's disease treated between 1963 and 1973 show that approximately 60% remain disease-free following treatment. Multiple node involvement in stage II, particularly associated with infraclavicular node disease, is identified as a group where the relapse rate is high. This presentation is associated particularly with NS. In a group of 78 patients treated with radiotherapy following staging laparotomy and splenectomy approximately 80% remain in complete remission. The preliminary results of treatment in PS IIIa patients are substantially the same as those for PS I and II; the results of treatment for NS and MC disease are similar. The significance of involvement of the spleen is discussed. Although it is probable that Hodgkin's disease spreads to the spleen through the blood stream it is suggested that splenic involvement does not necessarily indicate that the involvement of other extralymphatic structures such as liver and marrow has occurred. However, when the nodes in the porta hepatis are involved splenic Hodgkin's disease may well be associated with an increased risk of occult hepatic infiltration.

Fertility after unilateral orchidectomy and radiotherapy for patients with malignant tumours of the testis.

The results of treatment for patients with seminoma of the testis by orchidectomy and irradiation are so satisfactory that retroperitoneal lymph node dissection is no longer practised. However, this operation is still used routinely in some centres for patients with testicular teratomas despite the lack of evidence that it gives better results than those obtained with irradiation followed by removal of lymphographically demonstrable residual tumour and in the face of the high incidence of ejaculatory impotence which follows. On grounds of preservation of sexual function and fertility there is a great advantage to be gained from the latter form of treatment. Thirty-four of our patients between the ages of 25 and 45 years treated by irradiation to the para-aortic and iliac nodes for testicular tumours fathered 52 children to term after their treatment.