An evaluation of continuous subcutaneous infusions across seven NHS acute hospitals: is there potential for 48-hour infusions?

BACKGROUND: Continuous subcutaneous infusions (CSCIs) are commonly used in the United Kingdom as a way of administering medication to patients requiring symptom control when the oral route is compromised. These infusions are typically administered over 24 h due to currently available safety data. The ability to deliver prescribed medication by CSCI over 48 h may have numerous benefits in both patient care and health service resource utilisation. This service evaluation aims to identify the frequency at which CSCI prescriptions are altered at NHS Acute Hospitals. METHODS: Pharmacists or members of palliative care teams at seven acute NHS hospitals recorded anonymised prescription data relating to the drug combination(s), doses, diluent and compatibility of CSCIs containing two or more drugs on a daily basis for a minimum of 2 days, to a maximum of 7 days. RESULTS: A total of 1301 prescriptions from 288 patients were recorded across the seven sites, yielding 584 discrete drug combinations. Of the 584 combinations, 91% (n = 533) included an opioid. The 10 most-common CSCI drug combinations represented 37% of the combinations recorded. Median duration of an unchanged CSCI prescription across all sites was 2 days. CONCLUSION: Data suggests medication delivered by CSCI over 48 h may be a viable option. Before a clinical feasibility study can be undertaken, a pharmacoeconomic assessment and robust chemical and microbiological stability data will be required, as will the assessment of the perceptions from clinical staff, patients and their families on the acceptability of such a change in practice.

First-trimester diagnosis of Meckel-Gruber syndrome by fetal ultrasound with molecular identification of CC2D2A mutations by next-generation sequencing.

We describe a first-trimester ultrasound examination in which the finding of fetal encephalocele and the cystic appearance of the kidneys raised suspicion of Meckel-Gruber syndrome (MKS). On the basis of sonographic findings, the patient elected termination of pregnancy, and post-termination studies using next-generation sequencing of a gene panel revealed two mutations (one previously described and the other novel) in the gene CC2D2A. Mutations in CC2D2A are known to cause MKS and Joubert syndrome, thus providing molecular confirmation of the clinical suspicion of MKS and opening the possibility for future prenatal diagnosis. This case highlights the ability to detect important anomalies in the first trimester using ultrasound, even in low-risk situations. It also demonstrates the growing role of new sequencing technologies in fetal testing.

Immunoglobulin isotypes and functional anti-FVIII antibodies in response to FVIII treatment in Balb/c and C57BL/6 haemophilia A mice.

Previous studies have demonstrated that genetic factors play an important role in determining the likelihood of formation of anti-factor VIII (FVIII) antibodies in haemophilia A patients. We were interested in characterizing the spectrum of FVIII antibody formation and the primary and secondary immune responses after FVIII administration in two different exon 16-disrupted haemophilia A mouse strains, Balb/c and C57BL/6. Balb/c and C57BL/6 E16 haemophilia A mice were used in all experiments. Total FVIII antibodies and FVIII inhibitors were measured using ELISA and Bethesda assays respectively. T- and B-cell cytokines were quantified using ELISA and flow cytometry. FVIII antibodies, but not functional inhibitors were detectable 1 week after the first FVIII treatment in both strains. These antibodies mainly belonged to the IgM and IgA isotypes. After the fourth FVIII treatment, neutralizing anti-FVIII antibodies were detected in both mouse strains: Balb/c (mean inhibitory titer 58 BU) and C57BL/6 (mean inhibitory titer 82 BU). IgG1 levels were similar in both strains but the IgG2A and IgG2B subclasses were higher in C57BL/6 mice. The results of intracellular cytokine staining of T cells indicated that the FVIII-treated C57BL/6 mice produced more IL10 and Th1 cytokines than the FVIII-treated Balb/c mice. These studies show that C57BL/6 mice develop a stronger immune response towards FVIII than Balb/c mice. We propose that the enhanced Th1 and IL10 cytokine micro-environment induced in C57BL/6 mice is responsible for this difference. Therefore, genetic strain-dependent differences must be considered when evaluating immunological outcomes in mouse models of haemophilia A.

Breast fine needle aspiration cytology: a review of current practice in Australasia.

AIMS: To investigate breast fine needle aspiration (FNA) cytology in Australasia, in terms of laboratory demographics, specimens received and quality control (QC). METHODS: A questionnaire was sent to all laboratories enrolled in the FNA module of the Royal College of Pathologists of Australasia Cytopathology Quality Assurance Program (QAP), requesting information about specimens received in a 3-month period in 2001 and in 2008. RESULTS: Responses were received from 81/180 laboratories in 2001 and from 94/200 in 2008. The mean number of cases per 3 months was 137 in 2001 and 141 in 2008 and for the 42 laboratories responding on both occasions, the mean number of cases declined from 191 to 149 (P=0.001). The mean percentage of malignant cases was 11.7% in 2001 and 10.5% in 2008 and the mean percentages of unsatisfactory rates were 21.7% and 25.2%, respectively; 43.2% of laboratories in 2001 and 40.4% in 2008 reported fewer than 50 cases for the 3-month period. The unsatisfactory rate was inversely proportional to the number of cases received. Most QC (69.1% in 2001, 71.3% in 2008) was carried out by correlation with any later histology. With no histology available, 35.8% of laboratories in 2001 and 48.9% in 2008 did no further follow-up. Follow-up of all diagnostic categories increased from 30.9% in 2001 to 44% in 2008. CONCLUSIONS: Breast FNA cytology is still actively undertaken in Australasia, but numbers have declined. Unsatisfactory rates have reached the Australian recommended upper limit and are inversely proportional to the total number of cases received. Overall QC measures are unchanged and consideration of a review of breast FNA guidelines is suggested.

Blood transfusion for caesarean delivery complicated by placenta praevia.

AIM: This study was undertaken to determine if the need for red cell blood transfusion in placenta praevia could be predicted. METHODS: Data from a retrospective observational study of 246 obstetric patients, with placenta praevia, from 1999 to 2005 were analysed to generate a model to predict requirement for transfusion. RESULTS: Seventy-one patients were transfused. Independent risk factors for transfusion were gestational age at delivery of 32-35 weeks [odds ratio (OR): 2.6; 95% confidence interval (CI): 1.1-6.4] and caesarean combined with hysterectomy (OR: 29.4; 95% CI: 5.9-145.9; P < 0.001). No independent risk of transfusion was associated with maternal age, race, parity, smoking status, type of anaesthesia, caesarean combined with arterial balloon occlusion, grade of placenta, accreta and previous uterine surgery. CONCLUSIONS: Gestational age at delivery and type of surgery required are predictors of transfusion during caesarean for placenta praevia. Arterial balloon occlusion does not appear to increase transfusion risk and may be considered as one of the techniques in management.

Complications of percutaneous thoracostomy in neonates and infants.

OBJECTIVE: Percutaneous thoracostomy tubes are widely used in neonates, infants and children. The technique has a low complication rate. Lung perforation by a pigtail catheter is described in a single case report. STUDY DESIGN: This is a multi-center case series of neonates and infants who experienced thoracic organ injury following percutaneous chest tube placement between 2006 and 2015. RESULT: Eleven patients had chest tube-related thoracic organ injury. In six, tubes were placed during resuscitation. Gestational ages ranged from 24+6 weeks to term. Most of the chest tubes were pigtail catheters, and the most common injury was lung lobe perforation. Pericardium and mediastinum were also sites of injury. Some patients had small pleural effusions, with no other complications identified. CONCLUSION: Thoracic organ injury by percutaneous catheters may be more common than previously appreciated. Clinical and radiological findings are non-specific, and the diagnosis may not be apparent until autopsy.

Studies of renin activation and regulation of aldosterone and 18-hydroxycorticosterone biosynthesis in hyporeninemic hypoaldosteronism.

In an attempt to evaluate deficiencies of renin activation and adrenal zona glomerulosa biosynthesis in hyporeninemic hypoaldosteronism (HH), we studied active and inactive renin (AR and IR, respectively) responses to the dopamine antagonist metoclopramide, furosemide, and graded dose infusion of ACTH in 10 HH patients and 6 normal subjects. In HH patients, AR levels, but not IR levels, were decreased relative to normal values. While normal subjects had an AR response to metoclopramide, the HH patients did not. The AR response to furosemide in HH patients was markedly diminished compared to that in normal subjects. Plasma cortisol and corticosterone levels were in the normal range, but the zona glomerulosa products 18-hydroxycorticosterone (18-OHB) and aldosterone (Aldo) were low in HH patients. Plasma 18-OHB and Aldo responses to metoclopramide and furosemide were diminished, but cortisol and 18-OHB responses to ACTH were normal in the HH patients. Our observation that 18-OHB and Aldo responses to metoclopramide were diminished refutes the possibility that excessive adrenal zona glomerulosa dopaminergic activity could account for reduced biosynthesis of 18-OHB and Aldo in HH patients. Our results appear most consistent with the concept that the primary etiological factor in the HH syndrome is impairment of renal activation of renin.

Erythrocyte membrane sodium-potassium and magnesium ATPase in primary affective disorder.

Erythrocyte membrane Mg2+ ATPase and Na+-K+ ATPase were measured in patients with affective disorder, their well relatives, and normal controls during euthymic moods. On the average, the Mg2+ ATPase activity was high in subjects belonging to affective disorder families. However, the difference between normal and affective disordered individuals was not statistically significant. Only the well individuals from affective disorder pedigrees as a group had significantly higher than normal Mg2+ ATPase activity (p less than 0.05). The Na+-K+ ATPase activity was similar for all the groups, including normal, bipolar manic-depressive (with or without lithium), unipolar depressive, and well individuals. Lithium treatment did not seem to have any effect on Mg2+ ATPase. Even though the values of Na+-K+ ATPase in the lithium-treated group were high, it is not certain that this was due to lithium per se.

Determination of the optimal concentration of lithium for the prophylaxis of manic-depressive disorder.

A group of 29 bipolar manic-depressives completed a 12-month double-blind cross-over trial of low-dose and high-dose lithium prophylaxis. Twelve patients relapsed, and significantly more of the relapses occurred during the low-dose 6-month phase of the trial. There was a trend for relapse to occur within 2 months of an abrupt drop in plasma lithium level, and to occur more often in women than in men. The efficacy of low-dose lithium prophylaxis and the significance of rebound relapse are discussed.

Neurophysiological correlates of sibling pairs discordant for bipolar affective disorder.

Eleven sibling pairs discordant for bipolar disorder were compared on the basis of computerized EEGs and auditory evoked potentials. The findings suggest that CNS overarousal may be characteristic of trait bipolar disorder.

Interviewing bipolar patients and their families.

The authors report on the case ascertainment phase of a pedigree study of patients with bipolar affective disorder. The nature of the research interview, which necessarily probes for symptoms and signs of affective disorder, appeared to have a provocative effect on some subjects by exposing heavily defended conflicts related to the expression of affect. Although such studies are necessary, researchers must be sensitive to the needs of their subjects and not regard the ascertainment interview as benign and uncathected.

Lethal congenital non-spherocytic, non-immune hemolytic anemia with genital and other anomalies in two brothers.

Non-consanguineous healthy parents had 2 boys with severe, non-spherocytic, nonimmune hemolytic anemia, abnormalities of their external genitalia, flat occiput, dimpled earlobes, deep plantar creases, and increased space between their first and second toes. The birth of these children was separated by a spontaneous abortion at 3 months and delivery of a normal girl. We propose that these boys have a heretofore undescribed autosomal or X-linked recessive syndrome.

Autopsy findings in a severely affected infant with a 2q terminal deletion.

We describe a 37-week gestation female infant who was born with a terminal 2q deletion. Both of her parents had normal chromosomes. This infant had multiple anomalies, including hypertelorism, short palpebral fissures, microphthalmia, cleft lip/cleft palate, and abnormal ears. Autopsy documented Dandy-Walker malformation with severe hydrocephalus, aortopulmonary window, secundum atrial septal defect, duodenal atresia, incomplete rotation of the bowel, gonadal dysgenesis, uterus didelphys, and musculoskeletal defects. Compared with the other 6 children with 2q terminal deletion documented in the literature, this patient is the most severely affected. This patient is also the only one documented to have died and undergone autopsy examination. The findings in this case provide more data for the eventual description of a "terminal 2q deletion syndrome" and suggest that some abnormalities, such as gonadal dysgenesis, may be present in living children with this chromosome abnormality.

Lithium and carbamazepine interaction: possible neurotoxicity.

A case is described of a 22-year-old woman with bipolar affective disorder who developed severe neurotoxic symptoms when treated with a combined regimen of lithium carbonate and carbamazepine in therapeutic doses. An open A-B-C-B trial of the two medications separately and concurrently implicated a synergistic interaction between the two.

Pathology of culture-proven JK Corynebacterium pneumonia. An autopsy case report.

The first description of the pathologic characteristics of JK Corynebacterium pneumonia is presented. Occurring in a profoundly neutropenic patient, the pneumonia was characterized by massive fluid exudation in the alveoli with acute hemorrhage, significant proliferation of the bacteria beginning along the alveolar walls, and eventual alveolar wall necrosis. Other cases of JK Corynebacterium pneumonia are reviewed. This report emphasizes that JK Corynebacterium pneumonia has a high mortality and should be considered in patients with pulmonary deterioration and blood cultures positive for diphtheroids.

Novel natural products from soil DNA libraries in a streptomycete host.

As a route to accessing the potential chemical diversity of uncultivable microbes from the soil, combinatorial biosynthetic libraries were constructed by cloning large fragments of DNA isolated from soil into a Streptomyces lividans host. Four novel compounds, terragines A (1), B (2), C (3), and D (4), were isolated from recombinant 436-s4-5b1, and another novel compound, terragine E (5), was isolated from 446-s3-102g1. The structures were determined by a combination of spectroscopic techniques, primarily 2D NMR.

Effect of nutritional status on organic anion clearance by the swine liver.

Hepatic dysfunction follows a wide range of insults. Impaired excretion of organic dyes such as bilirubin often occurs before other obvious clinical defects in metabolic processes. Indocyanine green (ICG) is excreted through pathways similar to those of bilirubin. To determine the effectiveness of ICG as a marker of hepatic dysfunction related to clinical malnutrition, pigs received 5 mg/kg ICG with simultaneous sampling from the hepatic vein, pulmonary artery, and aorta over 3 hours. Group I remained well nourished, group II was fasted to a weight loss equal to 20% of initial body weight, and group III was fasted to a 20% weight loss and then refed until the animals regained their initial weight. Both systemic and intrinsic hepatic clearance were depressed significantly with fasting but returned above baseline after refeeding. No significant difference appeared between systemic and intrinsic hepatic clearance. Extraction ratios were low in all groups. In outbred swine, ICG clearance reflects the function of hepatic organic anion excretion in vivo, and venous sampling reflects intrinsic hepatic clearance. The impairment of the carrier-mediated transport system is reversible with refeeding.

Effect of route of nutrition on recovery of hepatic organic anion clearance after fasting.

BACKGROUND: Previous work documented a 40% depression of hepatic indocyanine green (ICG) clearance (ClICG) in pigs fasted to 20% weight loss, with return to normal within 12 days of food refeeding. ClICG in pigs is insensitive to changes in hepatic blood flow but very sensitive to changes in hepatic function (HF). Serial ClICG determinations were performed to quantify the effect of route of nutrient delivery on recovery of HF. METHODS: Fourteen pigs were fasted to 20% weight loss (12.8 days average) with both gastrostomy and intravenous catheters placed in each animal midway through the fast. ClICG was measured before fast, after fast, and after 12 days refeeding through the enteral or parenteral route at 125 kcal/kg/day with isonitrogenous, isocaloric diets containing 9% fat. Urine and stool were analyzed for total nitrogen. RESULTS: No significant differences appeared between groups in nitrogen output during fasting (4.5 +/- 1.2 gm/kg enteral, 4.6 +/- 1.2 gm/kg parenteral), in nitrogen intake (800 +/- 19 mg/kg/day enteral, 810 +/- 10 mg/kg/day parenteral), or in before or after fast ClICG, but enteral feeding produced more positive nitrogen balance. ClICG improved significantly with enteral but not with parenteral feeding. CONCLUSIONS: Enteral feeding produces faster nitrogen accrual and reverses the depression of major pathways of bilirubin and organic anion excretion associated with malnutrition. Parenteral feeding failed to improve organic anion clearance despite weight gain.

Protein tyrosine phosphorylation in streptomycetes.

Using phosphotyrosine-specific antibodies, we demonstrate that in several Streptomyces spp. a variety of proteins are phosphorylated on tyrosine residues. Tyrosine phosphorylation was found in a number of Streptomyces species including Streptomyces lividans, Streptomyces hygroscopicus and Streptomyces lavendulae. Each species exhibited a unique pattern of protein tyrosine phosphorylation. Moreover, the patterns of tyrosine phosphorylation varied during the growth phase and were also influenced by culture conditions. We suggest that metabolic shifts during the complex growth cycle of these filamentous bacteria, and possibly secondary metabolic pathways, may be controlled by the action of protein tyrosine kinases and phosphatases, as has been demonstrated in signal transduction pathways in eukaryotic organisms.

Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11.

This case report documents the first karyotypic, fluorescence in situ hybridization, and genetic analysis of an angiomatoid fibrous histiocytoma that arose and recurred in the arm of a 5.5-year-old girl. Complex rearrangements between chromosomes 2, 12, 16, and 17 were noted, as well as deletion in the long arm of chromosome 11. Flow cytometry revealed a normal cell population. The t(12;16) site was further investigated using reverse transcriptase-polymerase chain reaction. We found that the FUS (also known as TLS) gene from 16p11 combined with the ATF-1 gene from 12q13 to generate a chimeric FUS/ATF-1. The FUS gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma and in acute myeloid leukemia with t(16;21)(p11;q22), while the ATF-1 gene is rearranged in the t(12;22)(q13;q12) found recurrently in clear cell sarcomas (malignant melanoma of soft parts). Thus, the FUS/ATF-1 gene in angiomatoid fibrous histiocytoma is predicted to code for a protein that is very similar to the chimeric EWS/ATF-1 found in clear cell sarcoma.