Light echoes reveal an unexpectedly cool η Carinae during its nineteenth-century Great Eruption.

η Carinae is one of the most massive binary stars in the Milky Way. It became the second-brightest star in our sky during its mid-nineteenth-century 'Great Eruption', but then faded from view (with only naked-eye estimates of brightness). Its eruption is unique in that it exceeded the Eddington luminosity limit for ten years. Because it is only 2.3 kiloparsecs away, spatially resolved studies of the nebula have constrained the ejected mass and velocity, indicating that during its nineteenth-century eruption, η Car ejected more than ten solar masses in an event that released ten per cent of the energy of a typical core-collapse supernova, without destroying the star. Here we report observations of light echoes of η Carinae from the 1838-1858 Great Eruption. Spectra of these light echoes show only absorption lines, which are blueshifted by -210 km s(-1), in good agreement with predicted expansion speeds. The light-echo spectra correlate best with those of G2-to-G5 supergiants, which have effective temperatures of around 5,000 kelvin. In contrast to the class of extragalactic outbursts assumed to be analogues of the Great Eruption of η Carinae, the effective temperature of its outburst is significantly lower than that allowed by standard opaque wind models. This indicates that other physical mechanisms such as an energetic blast wave may have triggered and influenced the eruption.

Regression approaches in the test-negative study design for assessment of influenza vaccine effectiveness.

Influenza vaccination is the most practical means available for preventing influenza virus infection and is widely used in many countries. Because vaccine components and circulating strains frequently change, it is important to continually monitor vaccine effectiveness (VE). The test-negative design is frequently used to estimate VE. In this design, patients meeting the same clinical case definition are recruited and tested for influenza; those who test positive are the cases and those who test negative form the comparison group. When determining VE in these studies, the typical approach has been to use logistic regression, adjusting for potential confounders. Because vaccine coverage and influenza incidence change throughout the season, time is included among these confounders. While most studies use unconditional logistic regression, adjusting for time, an alternative approach is to use conditional logistic regression, matching on time. Here, we used simulation data to examine the potential for both regression approaches to permit accurate and robust estimates of VE. In situations where vaccine coverage changed during the influenza season, the conditional model and unconditional models adjusting for categorical week and using a spline function for week provided more accurate estimates. We illustrated the two approaches on data from a test-negative study of influenza VE against hospitalization in children in Hong Kong which resulted in the conditional logistic regression model providing the best fit to the data.

Management Approaches in WHO Grade III Meningioma: A National Oncology Trainees' Collaborative for Healthcare Research (NOTCH) UK Multi-Centre Retrospective Study.

AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

The resolution of mixtures of viable mammalian cells into homogeneous fractions by zonal centrifugation.

Large-scale separation of mixtures of mammalian cells was obtained with the A-1X zonal centrifuge rotor and density gradients consisting of Ficoll dissolved in modified Eagle's MEM suspension-culture medium. The cells remained viable as tested by plating efficiency or by motility observed with time-lapse photography. Rabbit thymocyte and HeLa cell mixtures were separated with 99 and 89 per cent purity, respectively. Mixtures of thymocytes and suspension-cultured, human acute leukemia cells (Roswell Park strain LKID) were separated with 93 and 91% purity, respectively. HeLa cells were isolated 92% pure from a mixture with horse leukocytes. A book of charts giving the sedimentation position and velocity versus time of cells in the A rotor under standard conditions of gradient composition, angular velocity, and temperature was prepared with the use of a computer program based on the differential sedimentation equation. The charts are used to estimate the centrifugation time necessary for maximum separation of cells. The success achieved in separating mixtures of cells points to the future possibility of large-scale fractionation of solid tissues, especially tumor tissues, into preparations cf viable cells of a single type.

Isolation of plasma membrane fragments from HeLa cells.

A method for isolating plasma membrane fragments from HeLa cells is described. The procedure starts with the preparation of cell membrane "ghosts," obtained by gentle rupture of hypotonically swollen cells, evacuation of most of the cell contents by repeated washing, and isolation of the ghosts on a discontinuous sucrose density gradient. The ghosts are then treated by minimal sonication (5 sec) at pH 8.6, which causes the ghost membranes to pinch off into small vesicles but leaves any remaining larger intracellular particulates intact and separable by differential centrifugation. The ghost membrane vesicles are then subjected to isopycnic centrifugation on a 20-50% w/w continuous sucrose gradient in tris-magnesium buffer, pH 8.6. A band of morphologically homogeneous smooth vesicles, derived principally from plasma membrane, is recovered at 30-33% (peak density = 1.137). The plasma membrane fraction contained a Na-K-activated ATPase activity of 1.5 micromole Pi/hr per mg, 3% RNA, and 13.8% of the NADH-cytochrome c reductase activity of a heavier fraction from the same gradient which contained mitochondria and rough endoplasmic vesicles. The plasma membranes of viable HeLa cells were marked with (125)I-labeled horse antibody and followed through the isolation procedure. The specific antibody binding of the plasma membrane vesicle fraction was increased 49-fold over that of the original whole cells.

Microsome-associated DNA.

Deoxyribonucleic acid has been isolated from the microsomes of mouse liver homogenates under conditions designed to prevent or greatly reduce mitochondrial and nuclear contamination. The DNA rapidly incorporates tritiated thymidine, and this, together with its reannealing characteristics after thermal denaturation, shows that it is not mitochondrial or typically nuclear DNA.

Mammary tumor virus antigen: sensitive immunoassay.

A rapid, sensitive immuno-assay for mammary tumor virus antigen based on inhibition of passive hemagglutination has been developed. The method permits measurement of this antigen in mouse milk from which the fat has been removed.

Increased maternofetal calcium flux in parathyroid hormone-related protein-null mice.

The role of parathyroid hormone-related protein (PTHrP) in fetal calcium homeostasis and placental calcium transport was examined in mice homozygous for the deletion of the PTHrP gene (PTHrP-/- null; NL) compared to PTHrP+/+ (wild-type; WT) and PTHrP+/- (heterozygous; HZ) littermates. Fetal blood ionized calcium was significantly reduced in NL fetuses compared to WT and HZ groups at 18 days of pregnancy (dp) with abolition of the fetomaternal calcium gradient. In situ placental perfusion of the umbilical circulation at 18 dp was used to measure unidirectional clearance of (45)Ca across the placenta in maternofetal ((Ca)K(mf)) and fetoplacental ((Ca)K(fp)) directions; (Ca)K(fp) was < 5% of (Ca)K(mf) for all genotypes. At 18 dp, (Ca)K(mf) across perfused placenta and intact placenta ((Ca)K(mf(intact))) were similar and concordant with net calcium accretion rates in vivo. (Ca)K(mf) was significantly raised in NL fetuses compared to WT and HZ littermates. Calcium accretion was significantly elevated in NL fetuses by 19 dp. Placental calbindin-D(9K) expression in NL fetuses was marginally enhanced (P < 0.07) but expression of TRPV6/ECaC2 and plasma membrane Ca2+-ATPase (PMCA) isoforms 1 and 4 were unaltered. We conclude that PTHrP is an important regulator of fetal calcium homeostasis with its predominant effect being on unidirectional maternofetal transfer, probably mediated by modifying placental calbindin-D(9K) expression. In situ perfusion of mouse placenta is a robust methodology for allowing detailed dissection of placental transfer mechanisms in genetically modified mice.

Artificial perfusion of the fetal circulation of the in situ mouse placenta: methodology and validation.

Here we present methodology and validation (including measurement of unidirectional maternofetal clearance (Kmf) of (45)Ca and (14)C-mannitol) for in situ perfusion of the mouse placenta. On day 18 of gestation (term=19 days) mice were anaesthetised and the uterus delivered into a saline bath (40 degrees C). A fetus was selected, the umbilical artery and vein catheterised and perfused with Krebs Ringer (pH 7.4) at 60 microl/min. (45)Ca/(14)C-mannitol (2 microCi/5 microCi in 50 microl saline) was injected via maternal tail vein. Perfusate samples were collected every 5 min for 45 min. Maternal carotid artery pressure was monitored throughout perfusion. A terminal maternal cardiac blood sample was taken and analysed. Placentas were immersion fixed and processed for electron microscopy. Kmf for (45)Ca and (14)C-mannitol was calculated as perfusate [(45)Ca or (14)C-mannitol] x perfusion rate/maternal plasma [(45)Ca or (14)C-mannitol]xplacental weight. Maternal cardiac blood chemistry at termination (n=8-15, mean+/-SEM) was as follows: pH 7.153+/-0.016, PCO(2) 45.48+/-2.06 mmHg, PO(2) 66.47+/-7.10 mmHg, Na(+) 151.4+/-1.2 mmol/l, K(+) 5.54+/-0.17 mmol/l, Ca(2+) 1.15+/-0.03 mmol/l, glucose 7.2+/-0.5 mmol/l, and lactate 1.76+/-0.77 mmol/l. A successful 45 min perfusion in which perfusate recovery was >95% occurred in >50% of animals. Perfusion did not alter placental morphology or carotid pressure. Kmf (microl/min/g placenta) for (45)Ca (66.0+/-8.4 (n=7)) was significantly higher than Kmf for (14)C-mannitol (20.0+/-2.4 (n=5)) (p<0.01). These data demonstrate physiological perfusion of the mouse placenta in situ and its usefulness for measurement of solute transfer.

Cholesterol efflux from macrophages mediated by high-density lipoprotein subfractions, which differ principally in apolipoprotein A-I and apolipoprotein A-II ratios.

High-density lipoprotein (HDL) was fractionated by preparative isoelectric focussing into six distinct subpopulations. The major difference between the subfractions was in the molar ratio of apolipoprotein A-I to apolipoprotein A-II, ranging from 2.1 to 0.5. The least acidic particles had little apolipoprotein A-II, were larger and contained the most lipid. The efflux capacity of the HDL subfractions was tested with mouse peritoneal macrophages and a mouse macrophage cell line (P388D1), either fed with acetylated low-density lipoprotein or free cholesterol. All the HDL subfractions were equally able to efflux cholesterol. The efflux was concentration dependant and linear for the first 6 h. The HDL subfractions bound with high affinity (Kd = 6.7-7.9 micrograms/ml) at 4 degrees C to the cell surface of P388D1 cells (211,000-359,000 sites/cell). Ligand blotting showed that all the HDL subfractions bound to membrane polypeptides at 60, 100, and 210 kDa. These HDL binding proteins may represent HDL receptors. In summary HDL particles, which differed principally in ratio of apolipoprotein A-I to apolipoprotein A-II behaved in a similar manner for both cholesterol efflux and cell surface binding.

Differential expression of surface membrane growth hormone receptor on human peripheral blood lymphocytes detected by dual fluorochrome flow cytometry.

Although several reports indicate proliferative and functional effects of human GH (hGH) on peripheral blood lymphocytes (PBL), no information is available about hGH receptor (GHR) expression in PBL subsets. Here, the surface membrane GHR levels were investigated in different human PBL subpopulations using a fluorescein isothiocyanate (FITC)-conjugated monoclonal antibody specific for the GHR (mAb263) in dual fluorochrome flow cytometric assays. Strong GHR expression was found in B-cells (CD20+), whereas CD2+ lymphocytes, including T-cells as well as natural killer cells, exhibited considerably lower levels of receptor expression. Similarly, using FITC-labeled recombinant hGH, receptor expression on CD20+ cells was significantly higher than that on CD2+ cells. Abundant expression of GHR in B-lymphocytes was confirmed by reverse transcriptase-polymerase chain reaction analysis of GHR messenger ribonucleic acid from isolated B-cells. Accordingly, the B-cell merits greater consideration as a GH target cell. The use of FITC-labeled mAb263 and hGH is of potential use for the study of GHR levels in patients exhibiting different types of growth disorders. Because of its high specificity for GHR, FITC-labeled mAb263 is also of considerable value for specifically demonstrating the presence of GHR, because hGH may interact with and act through PRL receptor, as shown previously in human neutrophils.

A novel monoclonal antibody recognizing human thymocytes and B-cell chronic lymphocytic leukemia cells.

This paper describes a new murine monoclonal antibody, UN5, raised against human thymocytes. This antibody recognizes a molecule of approximately 45 kDa on thymocytes. Flow cytometric analysis reveals a high intensity of labeling with the majority of thymocytes, whereas only CD20+ cells from peripheral whole-blood samples are weakly stained. Peripheral T cells, granulocytes, platelets and red blood cells do not express this antigen, while monocytes are only weakly labeled by UN5. Furthermore, the UN5 antibody discriminates between different types of B-cell malignancies, reacting with a subgroup of B-cell chronic lymphocytic leukemias and hairy cell leukemias, but not with the other kinds of hematopoietic malignancies tested. Antibody UN5 should prove a useful tool for the study of T-cell precursors and for analysis of both normal and neoplastic B cells.

Sulpiride trial in chronic schizophrenia with comparison of two dosage regimens.

In a study with both open and double-blind phases, a therapeutic response to sulpiride was first established in 18 chronic schizophrenic inpatients. Following this, two dosage regiments, a morning only dose, and the same daily total dose in two equal fractions at 8 a.m. and 4 p.m., were compared using a balanced design, crossover, placebo controlled study. Clinical effects were evaluated by means of the Brief Psychiatric Rating Scale (BPRS). There was a significant reduction in the mean BPRS score in all phases of the study. There was no significant difference between the mean BPRS scores resulting from the two dosage regimens. The study indicated that the two dosage regimens were equally efficacious.

Experimental induction of hypoparathyroidism with parathyroid hormone antibodies.

This study describes the effect of a single injection of parathyroid hormone antiserum on the serum calcium, serum phosphate, urinary cyclic AMP, and urinary phosphate levels in the intact perfused rat. A significant decline in serum calcium level with concomitant elevation in serum phosphate level and decreased urinary excretion of phosphate and cyclic AMP was noted. These findings strongly suggest that a transient hypoparathyroid state was induced by the parathyroid hormone antiserum.

Medical services provided to 2,394 patients at methadone programs in three states.

The type and amount of medical services provided to 2,394 patients in methadone maintenance programs in three states was studied. Data were obtained from on-site confidential interviews with the entire treatment staff at seven programs. It was found that there were marked differences in the number and type of medical staff. Thus, there was ten times more coverage by physicians at some programs than others. In general, there were notable differences in the treatment staff available. Comparable variations among the programs were found with respect to the actual provision of medical services. Thus, the number of patients seen by the medical staff on a weekly basis varied from a high of 185 patients to a low of 36 patients. Similarly, the proportion of each program's patients receiving medical treatment per week varied from 53 to 14 percent. Reasons for those variations in medical services are considered.

Five-year follow up of patients treated with inpatient psychotherapy at the Cassel Hospital for Nervous Diseases.

Twenty-eight patients who were admitted consecutively to a single-adult unit of the Cassel Hospital in 1977/8 were followed up 5 years after discharge. Those who were found to have improved at the end of treatment remained well 5 years later. These could be distinguished by their combination of neurotic psychopathology, considerable depression, superior intelligence, and lack of a chronic outpatient history. Patients who had improved 5 years after discharge did not show these characteristics, but had all spent at least 9 weeks on the waiting list and had the capacity to form close and helpful relationships. Patients who were judged to have improved were less dependent on the Health Service and their economic productivity was improved, often as a consequence of returning to education or training. Those who did not improve clinically continued to be admitted to hospital and tended to become less economically productive.

Effectiveness of knee replacement surgery in arthritis.

This study examined the effectiveness of knee replacement surgery in an elderly population suffering from arthritis. Four questionnaires which measured pain, mobility, anxiety, depression and social isolation were completed by the study group before and after surgery to assess changes in physical function, psychological state, social interaction and somatic sensation. A statistically significant difference was found in pain which was reduced from a median score of 3 before the operation to 0 afterwards on an intensity scale of 0-5. Statistically significant improvements were also found in the mobility/dependency scores and in the level of anxiety and depression following the operation. It was concluded that knee replacement is a highly effective treatment for arthritis of the knee, reducing pain, increasing mobility and improving the persons emotional state, thus improving the quality of life of the recipient. The use of separate questionnaires to measure single dimensions of quality of life as opposed to a single health profile is also discussed.

Safety and effectiveness of nurse telephone consultation in out of hours primary care: randomised controlled trial. The South Wiltshire Out of Hours Project (SWOOP) Group.

OBJECTIVE: To determine the safety and effectiveness of nurse telephone consultation in out of hours primary care by investigating adverse events and the management of calls. DESIGN: Block randomised controlled trial over a year of 156 matched pairs of days and weekends in 26 blocks. One of each matched pair was randomised to receive the intervention. SETTING: One 55 member general practice cooperative serving 97 000 registered patients in Wiltshire. SUBJECTS: All patients contacting the out of hours service or about whom contact was made during specified times over the trial year. INTERVENTION: A nurse telephone consultation service integrated within a general practice cooperative. The out of hours period was 615 pm to 1115 pm from Monday to Friday, 1100 am to 1115 pm on Saturday, and 800 am to 1115 pm on Sunday. Experienced and specially trained nurses received, assessed, and managed calls from patients or their carers. Management options included telephone advice; referral to the general practitioner on duty (for telephone advice, an appointment at a primary care centre, or a home visit); referral to the emergency service or advice to attend accident and emergency. Calls were managed with the help of decision support software. MAIN OUTCOME MEASURES: Deaths within seven days of a contact with the out of hours service; emergency hospital admissions within 24 hours and within three days of contact; attendance at accident and emergency within three days of a contact; number and management of calls in each arm of the trial. RESULTS: 14 492 calls were received during the specified times in the trial year (7308 in the control arm and 7184 in the intervention arm) concerning 10 134 patients (10.4% of the registered population). There were no substantial differences in the age and sex of patients in the intervention and control groups, though male patients were underrepresented overall. Reasons for calling the service were consistent with previous studies. Nurses managed 49.8% of calls during intervention periods without referral to a general practitioner. A 69% reduction in telephone advice from a general practitioner, together with a 38% reduction in patient attendance at primary care centres and a 23% reduction in home visits was observed during intervention periods. Statistical equivalence was observed in the number of deaths within seven days, in the number of emergency hospital admissions, and in the number of attendances at accident and emergency departments. Conclusions Nurse telephone consultation produced substantial changes in call management, reducing overall workload of general practitioners by 50% while allowing callers faster access to health information and advice. It was not associated with an increase in the number of adverse events. This model of out of hours primary care is safe and effective.