Does every patient need to be discussed at a multidisciplinary team meeting?

AIM: To evaluate the clinical impact and cost-effectiveness of a multidisciplinary team (MDT) meeting in a large hospital in the UK. MATERIALS AND METHODS: A management plan for colorectal cancer patients was recorded by the supervising surgical consultant prior to the MDT meeting using the available clinical information and the available reports for imaging and histopathology. The recorded outcomes were then compared with the outcomes documented at the subsequent MDT meeting. The cost of the MDT meeting was calculated based on the salaries of individuals involved plus relevant overheads. A range of opportunity costs were considered, the most significant of which was the expenditure required to re-provide direct clinical care displaced by the MDT. RESULTS: Over a 3 month period a sample of 47 random cases were reviewed from the colorectal MDT. In three patients, there were significant differences between the preliminary consultant decision and the MDT recommendation: in one case management was changed based on further information about patient co-morbidity and performance status. In only one case was there a material alteration to a CT report, which altered management. The annual costs of running this colorectal local MDT alone were estimated at £162,734+ per annum with opportunity costs of at least twice that. CONCLUSION: The costs of MDT meetings are very high producing a small clinical impact. At a time of increasing financial and capacity pressure in healthcare systems, the use of scarce resources may be better deployed elsewhere.

Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.

Crouzon syndrome is an autosomal dominant condition causing premature fusion of the cranial sutures (craniosynostosis) and maps to chromosome 10q25-q26. We now present evidence that mutations in the fibroblast growth factor receptor 2 gene (FGFR2) cause Crouzon syndrome. We found SSCP variations in the B exon of FGFR2 in nine unrelated affected individuals as well as complete cosegregation between SSCP variation and disease in three unrelated multigenerational families. In four sporadic cases, the normal parents did not have SSCP variation. Finally, direct sequencing has revealed specific mutations in the B exon in all nine sporadic and familial cases, including replacement of a cysteine in an immunoglobulin-like domain in five patients.

Author Correction: Remote sensing quantifies widespread abundance of permafrost region disturbances across the Arctic and Subarctic.

The original version of this Article contained an error in the author affiliations. Affiliation 5 incorrectly read 'Tyumen State Oil and Gas University, Tyumen, Tyument. Oblast, Russian Federation, 625000'.This has now been corrected in both the PDF and HTML versions of the Article.

Remote sensing quantifies widespread abundance of permafrost region disturbances across the Arctic and Subarctic.

Local observations indicate that climate change and shifting disturbance regimes are causing permafrost degradation. However, the occurrence and distribution of permafrost region disturbances (PRDs) remain poorly resolved across the Arctic and Subarctic. Here we quantify the abundance and distribution of three primary PRDs using time-series analysis of 30-m resolution Landsat imagery from 1999 to 2014. Our dataset spans four continental-scale transects in North America and Eurasia, covering ~10% of the permafrost region. Lake area loss (-1.45%) dominated the study domain with enhanced losses occurring at the boundary between discontinuous and continuous permafrost regions. Fires were the most extensive PRD across boreal regions (6.59%), but in tundra regions (0.63%) limited to Alaska. Retrogressive thaw slumps were abundant but highly localized (<10-5%). Our analysis synergizes the global-scale importance of PRDs. The findings highlight the need to include PRDs in next-generation land surface models to project the permafrost carbon feedback.

Superlinearity, saturation, and the PMT-Tailoring and calibration methodology for prompt radiation detectors.

This work illustrates predominant measureable nonlinearities in photomultiplier tubes (PMTs) and introduces a controllable one called "Superlinearity," signifying both a positive nonlinear response and the ability to extend linear operation by counteracting gain saturation mechanisms - charge depletion, space-charge field limitation, and secondary emission surface effects. Recognizing superlinearity and its effect on the temporal step response leads to a true definition of linearity, free of a small-signal linear assumption. Furthermore, given the prevalent use of glass microchannel-plate (MCP) PMTs in favor of a faster impulse response in spite of a small charge limit, we are motivated to examine their nonlinear amplitude response and deploy tailored gain bias string methods to fully harness the maximum linear gain as is usually done for transmissive metal mesh and reflective metal dynode PMTs. Our characterization methodology applies standard NIST-traceable calibrated laboratory equipment with absolute input-referenced techniques, examining step responses over many orders of magnitude in controlled illumination. By doing so, we quantitatively reveal the superlinearity strength independent of charge depletion, yielding true linear responsivity and effectively doubling the small-signal linear limit; this is very relevant to PMT modeling and charge deconvolution efforts. With further development, the tailoring strategies we introduce could be applied to MCP detectors, extracting all useful capillary charge with a significant improvement in large linear signal quality.

Immunoregulatory subsets of the T helper and T suppressor cell populations in homosexual men with chronic unexplained lymphadenopathy.

Unexplained, generalized lymphadenopathy in homosexual men, which can be a prodrome to the acquired immunodeficiency syndrome, is associated with impaired cell-mediated immunity, a low ratio of T helper-inducer to T suppressor-cytotoxic cells (defined by the T4 and T8 monoclonal antibodies), and hypergammaglobulinemia. We performed double-marker studies on T cells by using a panel of monoclonal antibodies (Ia, T17, TQ1, and Leu-8), which reportedly detect activation or functional subsets of the T4 and T8 T cell populations. The T4:TQ1- or T4:Leu-8- subset, which is the major helper subset for B cell responses, is normally represented in lymphadenopathy patients. A depression in the reciprocal subset, T4:TQ1+ or T4:Leu-8+, accounts for the T4 T cell defect. Similarly, the TQ1 and Leu-8 markers delineate the abnormality of T8 T cells: the T8:TQ1- or T8:Leu-8- subset is elevated, whereas the T8:TQ1+ or T8:Leu-8+ subset is normally represented. We found no evidence of excessive activation of T4 T cells by using the T17 or Ia monoclonal antibodies. We did find an overall increase in Ia-positive T cells; however, this was due to increased T8:Ia+ cells. In functional studies, immunoglobulin production induced by pokeweed was subnormal. Most lymphadenopathy patients had normal T helper cell function when combined with normal B cells. The dampened pokeweed responses could be partially explained by depression of the T4:TQ1+ (or T4:Leu-8+) subset (which has minor help-associated function) and/or greater than expected suppression. However, subnormal pokeweed responses could not be totally explained by immunoregulatory T cell abnormalities because we also found an intrinsic defect in the B cell responses of lymphadenopathy patients.

Synthesis of urea in cometary model ices and implications for Comet 67P/Churyumov-Gerasimenko.

Urea is considered a fundamental building block in prebiotic chemistry. Its formation on early Earth has not yet been explained satisfactorily and exogenous delivery has been considered. We report on the synthesis along with the first online and in situ identification of urea after exposing inorganic ices to ionizing radiation.

On the susceptibility of human platelets to aggregation by concanavalin A and the effect of this lectin on their response to ADP.

Concanavalin A aggregated gel-filtered platelets in 0.9% NaCl solution signifying cross-bridging by the lectin. Aggregation of these platelets by concanavalin A was temperature dependent; it did not occur at 0-4 degrees C unless the platelets were previously trypsinized. The level of aggregation of trypsinized platelets by concanavalin A at 0-4 degrees C was similar to that of untreated platelets at 37 degrees C. It is suggested that trypsin facilitates platelet aggregation by concanavalin A at 0-4 degrees C by causing a configurational change in membrane glycoproteins which orientates concanavalin A receptor sites into positions that favour lectin cross-bridging. Concanavalin A failed to aggregate platelets in plasma. Radioisotope studies showed that the amount of [3H]concanavalin A which combined with platelets in plasma was extremely low compared with gel-filtered platelets in saline. The aggregation of Ehrlich ascites cells by concanavalin A was considerably reduced when platelet-free plasma was added to the medium suggesting that it was due to the presence of concanavalin A-reactive components in the plasma. Concanavalin A inhibited the ADP-induced aggregation of platelets suspended in plasma or in a salts solution supplemented with calcium and fibrinogen, although the inhibitory effect was more conspicuous in the latter case. The results suggests that concanavalin A produces its inhibitory effect on ADP-induced platelet aggregation by interacting with membrane glycoproteins, and this further suggests their involvement in aggregation.

A change from stimulatory to blocking antibody activity in Graves' disease during pregnancy.

Remission of Graves' disease (GD) during pregnancy with recrudescence after delivery is commonly observed. However, as pregnancy is associated with type 2 rather than type 1 cytokine production, a decrease in thyroid-stimulating antibody (TSAb) activity alone is unlikely to account for the remission during pregnancy. We hypothesized that a change in the antibody characteristics may occur as pregnancy advances. Fifteen women were studied in the first, second, and third trimesters of pregnancy and 4 months postpartum. TSH receptor antibodies were determined using human thyroid cell cultures, and lymphocyte subsets were measured by flow cytometry. Median TSAb (determined by cAMP release) decreased from 280% (96-3200) to 130% (range, 35-350; P < 0.05) during pregnancy, but no significant change was noted with the TSH binding inhibitory antibody (TBII; determined by RRA). Thyroid stimulation-blocking antibody (TSBAb; inhibition of TSH-stimulated cAMP release) increased from 16 +/- 9% to 43 +/- 16% (mean +/- SD; P < 0.005). The increase in TSBAb was observed even among those patients who were in clinical remission before pregnancy. Overall, a negative correlation was observed between TSBAb activities and free T4 levels during pregnancy (r = -0.279; P < 0.05). Reciprocal changes in TSAb, TBII, and TSBAb levels were observed in the seven patients who relapsed during the postpartum period. In comparison, the healthy pregnant women (n = 14) were all negative for TSAb, TBII, and TSBAb throughout pregnancy. The absolute number of T lymphocytes, T helper cells, and natural killer cells, but not B cells, decreased significantly during pregnancy in both healthy women and GD patients. GD patients had significantly more CD5+ B cells at all stages of pregnancy compared to controls. In conclusion, a change in specificity from stimulatory to blocking antibodies was observed in GD patients during pregnancy and may contribute to the remission of GD during pregnancy.

Effects of interferon-gamma therapy on thyroid function, T-lymphocyte subpopulations and induction of autoantibodies.

Treatment with human leucocyte interferon (IFN alpha) has been associated with the development of thyroid autoimmunity and hypothyroidism, but it is not certain whether this phenomenon was a result of contamination with IFN gamma, which induced HLA class II antigen expression on T-lymphocytes. We prospectively studied 11 subjects (5 females and 6 males; mean age, 26.8 yr; range, 18-36) with chronic active hepatitis B who were randomized to receive recombinant human IFN gamma (rhIFN gamma; 10(6) U/m2.day, im, 3 times/week) for 16 weeks. Goiter was not present, and no patient had a history or family history of autoimmune diseases. Serial thyroid functions, including serum T4, T3, free thyroid hormone index, free T4 and TSH before, during, and on subsequent follow-up for a period of 1 yr were all normal. Eight patients had adequate serial samples for study of serological and lymphocyte subpopulations. None of the patients treated with rhIFN gamma developed thyroglobulin or thyroid microsomal antibodies. However, four patients developed antinuclear and smooth muscle autoantibodies during or after rhIFN gamma treatment. Treatment with rhIFN gamma resulted in a significant increase in circulating T-lymphocytes and HLA-DR-positive T-cells (P less than 0.05), with equal proportions of circulating CD4+ and CD8+ T-cells becoming DR positive. The percentage of HLA-DR-positive T-cells remained elevated after discontinuation of rhIFN gamma. Also, rhIFN gamma treatment led to a decrease in the number of circulating granulocytes and interleukin-2 receptor-positive cells. In conclusion, we did not observe any thyroid dysfunction or thyroid autoimmunity in our patients treated with the studied dose of rhIFN gamma, but induction of other autoantibodies was observed.

Effect of radioactive iodine therapy on cytokine production in Graves' disease: transient increases in interleukin-4 (IL-4), IL-6, IL-10, and tumor necrosis factor-alpha, with longer term increases in interferon-gamma production.

Spontaneous and mitogen-stimulated production of interleukin-4 (IL-4), IL-6, IL-10, IL-12, interferon-gamma (IFNgamma), and tumor necrosis factor-alpha were evaluated by enzyme-linked immunospot assay of peripheral blood mononuclear cells from patients with Graves' disease immediately before and at 4, 17, and 59 days after treatment with radioactive iodine. Patients had significantly reduced IL-4 and IFNgamma production before treatment compared with healthy controls. Both cytokines were increased to normal levels by day 17 after treatment, and IFNgamma remained at normal levels on day 59, whereas IL-4 returned to subnormal levels at this time. IL-12 production was initially normal and was not significantly altered by therapy. IL-6, IL-10, and tumor necrosis factor-alpha were also normal before radiotherapy, but increased significantly on day 17, returning to pretreatment levels by day 59. Thus, radioiodine treatment induced a transient increase in both proinflammatory and antiinflammatory cytokines and a more prolonged increase in IFNgamma production, the latter representing a definite shift toward a type 1 cytokine profile.

Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus.

The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.

Evaluation of CD5 and other differentiation antigens on human immunoglobulin-secreting cells using a combination of immunobead rosetting and reverse haemolytic plaque formation.

This paper describes a new method, with high specificity and sensitivity, for evaluating cell surface markes such as differentiation antigens and cytokine receptors on immunoglobulin-secreting cells. Mononuclear cells, freshly derived from peripheral blood or following stimulation in vitro with pokeweed mitogen or Staphylococcus aureus Cowan I, are partially depleted of T cells and monocytes using immunomagnetic beads (Dynabeads) coated with anti-CD2. The cells are incubated with Dynabeads coated with monoclonal antibody against the cell marker under investigation and then used in a protein A haemolytic plaque assay. Plaque-forming cells (PFC) with (marker-positive) and without (marker-negative) attached beads can be readily enumerated. Values are given for percentages of IgG-, IgA- and IgM-PFC bearing CD19, CD38, CD25 and CD5.

The quantitation of alternative pathway complement function by timed lysis assay.

A simple timed lysis assay is described for quantifying haemolytic complement activity in human serum. Classical pathway complement function was determined by measuring the time taken to lyse 50% of a standard suspension of antibody-coated sheep erythrocytes; the time required for 50% lysis of a standard rabbit erythrocyte suspension was similarly used to evaluate alternative pathway function. Because target erythrocytes prepared on different days gave slightly different 50% lysis times, it was necessary first to construct a series of calibration curves for converting 50% lysis times into CH50 U/ml. For this purpose, a range of dilutions of the standard human serum, of known haemolytic activity, was tested against erythrocytes prepared on 10 separate occasions. The standard serum was subsequently included with each batch of unknown sera and used to select the appropriate calibration curve for direct conversion of the 50% lysis time into CH50 U/ml. Eleven samples of normal human serum were tested by both the timed lysis assay and by the dilution methods of Mayer (1971) (classical) and Platts-Mills and Ishizaka (1974) (alternative pathway). Comparable results were obtained in all cases.

Comparison of monocyte separation methods using flow cytometric analysis.

We isolated normal, nonactivated human monocytes from peripheral blood by four different methods: (1) rosetting with sheep erythrocytes pretreated with 2-aminoethylisothiouronium bromide hydrobromide (AET) followed by monoclonal antibody (OKT3 (CD3), B1 (CD19), Leu7, Leu11 (CD16] and complement treatment; (2) adherence to gelatin/plasma-coated flasks; (3) adherence to plastic dishes; and (4) separation by the Sepracell technique. We monitored these monocyte separations by determining cell recoveries, OKT4A+ lymphocyte contamination, monocyte binding to human immunodeficiency virus (HIV), number of non-specific esterase-positive cells, and proportion of mononuclear cells reactive with a battery of monoclonal antibodies specific for monocytes. Our results indicate that of the four methods compared, adherence to gelatin/plasma-coated flasks produced the highest purity, recovery, and satisfactory binding to HIV with the fewest contaminating CD4+ T cells.

Comparison of T and B cell analyses on fresh and aged blood.

We have compared T and B cell analyses using whole blood, separated lymphocytes, and separated, frozen, then thawed lymphocytes to see how long blood can be kept before separation and analysis. We also examined the effect of various anticoagulants and the effect of diluting blood in culture media on T and B cell analysis over time. We found that the whole blood method is a very reliable method for T and B cell analysis, even 4 days after the blood is drawn, provided that heparin or ACD is the anticoagulant used. Separated lymphocytes and cryopreserved lymphocytes from blood that was separated within 24 h of collection was satisfactory; however, results were less consistent if separation was delayed more than 24 h. For lymphocyte separation, blood collected in heparin or ACD held up better over time than did blood collected in EDTA, and dilution with either RPMI 1640 or McCoy's medium gave better lymphocyte separation in older blood.

One-way mixed lymphocyte culture: differences between Chinese and Caucasian stimulator cells.

In "standardized" one-way mixed lymphocyte cultures, a pool of blood lymphocytes from randomly chosen Chinese subjects was a significantly stronger stimulus to Caucasian responder lymphocytes than was a pool of allogeneic cells from Caucasians. In contrast, Chinese lymphocytes did not respond more strongly to Caucasian cells than to Chinese cells. This could not be explained by an inherent racial difference in the capacity of blood lymphocytes to undergo blastogenesis. The implications of these findings for organ transplantation and routine testing of cell-mediated immune function are discussed.

Lymphocyte kinetics and precursor frequency-dependent recovery of CD4(+)CD45RA(+)CD62L(+) naive T cells following triple-drug therapy for HIV type 1 infection.

New therapeutic regimens have dramatically altered morbidity and mortality attributed to HIV-1 infection. Changes in lymphocyte subsets after treatment may mirror salutary clinical changes. Over 4 months we analyzed lymphocyte subsets in 20 patients starting new HIV-1 therapy. Absolute numbers of lymphocytes, CD4+ T cells, CD8+ T cells, and B cells increased significantly by 4 months, but CD8+ T cell and B cell increases were restricted to late-stage patients. Subset analysis revealed that the magnitude of recovering naive-phenotype CD4+ T cells (slope) correlated with the number of these cells present at baseline, equaling or exceeding the memory-phenotype slope within days if these naive cells were abundant at baseline. Five of 10 patients in whom naive-phenotype CD4+ T cells were absent at baseline partially repopulated these cells by 4 months. These findings have important implications for the origin and mechanisms of renewal of naive-phenotype CD4+ T cells following effective treatment for HIV-1 infection.

Serial determinations of HIV-1 titers in HIV-infected homosexual men: association of rising titers with CD4 T cell depletion and progression to AIDS.

Lymphocyte subset enumerations, antibody titers to specific proteins of human immunodeficiency virus (HIV), and measurement of infectious HIV titers in peripheral blood mononuclear cells were performed on serial blood specimens from 15 HIV-infected homosexual men with chronic lymphadenopathy syndrome (LAS); 6 of these men have subsequently progressed to AIDS (progressors), and 9 have remained clinically stable (nonprogressors). For the earliest samples studied, no test distinguished those who would progress to AIDS from those who have not. The two groups diverged significantly about 1 year before AIDS diagnosis in the progressor group. Virus titers rose in progressors but remained relatively stable in nonprogressors. CD4 T cells and the CD4 T cell subset, 4B4, declined more rapidly in progressors than in nonprogressors. HIV antibody titers tended to decline in progressors, but the differences were significant only for antibody and to the pol-encoded proteins, p51/65, and the gag-encoded polyprotein, p55. Before the onset of clinical AIDS, progressors are distinguished from nonprogressors by markedly different rates of CD4 cell depletion and virus replication, but the elements that control these dynamics remain to be defined.

Acromelic frontonasal dysostosis.

We report on 3 male and 2 female infants with acromelic frontonasal dysostosis. All 5 had a frontonasal malformation of the face and nasal clefting associated with striking symmetrical preaxial polysyndactyly of the feet and variable tibial hypoplasia. In contrast, the upper limbs were normal. This rare variant of frontonasal dysplasia may represent a distinct autosomal-recessive disorder. We suggest that the molecular basis of this condition may be a perturbation of the Sonic Hedgehog (SHH) signalling pathway, which plays an important part in the development of the midline central nervous system/craniofacial region and the limbs.