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This article discusses the impact of technology on the office leasing sector and the role of humans in the process. The panel of experts agrees that technology has become increasingly important in delivering customer service, but there is still a place for the human factor in finding and leasing office space. While technology can provide efficiency and data gathering capabilities, humans bring emotional understanding and subjective decision-making to the table. The experts believe that technology will continue to play a significant role in the industry, but humans will not be fully replaced. [Extracted from the article]

ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes.

Systematic and structured changes have been taking place in diabetes care over the last 6 years. The national service framework for diabetes was introduced in 2001 and set out key [...]

Sodium glucose cotransporter 2 (SGLT2) inhibitors are the latest class of oral hypoglycaemic agents approved to treat type II diabetes. Their use is increasing and as such more patients will present to critical care whilst on this treatment. However, there have been several case reports of euglycaemic diabetic ketoacidosis associated with the use of these agents. Under such circumstances the blood glucose is often normal or only moderately elevated and hence the diagnosis may be delayed resulting in inappropriate therapy. In this review we describe a case of SGLT2 mediated ketoacidosis who presented to our intensive care unit, discuss the proposed pathophysiology behind this development of ketoacidosis as well as its potential prevention, management and treatment.

Is there a role for prophylactic antibiotics? Infection of a prosthetic joint is associated with serious morbidity, can result in prolonged admission to hospital, and is potentially life threatening. Our [...]

Sentinel node biopsy for malignant melanoma Having this biopsy gives psychological benefits EDITOR--The editorial by Thomas and Patocskai summarises the current state of sentinel lymph node biopsy for malignant melanoma.[1] [...]

Glucagon-like peptide-1 (GLP-1) agonists control postprandial glucose and lipid excursion in type 2 diabetes; however, the mechanisms are unclear.

Approximately 10% of metastases from all primary neoplasms involve the skin, but for malignant melanoma the figure is 44%. (1) In some cases of melanoma this is the presenting feature, [...]

Resistant starch (RS) has been shown to beneficially affect insulin sensitivity in healthy individuals and those with metabolic syndrome, but its effects on human type 2 diabetes (T2DM) are unknown. This study aimed to determine the effects of increased RS consumption on insulin sensitivity and glucose control and changes in postprandial metabolites and body fat in T2DM. Seventeen individuals with well-controlled T2DM (HbA1c 46.6±2 mmol/mol) consumed, in a random order, either 40 g of type 2 RS (HAM-RS2) or a placebo, daily for 12 weeks with a 12-week washout period in between. At the end of each intervention period, participants attended for three metabolic investigations: a two-step euglycemic–hyperinsulinemic clamp combined with an infusion of [6,6-2H2] glucose, a meal tolerance test (MTT) with arterio-venous sampling across the forearm, and whole-body imaging. HAM-RS2 resulted in significantly lower postprandial glucose concentrations (P=0.045) and a trend for greater glucose uptake across the forearm muscle (P=0.077); however, there was no effect of HAM-RS2 on hepatic or peripheral insulin sensitivity, or on HbA1c. Fasting non-esterified fatty acid (NEFA) concentrations were significantly lower (P=0.004) and NEFA suppression was greater during the clamp with HAM-RS2 (P=0.001). Fasting triglyceride (TG) concentrations and soleus intramuscular TG concentrations were significantly higher following the consumption of HAM-RS2 (P=0.039 and P=0.027 respectively). Although fasting GLP1 concentrations were significantly lower following HAM-RS2 consumption (P=0.049), postprandial GLP1 excursions during the MTT were significantly greater (P=0.009). HAM-RS2 did not improve tissue insulin sensitivity in well-controlled T2DM, but demonstrated beneficial effects on meal handling, possibly due to higher postprandial GLP1.

Results of an exploratory phase 2 study showed that insulin degludec, a basal insulin with an action profile of longer than 42 h, provided similar glycaemic control when injected three times a week (IDeg 3TW) to once-daily insulin glargine (IGlar OD). To provide further evidence, we did two phase 3 trials to compare the efficacy and safety of IDeg 3TW with IGlar OD in insulin-naive patients with type 2 diabetes.

Intensive basal-bolus insulin therapy has been shown to improve glycaemic control and reduce the risk of long-term complications that are associated with type 1 diabetes mellitus. Insulin degludec is a new, ultra-longacting basal insulin. We therefore compared the efficacy and safety of insulin degludec and insulin glargine, both administered once daily with mealtime insulin aspart, in basal-bolus therapy for type 1 diabetes.

Introduction:A water-in-oil microemulsion is a thermodynamically stable emulsion that has the capacity to ‘‘hide’’ water-soluble molecules within a continuous oil phase. The very small size of the water droplets within the microemulsion means that these types of formulation can be applied topically to the skin, with the result that peptides and proteins can be delivered effectively into the dermal layer.Areas covered:This review discusses the general problems of peptide and protein delivery following topical application, and compares the possible routes of peptide and protein clearance and distribution within the body following topical administration. Several examples of successful peptide and protein delivery using microemulsions are discussed, in addition to the possible alterations in biological profiles following administration via this route.Expert opinion:Water-in-oil microemulsions present themselves as an effective means of topical delivery of peptides and proteins of all sizes, and in high doses. These formulations are a cheap, stable, pain-free means of delivery of peptides and proteins to the skin. An exciting area of potential development is the area of weight control management. The results using insulin, IGF-I and GHRP-6 given topically are particularly intriguing. Whether these results can be replicated in humans and whether the use of these drugs for potential treatment of obesity will be commercially viable will be particularly interesting.

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL–negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL–negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase–polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRBfusion–positive, BCR-ABL–negative CMPDs.

Background: Epidemiological studies suggest that hypopituitary patients have an increased risk for cardiovascular mortality. The dyslipidaemia associated with this condition is often characterised by an increase in total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol (LDL-C) and may contribute to these findings. The underlying mechanisms are not fully elucidated.Materials and Methods: LDL apolipoprotein B (apoB) production rate and metabolic clearance rate were measured in seven patients with hypopituitarism (including GH deficiency) under stable conventional replacement therapy (three males and four females; age 40–16.1 years; body mass index 29.0–6.1 kg/m2(means ± s.d.)) and seven age-, gender- and body mass index-matched control subjects with an infusion of 1-13C-leucine. Fasting lipid profile and lipid composition of LDL were also measured.Results: Fasting TC, triglycerides (TG), high-density lipoprotein-C, LDL-C and free fatty acid concentrations were not different between hypopituitary patients and control subjects. LDL-TG (P< 0.006) and LDL-TG/LDL apoB ratio (P< 0.02) were significantly increased in hypopituitary patients. LDL apoB pool size was not statistically different between patients and control subjects. In the hypopituitary patients, LDL apoB metabolic clearance rate (P< 0.05) and LDL apoB production rate (P< 0.02) were lower than in the control subjects.Conclusions: The present results suggest that LDL apoB turnover and LDL composition is altered in hypopituitary patients. Whether these findings explain the increased risk for cardiovascular disease in hypopituitary patients remains to be established.

We report 28 patients with advanced chronic graft-versus-host disease (cGVHD) treated with extracorporeal photopheresis (ECP). All had failed conventional immunosuppressive therapy. Of the patients, 27 had extensive cGVHD and 20 had more than 50% cutaneous surface area involvement. ECP was initiated approximately 2 years after onset of cGVHD and 3 years following allogeneic stem cell transplantation and administered fortnightly for 4 months and then monthly. Response was assessed using quantifiable disease measures, including skin score, liver function tests (LFTs), blood counts, and lung function tests. Regression analysis allowed assessment of any pretreatment clinical or laboratory parameters that predicted response. There were 25 patients who completed 3 months and 21 who completed 6 months of treatment. Systemic immunosuppression was stable or reduced in 86% of patients. There were 3 patients who died from cGVHD. After 6 months, median skin scores were 53% lower (P = .003) in sclerodermoid and lichenoid disease. Of 6 patients with mucosal ulceration, 3 improved. A nonsignificant improvement of LFTs occurred. We infer that ECP is effective even in patients with extensive cutaneous cGVHD of 2 years duration that is resistant to conventional therapy. Furthermore, both sclerodermoid and lichenoid subtypes responded. However, no baseline parameters predicted a favorable response to ECP, so patient selection must continue to be made on clinical grounds.

Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal T- and B-cell malignancies. The underlying molecular pathogenesis of this malignancy remains unclear. This study aimed to characterize oncogene abnormalities in PCLs. Using genomic microarray, we detected oncogene copy number gains of RAF1(3p25), CTSB (8p22), PAK1 (11q13), and JUNB (19p13) in 5 of 7 cases of mycosis fungoides (MF)/Sezary syndrome (SS) (71%), gains of FGFR1 (8p11), PTPN (20q13), andBCR (22q11) in 4 cases (57%), and gains ofMYCL1 (1p34), PIK3CA (3q26), HRAS(11p15), MYBL2 (20q13), and ZNF217 (20q13) in 3 cases (43%). Amplification of JUNB was studied in 104 DNA samples from 78 PCL cases using real-time polymerase chain reaction. Twenty-four percent of cases, including 7 of 10 cases of primary cutaneous CD30+ anaplastic large-cell lymphoma (C-ALCL), 4 of 14 MF, 4 of 22 SS, and 2 of 23 primary cutaneous B-cell lymphoma (PCBCL) showed amplification ofJUNB, and high-level amplification of this oncogene was present in 3 C-ALCL and 2 MF cases. JUNB protein expression was analyzed in tissue sections from 69 PCL cases, and 44% of cases, consisting of 21 of 23 SS, 6 of 8 C-ALCL, 5 of 10 MF, and 9 of 21 PCBCL, demonstrated nuclear expression of JUNB by tumor cells. Overexpression of JUNB also was detected in 5 C-ALCL and 2 SS cases. These results have revealed, for the first time, amplification and expression patterns of JUNB in PCL, suggesting thatJUNB may be critical in the pathogenesis of primary cutaneous T-cell lymphomas.

Primary cutaneous lymphomas (PCLs) represent a heterogeneous group of extranodal T- and B-cell malignancies. The underlying molecular pathogenesis of this malignancy remains unclear. This study aimed to characterize oncogene abnormalities in PCLs. Using genomic microarray, we detected oncogene copy number gains of RAF1(3p25), CTSB(8p22), PAK1(11q13),and JUNB(19p13) in 5 of 7 cases of mycosis fungoides (MF)/Sezary syndrome (SS) (71%), gains of FGFR1(8p11), PTPN(20q13), andBCR(22q11) in 4 cases (57%), and gains ofMYCL1(1p34), PIK3CA(3q26), HRAS(11p15), MYBL2(20q13), and ZNF217(20q13) in 3 cases (43%). Amplification of JUNBwas studied in 104 DNA samples from 78 PCL cases using real-time polymerase chain reaction. Twenty-four percent of cases, including 7 of 10 cases of primary cutaneous CD30+anaplastic large-cell lymphoma (C-ALCL), 4 of 14 MF, 4 of 22 SS, and 2 of 23 primary cutaneous B-cell lymphoma (PCBCL) showed amplification ofJUNB, and high-level amplification of this oncogene was present in 3 C-ALCL and 2 MF cases. JUNB protein expression was analyzed in tissue sections from 69 PCL cases, and 44% of cases, consisting of 21 of 23 SS, 6 of 8 C-ALCL, 5 of 10 MF, and 9 of 21 PCBCL, demonstrated nuclear expression of JUNB by tumor cells. Overexpression of JUNB also was detected in 5 C-ALCL and 2 SS cases. These results have revealed, for the first time, amplification and expression patterns of JUNBin PCL, suggesting thatJUNBmay be critical in the pathogenesis of primary cutaneous T-cell lymphomas.

The new World Health Organization (WHO) classification of hematopoietic and lymphoid malignancy represents the first worldwide consensus document on the classification of lymphoma/leukemia. Its aim is to supercede all existing classification systems, including the Revised European American Classification (REAL), and the organ-based classification of cutaneous lymphoma proposed in 1997 by the European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma project group. This article compares the REAL, EORTC, and WHO classifications with particular reference to cutaneous lymphoma. It identifies those entities that have been adopted from the EORTC classification, and illustrates important new entities in the category of cytotoxic T-/NK-cell lymphomas that characteristically present in the skin or subcutaneous tissue. However, WHO is not an organ-based classification and some categories (eg follicular B-cell lymphoma and peripheral T-cell lymphoma) include both cutaneous and systemic diseases, and these may have very different prognoses. It is, therefore, important that cancer registries are capable of recording sites of involvement for both B- and T-cell lymphomas so that the incidence and prognosis of cutaneous lymphomas can be established from national data sets in future years. (J Am Acad Dermatol 2003;48:93-102.)

OBJECTIVE: Hypopituitary GH-deficient patients have an increased cardiovascular mortality and GH replacement in this population has resulted in considerable therapeutic benefit. GH replacement involves administration of a potentially mitogenic substance to patients with a previous or residual pituitary tumour. Our objective was to evaluate whether GH replacement results in an increase in the size of pituitary tumours. METHODS: This was a non-randomised observational study on patients recruited from the endocrine clinic. All subjects had GH deficiency, proven on an insulin tolerance test and were divided into those who were or were not receiving long-term GH replacement. Comparison of change in pituitary size was made with interval radiological imaging of the pituitary. RESULTS: Seventy-five patients (40 men and 35 women) were in the study, 47 were on long-term GH replacement and there were 28 controls. The average length of treatment for the treated group was 3.6 patient years. Thirty-nine patients in the treated group had at least 2 years of GH treatment between imaging studies of the pituitary. Two patients in the treated group had an increase in pituitary size (non-functioning adenomas) and two in the control group (one functioning and one non-functioning adenoma adenoma). None of these four patients required further treatment. There was no statistically significant difference between the two groups. CONCLUSION: Using a representative cohort of hypopituitary patients attending an endocrine clinic, GH replacement was not associated with an increased pituitary tumour recurrence rate. Although the results are not conclusive, in the period of observation GH had little adverse effect but longer studies are required to be certain.

Two conferences were sponsored by the International Society for Cutaneous Lymphomas (ISCL) to gain consensus on definitions and terminology for clinical use in erythrodermic cutaneous T-cell lymphoma (E-CTCL). Three subsets of E-CTCL were defined: Sézary syndrome (“leukemic phase” E-CTCL), erythrodermic mycosis fungoides (secondary E-CTCL that develops in patients with mycosis fungoides), and E-CTCL, not otherwise defined. The hematologic criteria recommended for Sézary syndrome are intended to identify patients with a worse prognosis compared with the other E-CTCL subsets and consist of one or more of the following: (1) an absolute Sézary cell count of 1000 cells/mm3or more; (2) a CD4/CD8 ratio of 10 or higher caused by an increase in circulating T cells and/or an aberrant loss or expression of pan-T cell markers by flow cytometry; (3) increased lymphocyte counts with evidence of a T-cell clone in the blood by the Southern blot or polymerase chain reaction technique; or (4) a chromosomally abnormal T-cell clone. For staging purposes, it is proposed that these criteria define the B2 blood rating and that the B2 rating be considered equivalent to nodal involvement. (J Am Acad Dermatol 2002;46:95-106.)

Data were analyzed from 23 patients with Sézary syndrome (defined by erythroderma, more than 10% circulating atypical mononuclear cells, and peripheral blood T-cell clone) undergoing monthly extracorporeal photopheresis as the sole therapy for up to 1 year. The cohort showed a significant reduction of skin scores during treatment (P = .001). Thirteen patients (57%) achieved a reduction in skin score greater than 25% from baseline at 3, 6, 9, or 12 months (responders). Reduction in skin score correlated with reduction in the Sézary cell count as a percentage of total white cell count (P = .03). Responders and nonresponders were compared. None of the measured parameters was significantly different between the 2 groups. It was assessed whether any of the baseline parameters predicted outcome. A higher baseline lymphocyte count was significantly associated with a decrease in skin score at 6 months (P < .05). A higher baseline Sézary cell count as a percentage of total white cell count predicted a subject was more likely to be a responder after 6 months of treatment (P = .021). No other parameters predicted responder status. These data show that the modest falls in CD4, CD8, and Sézary cell counts were seen in all patients and might have resulted from lymphocyte apoptosis. This mechanism could explain the more favorable response seen in patients with higher percentages of Sézary cells in the peripheral blood. Alternatively, minimum tumor burden might be required for the induction of a cytotoxic response. Analysis of tumor-specific cytotoxic T cells is needed to investigate these possibilities further.

Nine patients with mycosis fungoides (age range 27-67) underwent autologous peripheral blood stem cell transplantation (PBSCT). All patients had tumor-stage disease, and four had lymph node involvement. Eight patients exhibited a peripheral blood T cell clone using PCRSSCP analysis of the TCR gamma gene, six prior to harvest and two at the time of harvest. Mobilization of CD34stem cells was achieved with etoposide and G-CSF. Harvested cells were positively selected for CD34. After negative selection for CD4 and CD8, only two samples became PCR negative. Conditioning prior to reinfusion of stem cells was achieved with various combinations of total skin electron beam (TSEB), total body irradiation (TBI), and chemotherapy, depending upon the patient's prior exposure to radiotherapy. One patient failed to engraft and died of candidal septicemia 15 days posttransplant. The other eight patients achieved complete remission, but this was short-lived in four (median disease-free survival [DFS] 2 months) and prolonged in three (median DFS 11 months). Those with a short DFS were distinguished by rapid tumor onset prior to transplant but not by stage at transplant. Loss of a detectable T cell clone after manipulation of the harvest did not discriminate between the two groups, but rapid relapsers had been subjected to a greater degree of T cell depletion, possibly indicating a compromised cytotoxic response post-PBSCT. The median survival of the cohort is four years from tumor onset, 15 months from PBSCT, and 27 months from the date a peripheral blood clone was first detected in the presence of tumor-stage disease. Rapid relapse was associated with poor overall survival. Our data demonstrate the value of PBSCT for inducing remission in tumor-stage mycosis fungoides. Reinfusion of neoplastic cells could be avoided by harvesting stem cells at an earlier stage in the disease process, preferably before a T cell clone is detectable in the peripheral blood. Alternatively T cell depletion should be restricted to the CD4 subset.

Erythrodermic cutaneous T-cell lymphoma (CTCL) includes patients with erythrodermic mycosis fungoides who may or may not exhibit blood involvement and Sézary syndrome and in whom hematological involvement is, by definition, present at diagnosis. These patients were stratified into 5 hematologic stages (H0-H4) by measuring blood tumor burden, and these data were correlated with survival. The study identified 57 patients: 3 had no evidence of hematologic involvement (H0), 8 had a peripheral blood T-cell clone detected by polymerase chain reaction (PCR) analysis of the T-cell receptor gene and less than 5% Sézary cells on peripheral blood smear (H1), and 14 had either a T-cell clone detected by Southern blot analysis or PCR positivity with more than 5% circulating Sézary cells (H2). Twenty-four patients had absolute Sézary counts of more than 1 × 109 cells per liter (H3), and 8 patients had counts in excess of 10 × 109 cells per liter (H4). The disease-specific death rate was higher with increasing hematologic stage, after correcting for age at diagnosis. A univariate analysis of 30 patients with defined lymph node stage found hematologic stage (P = .045) and lymph node stage (P = .013) but not age (P = .136) to be poor prognostic indicators of survival. Multivariate analysis identified only lymph node stage to be prognostically important, although likelihood ratio tests indicated that hematologic stage provides additional information (P = .035). Increasing tumor burden in blood and lymph nodes of patients with erythrodermic CTCL was associated with a worse prognosis.The data imply that a hematologic staging system could complement existing tumor-node-metastasis staging criteria in erythrodermic CTCL.

We report 6 cases of pseudoepitheliomatous hyperplasia (PEH) mimicking squamous cell carcinoma in association with an atypical CD30+dermal infiltrate. Three patients had lymphomatoid papulosis type A, and 3 patients had cutaneous CD30+lymphoma. All 6 cases showed histologic evidence of PEH with keratinocyte atypia. In 4 cases there was significant atypia to prompt a diagnosis of squamous cell carcinoma. Three of these received treatment with wide local excision and 2 had been engrafted. Immunohistochemical staining for epidermal growth factor (EGF) and transforming growth factor α (TGF-α) showed similar expression in lesional and perilesional skin. Epidermal growth factor receptor (EGFR) expression by the proliferating epithelium was similar to that of the suprabasal adjacent normal epidermis. There was no aberrant expression of EGF, TGF-α, and EGFR by atypical lymphocytes. These cases demonstrate that PEH associated with CD30+lymphoproliferative disease may closely resemble squamous cell carcinoma, thereby leading to inappropriate diagnosis and treatment. (J Am Acad Dermatol 2001;44:239-47.)

Purpose.This study was aimed at examining the extent and mechanismof uptake of cobalamin (Cbl)-conjugated peptides in vitro and in vivo. Methods.To enable acquisition of quantitative absorption data ofCbl-peptides, metabolically stable octapeptides (DP3), with (Cbl-Hex-DP3)or without a hexyl spacer (Cbl-DP3), were coupled to Cbl andradiolabeled. For comparison, LHRH coupled to Cbl was used as metabolicallysusceptible peptide. Biological recognition of Cbl-peptides was studiedin the physiological order: binding by Intrinsic Factor (IF), recognitionand transport of the IF-complexes by IF-Cbl receptors (IFCR) onCaco-2 monolayers and oral absorption of the Cbl-conjugates in the rat. Results.All Cbl-peptides bound to IF and the IF-complexes wererecognized by IFCR receptors on Caco-2 monolayers. Binding wassaturable and could be inhibited by a 20-fold excess of IF-Cbl, but notof Non-intrinsic Factor (NIF)-Cbl. Oral administration of these ligandsto rats resulted in absorption of 53%, 45%, 42%, and 23% of theapplied radioactivity for Cbl, Cbl-LHRH, Cbl-Hex-DP3, and Cbl-DP3,respectively. Simultaneous administration of a >105-fold excess ofunlabeled Cbl reduced uptake of all compounds to <4%. Tissuedistribution and elimination of the metabolically stable Cbl-conjugates werecomparable to Cbl. Conclusions.The endogenous Cbl uptake pathway can be exploitedfor oral peptide delivery as indicated by the specific and high (40–45%)uptake of metabolically stable Cbl-coupled octapeptides.

Previous cytogenetic studies of primary cutaneous T-cell lymphoma (CTCL) were based on limited numbers of patients and seldom showed consistent nonrandom chromosomal abnormalities. In this study, 54 tumor DNA samples from patients with CTCL were analyzed for loss of heterozygosity on 10q. Allelic loss was identified in 10 samples, all of which were from the 44 patients with mycosis fungoides (10/44 patients; 23%). Of the patients with allelic loss, 3 were among the 29 patients with early-stage myosis fungoides (T1 or T2) (3/29 patients; 10%), whereas the other 7 were among the 15 patients with advanced cutaneous disease (T3 or T4) (7/15 patients; 47%). The overlapping region of deletion was between 10q23 and 10q24. In addition, microsatellite instability (MSI) was present in 13 of the 54 samples (24%), 12 from patients with mycosis fungoides and 1 from a patient with Sezary syndrome. There was also an association between MSI and disease progression in patients with mycosis fungoides, with 6 of 15 (40%) patients with MSI having advanced cutaneous disease and only 6 of 29 (21%) having early-stage disease. Samples with allelic loss on 10q were analyzed for abnormalities of the tumor suppressor genePTEN (10q23.3). No tumor-specific mutations were detected, but homozygous deletion was found in 2 patients. Thus, we found loss of heterozygosity on 10q and MSI in advanced cutaneous stages of mycosis fungoides. These findings indicate that a tumor suppressor gene or genes in this region may be associated with disease progression. Furthermore, abnormalities of PTEN may be important in the pathogenesis of mycosis fungoides, but our data imply that this gene is rarely inactivated by small deletions or point mutations.

OBJECTIVES

We have undertaken a retrospective analysis of all positron emission tomography (PET) scans carried out at St Thomas’ Hospital, London, since 1994 to establish the sensitivity and specificity of this radiologic technique in cutaneous malignant melanoma. In particular, we have identified those patients with primary cutaneous malignant melanoma in whom PET scanning revealed in-transit or regional spread to nodes and those patients with known regional spread in whom PET scanning revealed distant metastases. We defined our false-negative results as a negative scan result with positive histology or subsequent clinical progression of disease. False-positive results were defined as a suspect scan with negative histology or no subsequent progression of disease. PET scanning had an overall sensitivity of 78% and specificity of 87%; however, subset analysis (M. D. Anderson staging system) showed a sensitivity of 50% for stage I disease (34 patients and 35 scans) and 33% for stage II disease (9 patients and 9 scans) with specificities of 87% and 100%, respectively. For stage III disease (16 patients and 17 scans), PET showed a sensitivity of 93% and specificity of 50%. Overall, 35% of patients with true-positive scans had their disease restaged. We can conclude therefore that PET is valuable as a staging procedure in patients with known regional spread but is suboptimal in the prediction of outcome in stage I or stage II disease. (J Am Acad Dermatol 2000;42:606-11.)

Diagnosing Sezary syndrome (SS) on clinicopathological grounds alone is far from straightforward, particularly in the early stages of the disease. Atypical lymphocytes may be seen in the peripheral blood of patients with reactive forms of erythroderma, so additional criteria are needed to establish the diagnosis of a T-cell leukemia/lymphoma. A wide variety of confirmatory tests have been proposed in the literature, but there has been no systematic attempt to compare the specificity and sensitivity of these different methods. Recent data indicate that T-cell receptor (TCR) gene analysis is the most useful test currently available and that methods based on polymerase chain reaction are more sensitive than Southern blot analysis. We propose that the diagnostic criteria for SS should include erythroderma, atypical circulating mononuclear cells, and evidence of a clonal T-cell population in the peripheral blood. Clonality can be established with certainty by cytogenetic or TCR gene analysis, but only the latter is sufficiently sensitive to be of value in routine diagnosis. Immunophenotypic data showing an expanded CD4^+/CD7^- population, an elevated CD4/CD8 ratio, or restricted V beta expression are not specific to T-cell malignancy and should not be used as a sole diagnostic criteria in SS. Entry criteria for future clinical studies will need to be more rigorous if meaningful comparisons are to be made between different treatment options. (J Am Acad Dermatol 1999;41:254-9.)

There is evidence that melatonin may play a role in modulating pituitary secretion, although the mechanisms are unclear. We examined the effects of a single dose of oral melatonin (5mg) on exercise-induced GH secretion. In a randomised, double-blind, placebo-controlled study, seven healthy male subjects undertook an initial period of graded bicycle ergometric exercise to determine maximum workload and oxygen uptake (VO(2max)). Subjects were subsequently studied on two further occasions, receiving either melatonin or placebo in random order at the onset of each study (-60min). At 0 min a period of bicycle exercise was performed for 8 min at a workload corresponding to 70% of that achieved at VO(2max). Serum GH and IGF-binding protein-1 (IGFBP-1) concentration was measured at 15-min intervals from the onset of the study until 120 min post-exercise. Blood was also sampled for the measurement of plasma glucose, insulin, non-esterified fatty acids, IGFBP-3, melatonin and vasopressin concentration. There was an exercise-induced increase in GH concentration following melatonin which was greater compared with placebo as assessed by both area under the curve (P<0.01) and peak increase in GH levels (P<0.01). The peak increase in IGFBP-1 levels post-exercise was also significantly greater following melatonin compared with placebo (P<0. 01) but did not quite reach levels of significance as measured by area under the curve (P=0.07). Since exercise-induced GH secretion is thought to be mediated predominantly through a hypothalamic pathway, it seems likely that melatonin facilitates GH secretion at a hypothalamic level.

Twelve biologically active derivatives of vitamin B12 (cyanocobalamin) have been synthesized in which spacers were attached to the ribose-5‘-hydroxyl group of vitamin B12. Their potential to act as oral delivery agents for proteins, nanospheres, or immunogens using the vitamin B12 uptake system was evaluated by determining their affinity for intrinsic factor (IF) and non-IF. The ribose-5‘-hydroxyl group of vitamin B12 was activated through the use of 1,1‘-carbonyldiimidazole (CDI), 1,1‘-carbonyldi(1,2,4-triazole) (CDT), or di(1-benzotriazolyl) carbonate (DBTC). Subsequent addition of an aminoalkane, diaminoalkane, or alkane diacid dihydrazide gave rise to vitamin B12 derivatives suitable for attachment to various proteins, peptides, or nanospheres to enable oral delivery utilizing the vitamin B12 uptake system. The ribose-5‘-carbamate derivatives were found to possess similar affinity for intrinsic factor as that of the e-monocarboxylic acid of vitamin B12. The affinity for non-IF was similar to cyanocobalamin or even higher for some of the smaller derivatives. Polysciences nanoparticles derivatized with vitamin B12 5‘-carbamate adipic dihydrazide into CaCo-2 cells showed significantly higher levels of transport of the particles, when compared to unmodified particles.

SummaryThe polymeric and monomeric (7S) forms of the nitrophenyl-specific MOPC-315 murine IgA myeloma protein were examined for their capacity to inhibit the consumption of guinea-pig complement (C) by the C-activating protein DNP46BSA and by antigen-antibody (Ag-Ab) complexes. On a molar basis. 13S IgA was slightly (2–3 fold) more efficient than 7S IgA in inhibiting C consumption by DNP-BSA. When mixed with IgG antibodies prior to incubation with a non-complement-fixing antigen (TNP-KLH). 13S IgA was considerably more effective than 7S IgA in preventing the formation of Ag-Ab complexes able to fix C. The degree of inhibition observed was related to the concentration of C used in the assay, being greater at lower C concentrations.Australian Journal of Experimental Biology and Medical Science (1984) 62, 1–10; doi:10.1038/icb.1984.1

Kaposi's sarcoma (KS) is an enigmatic tumour of uncertain histogenesis. Epidemiological data have long suggested that KS may be caused by an infectious agent, possibly sexually transmitted. Following the documentation of human herpesvirus 8 (HHV8) and its strong association with all forms of KS, it now appears that the putative agent has at last been identified. As KS is rare in females, a unique group was screened for the presence of HHV8 using both conventional solution‐phase polymerase chain reaction (PCR) and the newly described technique of TaqMan® PCR. The presence of HHV8 was demonstrated in 10/12 of these female patients. This further supports the direct role of HHV8, in conjunction with cytokines and other factors, in the pathogenesis of KS. © 1997 John Wiley & Sons, Ltd.

LTB provokes a systemic immune response and exerts adjuvant effects on mucosal immune responses to unrelated antigens. The binding and uptake of fluorescein-labelled LTB in the normal villus epithelium was compared to that in Peyer's patch dome epithelium in mouse intestine. LTB was bound by the GM1-receptor and taken up extensively by both tissues, indicating that not only the Peyer's patches but also the normal villus epithelium play a significant role in the transport of orally administered antigens. These results were supported by transport studies in the human intestinal epithelial cell line Caco-2 using 125I-LTB. After 2 h incubation, 5.1 ± 0.1% and 5.9 ± 0.1% of the added radioactivity was transported in the apical to basolateral and basolateral to apical direction, respectively. Less than 1% of the transported radioactivity was immunoprecipitated with anti-LTB antiserum indicating that LTB was extensively degraded during the transport. The results suggest that normal enterocytes play a significant role in the binding, uptake and transport of orally administered LTB.

Mitochondrial encephalomyopathy is a genetic disorder for which there is at present no cure. Conventional treatment regimes may not be effective in preventing weight loss and muscle wasting in many patients. Recombinant human GH has been shown to have anabolic effects on protein metabolism and to reduce muscle wasting in various diseases. We have treated a patient known to have myoclonus, epilepsy with ragged red fibres (MERRF) with a high protein diet for 1 month followed by a high protein diet and GH therapy for 1 month. To assess the benefit of these treatments the patient underwent whole body protein turnover, myometric and body composition studies at baseline, following the high protein diet (100 g/day) and following GH therapy. Whole body protein synthesis (and protein breakdown) increased following a high protein intake and was further enhanced by treatment with GH and a high protein diet. Body composition did not change significantly following treatment with either the high protein diet or GH but there was an improvement in muscle performance following GH treatment. Mitochondrial encephalomyopathy, a wasting disorder, may be a disease in which the known protein anabolic effect of GH may have a therapeutic benefit.

OBJECTIVES
To investigate the effects of IGF-I and insulin at doses equipotent with respect to hypoglycaemic effect on IGF-I concentrations (free and bound), IGF binding proteins, catecholamines and potassium levels. DESIGN
A glucose and amino acid clamp technique was used to investigate the effects of a 3 h intravenous infusion of either IGF-I 43.7 pmol/kg/min (20 mug/kg/ h) or insulin 3.4 pmol/kg/min (0.5 mU/kg/min). MEASUREMENTS
Circulating levels of total IGF-I, free and bound IGF-I, insulin, IGFBP-1, IGFBP-3, ALS, catecholamines and potassium were measured. PATIENTS
6 normal human volunteers aged 21-49. RESULTS
During the IGF-I infusion, IGF-I levels increased (P &lt; 0.01) (26.6 ± 2.8-88.9 ± 14.2 nmol/l) and insulin levels fell (P &lt; 0.05) (16.7 ± 2.9-7.2 ± 1.6 mu/l). During the insulin infusion, insulin levels increased (P &lt; 0.01) (11.7 ± 1.6-56.7 ± 16 mu/l) and there was no change in IGF-I. There was no significant change in IGFBP-3 or ALS during the IGF-I or insulin infusions. There was a significant (P &lt; 0.05) fall in IGFBP-1 levels from 27.1 ± 4.1-8.06 ± 1.6 mug/l during the insulin infusion and a significant (P &lt; 0.05) rise during the first 120 min of IGF-I infusion from 28.6 ± 6.3-67.9 ± 10.6 mug/l. There was a significant (P &lt; 0.05) increase in free IGF-I and IGF-I bound to the 150 and 50 kD plasma fractions during the IGF-I infusion. At basal and the end of the IGF-I infusion adrenaline levels (pmol/l) were: 173 ± 22 and 174 ± 28; dopamine levels (pmol/l) were: 415 ± 87 and 470 ± 87; plasma potassium (mmol/l) was 4.2 ± 0.06 and 3.56 ± 0.13. At basal and the end of the insulin infusion adrenaline levels (pmol/l) were: 160 ± 38 and 163 ± 21; dopamine levels (pmol/l) were: 238 ± 26 and 316 ± 31; plasma potassium (mmol/l) was 4.2 ± 0.07 and 3.92 ± 0.17. There were no significant changes in plasma catecholamine concentrations with either infusion but potassium concentrations were significantly (P &lt; 0.05) reduced during the IGF-I infusion. CONCLUSIONS
We conclude that an infusion of IGF-I resulted in increased levels of both free and bound IGF-I. IGF-I and insulin under conditions of adequate substrate supply have acute effects on IGFBP-1 and potassium physiology, but have little effect on IGFBP-3, ALS or catecholamines.