Obesity is a strong risk factor for short-term mortality and adverse outcomes in Mexican patients with COVID-19: a national observational study.

Conflicting results have been obtained through meta-analyses for the role of obesity as a risk factor for adverse outcomes in patients with coronavirus disease-2019 (COVID-19), possibly due to the inclusion of predominantly multimorbid patients with severe COVID-19. Here, we aimed to study obesity alone or in combination with other comorbidities as a risk factor for short-term all-cause mortality and other adverse outcomes in Mexican patients evaluated for suspected COVID-19 in ambulatory units and hospitals in Mexico. We performed a retrospective observational analysis in a national cohort of 71 103 patients from all 32 states of Mexico from the National COVID-19 Epidemiological Surveillance Study. Two statistical models were applied through Cox regression to create survival models and logistic regression models to determine risk of death, hospitalisation, invasive mechanical ventilation, pneumonia and admission to an intensive care unit, conferred by obesity and other comorbidities (diabetes mellitus (DM), chronic obstructive pulmonary disease, asthma, immunosuppression, hypertension, cardiovascular disease and chronic kidney disease). Models were adjusted for other risk factors. From 24 February to 26 April 2020, 71 103 patients were evaluated for suspected COVID-19; 15 529 (21.8%) had a positive test for SARS-CoV-2; 46 960 (66.1%), negative and 8614 (12.1%), pending results. Obesity alone increased adjusted mortality risk in positive patients (hazard ratio (HR) = 2.7, 95% confidence interval (CI) 2.04-2.98), but not in negative and pending-result patients. Obesity combined with other comorbidities further increased risk of death (DM: HR = 2.79, 95% CI 2.04-3.80; immunosuppression: HR = 5.06, 95% CI 2.26-11.41; hypertension: HR = 2.30, 95% CI 1.77-3.01) and other adverse outcomes. In conclusion, obesity is a strong risk factor for short-term mortality and critical illness in Mexican patients with COVID-19; risk increases when obesity is present with other comorbidities.

Effects of nonylphenol on vitellogenin synthesis in adult males of the spotted ray Torpedo marmorata.

The aim of this investigation was to assess the effects of nonylphenol (NP), an oestrogen-like environmental pollutant, on the vitellogenin (VTG) synthesis in adult males of the aplacental viviparous cartilaginous fish Torpedo marmorata. The VTG recovery in males is considered a biomarker of xeno-oestrogenic pollution as this lipophosphoglycoprotein is physiologically induced by oestrogens only in females of oviparous and ovoviparous vertebrates. Using in situ hybridization and immunohistochemistry, T. marmorata males injected with nonylphenol showed the presence of VTG in the liver and the kidney. In particular, vtg messenger (m)RNA and VTG protein were expressed in the liver, whereas in the kidney cells only the presence of VTG was recorded. By contrast, no expression for VTG was detected in the testis. These results demonstrate that in T. marmorata NP induces the expression of vtg only in the liver; the presence of VTG in the kidney and its absence in the testis are discussed.

Lipovitellin constitutes the protein backbone of glycoproteins involved in sperm-egg interaction in the amphibian Discoglossus pictus.

Our knowledge of the molecules that interact with sperm at the egg membrane is restricted to a short list. In the eggs of Discoglossus pictus, fusion with sperm is limited to a differentiated structure, the dimple, offering several advantages for detecting molecules involved in fertilization. Previous studies have identified fucosylated glycoproteins of 200, 260, and 270 kDa located at the surface of the dimple that are able to bind sperm in vitro. Here, we show that dimple glycoproteins and a protein represented by a 120-kDa band released following gel-into-gel SDS-PAGE of both glycoproteins share the same N-terminal amino acid sequence, which itself is similar to the N-termini of Xenopus liver-synthesized vitellogenin (VTG) and the lipovitellin 1. MALDI/MS mass spectrometry indicated that the 120-kDa band is part of both gps 200 and 270/260. A 117-kDa major protein of the egg lysate exhibits the same MALDI/MS spectrum, and LC-MSMS indicates that this is a lipovitellin 1 (DpLIV) that coincides with the 120-kDa band and is responsible for the formation of the 200-270-kDa dimers. Therefore, lipovitellin 1 constitutes the protein backbone of the dimple glycoconjugates. In vitro assays using polystyrene beads coated with DpLIV or with its dimers indicate that significant sperm binding occurs only with DpLIV dimers. In amphibians, VTG is taken up by the oocyte, where it releases lipovitellins destined to form yolk. In Discoglossus, our data suggest that yolk proteins are also synthesized by the oocyte. The dimple forms in the ovulated oocyte following the exocytosis of vesicles that likely expose DpLIVs at their membrane. Indeed, in whole mounts of immunostained eggs, anti-vitellogenin antibodies label only the surface of the dimple.

Clinical features associated with early drop-out among outpatients with unipolar and bipolar depression.

Drop-out from follow-up visits carries significant burden for people diagnosed with depression. The present study assesses multiple clinical moderators of drop-out among depressed outpatients. We retrospectively followed-up 131 outpatients over 6 months: 78 major depressive disorder (MDD), and 53 bipolar disorder (BD-I = 24; BD-II = 29) patients diagnosed according to the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Participants were assessed with standard rating scales administered by experienced psychiatrists. Upon descriptive and Cox regression analyses, 17/53 BDs (32%) dropped-out; the overall survival time until drop-out was 57.94 ± 17.79 days. BD drop-outs were younger, had an earlier age at onset, shorter illness duration, lower rates of lifetime obsessive-compulsive disorder/suicidal behavior, higher rates of substance use disorder (SUD), anxious and mixed features of depression compared to BDs attending up to six months. Among MDD patients, 10/78 cases (13%) dropped-out by month-6 with an average survival of 42.40 ± 16.45 days. Earlier age of onset, younger age, positive family history for mood disorders, lower rates of lifetime generalized anxiety disorder were significantly more frequent among drop-outs than completers, as opposite to SUD, and lifetime recurrent depression. Older age predicted lower drop-out among BDs and MDDs, although with almost null hazard ratio (HR) = 0.928, p < 0.01 vs. HR = 0.941, p < 0.01, respectively. Higher rates of lifetime SUD predicted higher drop-out rates by month-6 among MDDs (HR = 5.477, p = 0.02). Limitations of the study: retrospective design, small sample size, lack of objective measures of treatment-adherence/mood rating during follow-up. Drop-out is common in the real-world setting, warranting specific interventions since the beginning of the treatment.

Assessment of Residual Radioactivity by a Comprehensive Wireless, Wearable Device in Thyroid Cancer Patients Undergoing Radionuclide Therapy and Comparison With the Results of a Home Device: A Feasibility Study.

Objective: To investigate the feasibility of using a wireless wearable device (WD) in differentiated thyroid cancer (DTC) patients undergoing radionuclide therapy with I-131 (RAI) and protected hospitalization, this study compared the measurements of residual radioactivity obtained with those registered by a permanent environmental home device (HD). Methods: Twenty consecutive patients undergoing RAI hospitalized in restricted, controlled areas were enrolled. The patients underwent comprehensive monitoring of vital/nonvital parameters. We obtained 45580± 13 measurements from the WD, detecting the residual radioactivity for each patient during approximately 56 hours of hospitalization, collecting data 53 times per hour. The samples, collected during daily activities, were averaged every two hours, and the results correlated with those from the HD. Bland-Altman analysis was also used to evaluate the agreement between the two techniques. Results: A significant relationship between the WD and HD was observed (r = 0.96, p < 0.0001). Bland-Altman analysis recognized the agreement between measurements by the WD and HD. The mean value at the end of the first day of hospitalization was 80.81 microSv/h and 60.77 microSv/h (p = ns for WD and HD), whereas those at the end of the second day were 47.08 and 24.96 (p = ns). In the generalized linear model (GLM), a similar trend in performance across time was found with the two techniques. Conclusion: This study demonstrates good agreement between the residual radioactivity measures estimated by the WD and HD modalities, rendering them interchangeable. This approach will allow both the optimization of medical staff exposure and safer patient discharge. Abbreviations: wireless device (WD); differentiated thyroid cancer (DTC); radionuclide therapy with I-131 (RAI); home device (HD); generalized linear model (GLM).

MWCNT/rGO/natural rubber latex dispersions for innovative, piezo-resistive and cement-based composite sensors.

The present study is focused on the development and characterization of innovative cementitious-based composite sensors. In particular, multifunctional cement mortars with enhanced piezoresistive properties are realized by exploiting the concept of confinement of Multiwall Carbon Nanotubes (MWCNTs) and reduced Graphene Oxide (rGO) in a three-dimensional percolated network through the use of a natural-rubber latex aqueous dispersion. The manufactured cement-based composites were characterized by means of Inelastic Neutron Scattering to assess the hydration reactions and the interactions between natural rubber and the hydrated-cement phases and by Scanning Electron Microscopy and X-Ray diffraction to evaluate the morphological and mineralogical structure, respectively. Piezo-resistive properties to assess electro-mechanical behavior in strain condition are also measured. The results show that the presence of natural rubber latex allows to obtain a three-dimensional rGO/MWCNTs segregate structure which catalyzes the formation of hydrated phases of the cement and increases the piezo-resistive sensitivity of mortar composites, representing a reliable approach in developing innovative mortar-based piezoresistive strain sensors.

Morphological and molecular responses in ovaries of Mytilus galloprovincialis collected in two different sites of the Naples Bay.

Mytilus galloprovincialis female specimens were collected from two mussel farms located in two sites next to Castel dell'Ovo, a historical complex located in the Naples Bay. Such sites were named, respectively, A-area and B-area for the different microbiological parameters so that mussels from A-area can be sold without purification, whereas mussels from B-area must be purified before sale. The mussels were collected during the nonreproductive (summer 2009) and reproductive periods (autumn 2009). Gonadosomatic index, structural organization of the ovary, presence of apoptosis, estrogen receptors expression, as well as the bisphenol A (BPA) content in the ovaries, were evaluated. Ovaries from specimens collected in area B showed a different and significant distribution of the investigated biomarkers as well as of BPA content in respect to those measured in the A-area specimens, confirming that mussels are valid sentinel organisms to biomonitor in the Naples bay too.

Prognostic role of topoisomerase-IIalpha in advanced ovarian cancer patients.

To our knowledge, very few data about the role of Topoisomerase IIalpha (TOPO-IIalpha), an enzyme involved in critical steps of tumour cell proliferation and chemoresistance are currently available in ovarian cancer patients. The aim of this study was to investigate the prognostic value of TOPO-IIalpha expression in a large, single institution series of 96 primary untreated advanced ovarian cancer patients admitted to the Gynecologic Oncology Unit, Catholic University of Campobasso and Rome. Immunohistochemistry was carried out by using the MoAb anti-human TOPO-IIalpha antibody (clone Ki-S1). TOPO-IIalpha immunoreaction was observed in 70 out of 96 cases (72.9%), and the percentages of positively stained cells ranged between 1 and 83% (median=10%). There was no association with clinico-pathological parameters. During the follow up period, progression and death of disease were observed in 76 (79.2%) and 45 (46.9%) cases. A statistically significant direct association between the percentages of positively immunostained tumour cells and the relative risk of death was observed (chi(2)=6.6, P-value=0.0101). In multivariate analysis, only platinum resistance, advanced stage of disease and high levels of TOPO-IIalpha expression retained an independent negative prognostic role for OS. The unfavourable role of high TOPO-IIalpha expression was maintained only in the subgroup of platinum resistant recurrent ovarian cancer patients, be TOPO-IIalpha expression evaluated as continuous variable (chi(2)=5.1, P-value=0.024), or by means of the defined cutoff point. Our study suggests that the assessment of TOPO-IIalpha could be helpful to identify poor prognosis platinum-resistant ovarian cancer patients, potentially candidates to investigational agents.

Cutaneous sterile granulomas/pyogranulomas, leishmaniasis and mycobacterial infections.

Cutaneous "sterile" granulomas represent a group of uncommon skin disorders of unknown aetiopathogenesis. Many diseases are included in this group (for example, sterile granuloma/pyogranuloma syndrome and reactive histiocytosis). The definition of sterile is based on the exclusion of other possible aetiological agents (for example, microorganisms or foreign body). Many techniques are used to rule out a microbial aetiology including cytology, histology, immunohistochemistry and culture. However, some organisms are "fastidious" and difficult to culture or to identify with routine methods, and molecular studies are necessary. This is particularly true for mycobacteria (for example, canine leproid granuloma syndrome) and Leishmania. Recently, studies in human and veterinary medicine have proved the presence of microorganisms (mycobacteria and Leishmania) using a polymerase chain reaction technique in specimens previously diagnosed as sterile. Therefore, it is very important, with the development of new technologies, to use a multidisciplinary diagnostic approach to definitively rule out any microorganism before declaring a disease sterile.

Transformation by the simian virus 40 T antigen is regulated by IGF-I receptor and IRS-1 signaling.

Previous work has shown that the Simian Virus 40 T antigen (T antigen) cannot transform mouse embryo fibroblasts (MEFs) that do not express the type 1 insulin-like growth factor receptor (IGF-IR). We have now investigated the mechanism(s) by which the transforming activity of T antigen is affected by IGF-IR signaling. We demonstrate that transformation by T antigen of MEFs and several other cell lines requires an insulin receptor substrate-1 (IRS-1) phosphorylated on tyrosines. If IRS-1 is not expressed, or is serine phosphorylated or otherwise inactive, T antigen fails to transform cells in culture. For instance, while T antigen cannot transform 32D myeloid cells (that do not express IRS-1), its transforming activity is restored by the expression of a wild-type IRS-1, but not of an IRS-1 mutated at the PI3K binding sites. The importance of IRS-1 activation of PI3K in T-antigen transformation is supported by the finding that a constitutively activated p110 subunit of PI3K, a target of IRS-1, overcomes the inability of T antigen to transform MEFs with a serine phosphorylated IRS-1. Taken together, these results indicate that the IRS-1/PI3K signaling is one of the mechanisms regulating transformation by the SV40 T antigen. We propose that the requirement for a tyrosyl-phosphorylated IRS-1 provides a mechanism to explain the failure of T antigen to transform MEFs with deleted IGF-IR genes.

Regulation of Id gene expression by type I insulin-like growth factor: roles of Stat3 and the tyrosine 950 residue of the receptor.

Id proteins are known to play important roles in the proliferation and differentiation of many cell types. The type 1 insulin-like growth factor receptor (IGF-IR), activated by its ligand, induces the differentiation of 32D IGF-IR cells, a murine hematopoietic cell line, expressing a human IGF-IR. Expression in 32D IGF-IR cells of a dominant negative mutant of Stat3 (DNStat3) inhibits IGF-I-mediated differentiation. DNStat3 causes a dramatic increase in Id2 gene expression. This increase, however, is IGF-I dependent and is abrogated by a mutation at tyrosine 950 of the IGF-IR. These results indicate that in 32D cells, the IGF-IR regulates the expression of the Id2 gene and that this regulation is modulated by both positive and negative signals. Our results also suggest that in this model, Id2 proteins influence the differentiation program of cells but are not sufficient for the full stimulation of their proliferation program.

The insulin-like growth factor I receptor as a physiologically relevant target of p53 in apoptosis caused by interleukin-3 withdrawal.

The wild-type p53 protein is known to modulate apoptosis induced in 32D murine hemopoietic cells by interleukin-3 withdrawal. In 32D cells and in 32D cells constitutively expressing a temperature-sensitive mutant of p53 (32Dtsp53), overexpression of a wild-type (but not a mutant) insulin-like growth factor I receptor (IGF-IR) protects these cells from apoptosis. A tsp53 in its wild-type conformation causes a decrease in the levels of IGF-IRs, and this decrease is accompanied by increased sensitivity of these cells to apoptosis. However, when the expression of the IGF-IR cDNA is regulated by a viral promoter, IGF-IR levels are not decreased by a wild-type p53, and apoptosis does not occur. These findings show that, in 32Dtsp53 cells, the IGF-IR is a physiologically relevant target of p53 in the process of apoptosis.

Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis.

The type 1 insulin-like growth factor receptor (IGF-1R), activated by its ligands, protects several cell types from a variety of apoptotic injuries. The main signaling pathway for IGF-1R-mediated protection from apoptosis has been previously elucidated and rests on the activation of phosphatidylinositol 3-kinase, Akt/protein kinase B, and the phosphorylation and inactivation of BAD, a member of the Bcl-2 family of proteins. In 32D cells (a murine hemopoietic cell line devoid of insulin receptor substrate 1 [IRS-1]), the IGF-1R activates alternative pathways for protection from apoptosis induced by withdrawal of interleukin-3. One of these pathways leads to the activation of mitogen-activated protein kinase, while a third pathway results in the mitochondrial translocation of Raf and depends on the integrity of a group of serines in the C terminus of the receptor that are known to interact with 14.3.3 proteins. All three pathways, however, result in BAD phosphorylation. The presence of multiple antiapoptotic pathways may explain the remarkable efficacy of the IGF-1R in protecting cells from apoptosis.

Infection by Ascaris lumbricoides and bronchial hyper reactivity: an outstanding association in Venezuelan school children from endemic areas.

Asthma and other respiratory diseases have increased in the last years among Venezuelan children from helminthic endemic areas where the infection by Ascaris lumbricoides has been associated to bronchial airway inflammation in parasitized individuals. The aim of this work was to investigate the possible associations between the development of bronchial hyper reactivity and the immune response against A. lumbricoides in urban and rural children. We evaluated 470 school children from rural and urban communities. Pulmonary function tests were performed and >or=20% PC(20) changes were considered as a positive diagnostic of bronchial hyper reactivity. The prevalence and intensity of A. lumbricoides infection was determined by faecal examination. Specific serum IgE levels using a modified ELISA and skin prick tests against A. lumbricoides and the common allergen Dermatophagoides pteronyssinus were done. The number of circulating lymphocyte sub populations was determined by flow cytometry analysis. In rural children, bronchial hyper reactivity was associated with increased specific levels of anti-A. lumbricoides IgE (p<0.0001) and skin test positivity for A. lumbricoides (p<0.0001). The percentage of FEV1 predictive values correlated inversely (p<0.0001) with anti-A. lumbricoides IgE levels. Elevated numbers of circulating CD3+CD4+ and CD20+CD23+ cells were found in rural children with bronchial hyper reactivity compared to their asymptomatic counterparts. They correlated positively with anti-A. lumbricoides IgE levels (p<0.005 and <0.0001, respectively). In contrast, in urban children, bronchial hyper reactivity was associated with elevated anti-D. pteronyssinus IgE levels (p=0. 0089), skin hyper reactivity towards this aero allergen (p=0.003) and to an increase in the number of CD3+CD8+ (p<0.0001). Our results suggest that the IgE response against A. lumbricoides infection may be involved in the development of bronchial hyper reactivity among rural children from endemic areas and also that improved hygienic conditions in the urban environment is associated with increased responses to airborne allergens.

Endometrial carcinoma recurring as carcinosarcoma: report of two cases.

Endometrial carcinosarcoma is a rare, aggressive disease, accounting for approximately 3% of all uterine neoplasms. The emergence of sarcomatous elements is considered the evolution of subclones arising from high grade endometrial carcinomas. Here, we report two cases of primary endometrial carcinomas recurring as carcinosarcoma. Case 1. a 58-year-old postmenopausal woman diagnosed to have a poorly differentiated endometrial endometrioid adenocarcinoma (FIGO stage IB) developed an intra-abdominal recurrence of disease after 17 months from diagnosis. Histopathological analysis documented a biphasic neoplasia consisting of an epithelial (grade 3 endometrial endometrioid adenocarcinoma) and a sarcomatous component. Salvage chemotherapy with cisplatin, ifosfamide, epirubicin, and then with taxotere was attempted. The patient died after 2 months. Case 2. A 56-year-old woman with a diagnosis of grade 3 endometrial adenosquamous carcinoma of the endometrium (FIGO stage IIIA) experienced pelvic recurrence after five months from completion of chemotherapy. Definitive histology was malignant mixed mesodermal tumor with focal areas of chondrosarcomatous elements. The patient was triaged to exclusive concomitant chemoradiotherapy and salvage chemotherapy. The patient died after 3 months. We describe two cases of high grade endometrial carcinomas recurring as carcinosarcoma, thus providing evidence that the metaplastic sarcomatous evolution is a very rare event which can occur in patients with anaplastic endometrial cancer.

Stabilization of the Ras oncoprotein by the insulin-like growth factor 1 receptor during anchorage-independent growth.

R- cells are 3T3 cells derived from mouse embryos with a targeted disruption of the type 1 insulin-like growth factor receptor (IGF-IR) genes. R- cells are refractory to transformation by a variety of viral and cellular oncogenes, including an activated Ras. R- cells stably transfected with an activated Ha-Ras (R-Ras cells) fail to form colonies in soft agar. An IGF-IR truncated at residue 1245 cannot transform R- cells, even when strongly overexpressed. However, the combination of the truncated IGF-IR and an activated Ras induces transformation of R- cells. We show here that the Ras oncoprotein is rapidly degraded when R-Ras cells are grown under anchorage-independent conditions and that signaling from the truncated IGF-IR stabilizes Ras. In monolayer cultures, Ras levels remain constant regardless of the presence or absence of IGF-IR signaling. These results directly explain why Ras cannot transform mouse embryo fibroblasts devoid of IGF-IR. They also suggest a more generalized, alternative mechanism for transformation by Ras and, implicitly, another possible way for targeting Ras in tumor cells.

Protective effect of the insulin-like growth factor I receptor on apoptosis induced by okadaic acid.

Okadaic acid (OKA), a potent inhibitor of serine phosphatases at concentrations as low as 20-25 nM, induces apoptosis of R- mouse embryo fibroblasts, which are 3T3-like cells devoid of type 1 insulin-like growth factor receptors (IGF-IRs). From R- cells, we have generated (by stable transfection) cell lines with IGF-IR numbers ranging from 0 (R- cells) to >10(6) receptors per cell. The wild-type IGF-IR protects R- cells from OKA-induced apoptosis, its protective effect being exquisitely dependent on the number of receptors. A small increment in wild-type receptor number (from 15 x 10(3) to 22 x 10(3) receptors/cell) is sufficient to change R(-)-derived cells from sensitive to resistant to apoptosis. We have also studied the effect of various mutations of the IGF-IR on its ability to protect R(-)-derived cells from OKA-induced apoptosis. Our data indicate a correlation between protection from apoptosis and the ability of the receptor to respond to insulin-like growth factor I with mitogenesis.

Anti-apoptotic signaling of the IGF-I receptor in fibroblasts following loss of matrix adhesion.

The type 1 insulin-like growth factor receptor (IGF-IR) is known to protect cells from a variety of apoptotic injuries. In several instances, the anti-apoptotic effect of the wild type IGF-IR is more evident under conditions of anchorage-independence than in cells in monolayer cultures. We have investigated IGF-IR signaling in cells in anoikis, a form of apoptosis that occurs when cells are denied attachment to the extra-cellular matrix. IGF-I protects mouse embryo fibroblasts (MEF) from anoikis caused by withdrawal of growth factors. Survival is dependent on the concentration of IGF-I and a sufficient number of functional IGF-I receptors. In this model, IGF-I protection correlates best with ras activation and cell-to-cell aggregation, while PI3-kinase, Akt and MAP kinases seem to play a lesser, alternative role.

Glucose evaluation trial for remission (GETREM) in type 1 diabetes: a European multicentre study.

OBJECTIVE: Strict metabolic control during the 1st year of type 1 diabetes is thought to be a key factor for achieving clinical remission. The aims of this study were two-fold: (i) to evaluate the frequency and duration of spontaneous remission (defined according to the parameters issued by the International Diabetic Immunotherapy Group (IDIG)) in a European population of consecutive recent onset type 1 diabetes patients (aged 5-35 years), followed-up for a period of 36 months with a common protocol of intensive insulin therapy and without adjunct immune-intervention; and (ii) to identify the predictive factors for clinical remission. RESEARCH DESIGN AND METHOD: A total of 189 consecutive patients with newly diagnosed type 1 diabetes according to ADA criteria were recruited in participating centres (Belgium, Czech Republic, Estonia, France, Germany, Hungary, Italy, Poland, Romania, Sweden and Turkey) and followed-up for a period of up to 36 months. In all patients, intensive insulin therapy was implemented consisting of three or four injections of regular insulin daily with NPH insulin at bedtime. Adjustment of insulin dose was made according to a common protocol. Various clinical characteristics (age, gender, severity of presentation, etc.), history (presence of diabetic siblings in the family, etc.) and integrated parameters of metabolic control (HbA(1c), blood glucose, the total insulin dose at hospital discharge adjusted for body weight) were collected. RESULTS: Twenty-two patients (11.6%) experienced remission. The median duration of remission was 9.6 months and the range was 31 months. There was a wide variation among centres. Logistic regression analysis focused on the centre as the main variable in achieving remission. CONCLUSION: Remission was shown to be very heterogeneous between centres depending on 'other factors' such as patient care and family awareness of the disease rather than on 'measurable factors' such as sex, age, HbA(1c) and severity of presentation at diagnosis. Using intensive insulin therapy and optimisation of metabolic control, remission occurred in nearly one out of eight patients.

Domains of the insulin-like growth factor I receptor required for the activation of extracellular signal-regulated kinases.

The type 1 insulin-like growth factor receptor (IGF-IR) activates the extracellular signal-regulated kinases (ERK1 and -2). The two major substrates of the IGF-IR, insulin receptor substrate-1 (IRS-1) and the Shc proteins, are known to contribute to this activation. We investigated the domains of the IGF-IR required for the activation of the ERK proteins. To facilitate this study, we used a cell line (32D cells) that lacks IRS-1. In the absence of IRS-1, ERK activation is inhibited if the IGF-IR is mutated at two domains: tyrosine Y950 and a serine quartet at 1280-1283. Expression of IRS-1 in 32D cells expressing the double mutant IGF-IR restores ERK activation. The importance of the C-terminus of the IGF-IR in ERK activation (in the absence of IRS-1) is confirmed by the failure of the insulin receptor to give a sustained activation of ERK. In this model system, there is a good, but not exact, correlation between ERK activation and cell survival after withdrawal of growth factors.