Polytobacco product use among current cigarette smokers in Hong Kong, China: results from population surveys (2015-17).

BACKGROUND: Polytobacco product use is increasingly popular, but little is known about the prevalence, trend, and factors of such use particularly in non-western countries. METHOD: A representative sample of 1139 current cigarette smokers aged 15+ (84.1% male) were telephone interviewed in Tobacco Control Policy-related Surveys in 2015-2017. Information collected included poly-tobacco use (PTU), smoking and socio-demographic characteristics. Associations of current PTU with related factors were analyzed using logistic regression with adjustment for confounders. Prevalence was weighted by age and sex of current cigarette users in the general population. RESULTS: Eighty-four point one percent (95% CI 81.4-86.6%) were exclusive cigarette smokers. Fifteen point nine percent (13.4-18.6%) were current polytobacco product users, 12.3% (10.2-14.8%) used one tobacco product and 2.52% (1.59-3.97%) used two tobacco products in addition to cigarette. Cigarette use with cigar was more common (6.28%, 4.75-8.27%), and the least used product with cigarette was e-cigarette (1.05%, 0.44-2.50%). The changes in overall prevalence of PTU by number of products use varied in 3 years. Current PTU was associated with being male (AOR 2.01, 95% CI 1.12-3.61), younger age (AORs range from 1.34-4.65, P for trend < .001) and less ready to quit (2.08, 1.09-3.97). CONCLUSIONS: Prevalence of PTU increased slowly by year, one tobacco product use with cigarette was more common. The most used tobacco product with cigarette was cigar. Being male, younger and less ready to quit were associated with current PTU.

Utility of azathioprine, methotrexate and cyclosporine as steroid-sparing agents in chronic alopecia areata: a retrospective study of continuation rates in 138 patients.

BACKGROUND: The management of chronic alopecia areata (CAA) is challenging. There is currently no therapy that produces consistent successful hair regrowth. Systemic therapies, including prednisolone and steroid-sparing agents (SSA), are often tried in patients with CAA. As there are no head-to-head clinical trials that compare efficacy of one SSA over another, retrospective studies of treatment in clinical practice may help guide clinical practice. OBJECTIVE: To investigate the utility of SSAs in the treatment of AA. METHODS: An electronic medical records search identified patients with AA and those prescribed azathioprine, cyclosporine or methotrexate between 2002 and 2019. Type of AA, treatment duration, reason for cessation, use of concurrent prednisolone, dose of prednisolone and duration of prednisolone use were recorded. The primary outcome was SSA continuation rate at 6 and 12 months. RESULTS: A total of 852 AA patients were identified, among whom 138 patients had been treated with azathioprine, methotrexate or cyclosporine. Of these 138 patients treated with a SSA, 92 (66.7%) continued treatment for at least 12 months: 75.3% (55/73) of azathioprine users, 50% (11/22) of methotrexate users and 60.5% (26/43) of cyclosporine users. At 12 months, 67.3% of azathioprine users required concurrent prednisolone at a mean dose of 5.6 mg daily, 63.6% of methotrexate users required prednisolone at a mean dose of 5 mg daily and 57.7% of cyclosporine users required prednisolone at a mean dose of 8.7 mg daily. The SSA was ceased due to an adverse event in 15.9% of patients and a lack of efficacy in 17.4%. CONCLUSION: The most well-utilized SSA for CAA patients at our clinic was azathioprine. This study highlights that most CAA patients who commence treatment with azathioprine, methotrexate or cyclosporine continue that treatment for at least 12 months and most require concurrent low-dose prednisolone to maintain remission or promote continued hair regrowth.

Risk prediction models for delirium in the intensive care unit after cardiac surgery: a systematic review and independent external validation.

Numerous risk prediction models are available for predicting delirium after cardiac surgery, but few have been directly compared with one another or been validated in an independent data set. We conducted a systematic review to identify validated risk prediction models of delirium (using the Confusion Assessment Method-Intensive Care Unit tool) after cardiac surgery and assessed the transportability of the risk prediction models on a prospective cohort of 600 consecutive patients undergoing cardiac surgery at a university hospital in Hong Kong from July 2013 to July 2015. The discrimination (c-statistic), calibration (GiViTI calibration belt), and clinical usefulness (decision curve analysis) of the risk prediction models were examined in a stepwise manner. Three published high-quality intensive care unit delirium risk prediction models (n=5939) were identified: Katznelson, the original PRE-DELIRIC, and the international recalibrated PRE-DELIRIC model. Delirium occurred in 83 patients (13.8%, 95% CI: 11.2-16.9%). After updating the intercept and regression coefficients in the Katznelson model, there was fair discrimination (0.62, 95% CI: 0.58-0.66) and good calibration. As the original PRE-DELIRIC model was already validated externally and recalibrated in six countries, we performed a logistic calibration on the recalibrated model and found acceptable discrimination (0.75, 95% CI: 0.72-0.79) and good calibration. Decision curve analysis demonstrated that the recalibrated PRE-DELIRIC risk model was marginally more clinically useful than the Katznelson model. Current models predict delirium risk in the intensive care unit after cardiac surgery with only fair to moderate accuracy and are insufficient for routine clinical use.

Plasma uric acid effects on glomerular haemodynamic profile of patients with uncomplicated Type 1 diabetes mellitus.

AIMS: Increased plasma uric acid (PUA) levels are associated with impaired renal function in patients with Type 1 diabetes, but the mechanisms are not well understood. Our aim was to evaluate whether higher PUA levels are associated with increased afferent arteriolar resistance in patients with Type 1 diabetes vs. healthy controls, thereby influencing renal function. METHODS: PUA, GFR (inulin) and effective renal plasma flow (ERPF; para-aminohippurate) were measured in 70 otherwise healthy patients with Type 1 diabetes and 60 healthy controls. Gomez's equations were used to estimate afferent (RA ) and efferent (RE ) arteriolar resistances, glomerular hydrostatic pressure (PGLO ) and filtration pressure (ΔPF ). The relationships between PUA and glomerular haemodynamic parameters were evaluated by univariable linear regression correlation coefficients. RESULTS: In patients with Type 1 diabetes, higher PUA correlated with lower PGLO (P = 0.002) and ΔPF (P = 0.0007), with higher RA (P = 0.001), but not with RE (P = 0.55). These associations were accompanied by correlations between higher PUA with lower GFR (P = 0.0007), ERPF (P = 0.008), RBF (P = 0.047) and higher RVR (P = 0.021). There were no significant correlations between PUA and renal haemodynamic parameters in the healthy controls. CONCLUSIONS: The association between higher PUA with lower GFR and lower ERPF in patients with Type 1 diabetes is driven by alterations in the estimated RA . PUA-mediated RA may be caused by increased tone or thickening of the afferent renal arteriole, which might potentiate renal injury by causing ischaemia to the renal microcirculation.

Glomerular haemodynamic profile of patients with Type 1 diabetes compared with healthy control subjects.

AIMS: To evaluate the glomerular haemodynamic profile of patients with Type 1 diabetes with either renal hyperfiltration (GFR ≥ 135 ml/min/1.73 m2 ) or renal normofiltration (GFR 90-134 ml/min/1.73 m2 ) during euglycaemic and hyperglycaemic conditions, and to compare this profile with that of a similar group of healthy control subjects. METHODS: Gomez's equations were used to derive afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. RESULTS: At baseline, during clamped euglycaemia, patients with Type 1 diabetes and hyperfiltration had lower mean ± sd afferent arteriolar resistance than both those with Type 1 diabetes and normofiltration (914 ± 494 vs. 2065 ± 597 dyne/s/cm5 ; P < 0.001) and healthy control subjects (1676 ± 707 dyne/s/cm(5) ; p < 0.001). By contrast, efferent arteriolar resistance was similar in the three groups. Patients with Type 1 diabetes and hyperfiltration also had higher mean ± sd glomerular hydrostatic pressure than both healthy control subjects and patients with Type 1 diabetes and normofiltration (66 ± 6 vs. 60 ± 3 vs. 55 ± 3 mmHg; P < 0.05). Similar findings for afferent arteriolar resistance, efferent arteriolar resistance, glomerular hydrostatic pressure and filtration pressure were observed during clamped hyperglycaemia. CONCLUSION: Hyperfiltration in Type 1 diabetes is primarily driven by alterations in afferent arteriolar resistance rather than efferent arteriolar resistance. Renal protective therapies should focus on afferent renal arteriolar mechanisms through the use of pharmacological agents that target tubuloglomerular feedback, including sodium-glucose cotransporter 2 inhibitors and incretins.

The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus.

AIMS/HYPOTHESIS: High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. METHODS: Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFRINULIN] ≥ 135 ml min⁻¹ 1.73 m⁻², n = 28) or normofiltration (n = 21) and healthy control individuals (n = 18). RESULTS: Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165 ± 9 vs 113 ± 2 and 116 ± 4 ml min⁻¹ 1.73 m⁻², respectively, p < 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p < 0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p ≤ 0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p < 0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p < 0.01). CONCLUSIONS/INTERPRETATION: Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.

Optimal water supply reservoir operation by leveraging the meta-heuristic Harris Hawks algorithms and opposite based learning technique.

To ease water scarcity, dynamic programming, stochastic dynamic programming, and heuristic algorithms have been applied to solve problem matters related to water resources. Development, operation, and management are vital in a reservoir operating policy, especially when the reservoir serves a complex objective. In this study, an attempt via metaheuristic algorithms, namely the Harris Hawks Optimisation (HHO) Algorithm and the Opposite Based Learning of HHO (OBL-HHO) are made to minimise the water deficit as well as mitigate floods at downstream of the Klang Gate Dam (KGD). Due to trade-offs between water supply and flood management, the HHO and OBL-HHO models have configurable thresholds to optimise the KGD reservoir operation. To determine the efficacy of the HHO and OBL-HHO in reservoir optimisation, reliability, vulnerability, and resilience are risk measures evaluated. If inflow categories are omitted, the OBL-HHO meets 71.49% of demand compared to 54.83% for the standalone HHO. The HHO proved superior to OBL-HHO in satisfying demand during medium inflows, achieving 38.60% compared to 20.61%, even though the HHO may have experienced water loss at the end of the storage level. The HHO is still a promising method, as proven by its reliability and resilience indices compared to other published heuristic algorithms: at 62.50% and 1.56, respectively. The Artificial Bee Colony (ABC) outcomes satisfied demand at 61.36%, 59.47% with the Particle Swarm Optimisation (PSO), 55.68% with the real-coded Genetic Algorithm (GA), and 23.5 percent with the binary GA. For resilience, the ABC scored 0.16, PSO scored 0.15, and real coded GA scored 0.14 whilst the binary-GA has the worst failure recovery algorithm with 0.09.

Reversible posterior leukoencephalopathy syndrome in Chinese children induced by chemotherapy: a review of five cases.

This is a retrospective review of the clinico-radiological features and neurological outcomes of reversible posterior leukoencephalopathy syndrome episodes in Chinese cancer children receiving chemotherapy in a regional hospital in Hong Kong from 1998 to 2008. Five children (3 males and 2 females) with a mean age of 7 years were identified, four of whom had acute lymphoblastic leukaemia and one had a central nervous system germ cell tumour. Presenting symptoms included seizures (100%), altered mental function (100%), headache (40%), and visual disturbance (60%). The mean systolic blood pressure at presentation was 158 mm Hg. Approximately 80% had typical radiological features of reversible posterior leukoencephalopathy syndrome. All showed complete recovery after the acute stage, but one subsequently developed epilepsy. Two patients ultimately died of refractory malignant disease. Two others were followed up for a mean of 6 years, and remained neurologically normal. This report was the first case review documenting reversible posterior leukoencephalopathy syndrome in Chinese cancer children. The clinico-radiological features and neurological outcomes were similar to those reported in western series. Early recognition of the syndrome is important to facilitate appropriate treatment. The central nervous system damage may not be reversible and thus long-term follow-up is warranted.

Self-driving laboratory for accelerated discovery of thin-film materials.

Discovering and optimizing commercially viable materials for clean energy applications typically takes more than a decade. Self-driving laboratories that iteratively design, execute, and learn from materials science experiments in a fully autonomous loop present an opportunity to accelerate this research process. We report here a modular robotic platform driven by a model-based optimization algorithm capable of autonomously optimizing the optical and electronic properties of thin-film materials by modifying the film composition and processing conditions. We demonstrate the power of this platform by using it to maximize the hole mobility of organic hole transport materials commonly used in perovskite solar cells and consumer electronics. This demonstration highlights the possibilities of using autonomous laboratories to discover organic and inorganic materials relevant to materials sciences and clean energy technologies.

Identification of ubiquitin ligases required for skeletal muscle atrophy.

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations: In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background: In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose: The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations: An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion: In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

The Critical Care Society of Southern Africa Consensus Statement on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), intensive care is faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience daily the consequences of limited resources. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are frequently necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this consensus statement is to examine key questions that arise when considering the status of ICU resources in SA, and more specifically ICU admission, rationing and triage decisions. The accompanying guideline in this issue is intended to guide frontline triage policy and ensure the best utilisation of intensive care in SA, while maintaining a fair distribution of available resources. Fair and efficient triage is important to ensure the ongoing provision of high-quality care to adult patients referred for intensive care. Recommendations. In response to 14 key questions developed using a modified Delphi technique, 29 recommendations were formulated and graded using an adapted GRADE score. The 14 key questions addressed the status of the provision of ICU services in SA, the degree of resource restriction, the efficiency of resource management, the need for triage, and how triage could be most justly implemented. Important recommendations included the need to formally recognise and accurately quantify the provision of ICU services in SA by national audit; actively seek additional resources from governmental bodies; consider methods to maximise the efficiency of ICU care; evaluate lower level of care alternatives; develop a triage guideline to assist policy-makers and frontline practitioners to implement triage decisions in an efficient and fair way; measure and audit the consequence of triage; and promote research to improve the accuracy and consistency of triage decisions. The consensus document and guideline should be reviewed and revised appropriately within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, recommendations and a guideline have been developed to guide policy-making and assist frontline triage decision-making in SA. These documents are not a complete plan for quality practice but rather the beginning of a long-term initiative to engage clinicians, the public and administrators in appropriate triage decision-making, and promote systems that will ultimately maximise the efficient and fair use of available ICU resources.

The Critical Care Society of Southern Africa Consensus Guideline on ICU Triage and Rationing (ConICTri).

Background. In South Africa (SA), administrators and intensive care practitioners are faced with the challenge of resource scarcity as well as an increasing demand for intensive care unit (ICU) services. ICU services are expensive, and practitioners in low- to middle-income countries experience the consequences of limited resources daily. Critically limited resources necessitate that rationing and triage (prioritisation) decisions are routinely necessary in SA, particularly in the publicly funded health sector. Purpose. The purpose of this guideline is to utilise the relevant recommendations of the associated consensus meeting document and other internationally accepted principles to develop a guideline to inform frontline triage policy and ensure the best utilisation of adult intensive care in SA, while maintaining the fair distribution of available resources. Recommendations. An overall conceptual framework for the triage process was developed. The components of the framework were developed on the basis that patients should be admitted preferentially when the likely incremental medical benefit derived from ICU admission justifies admission. An estimate of likely resource use should also form part of the triage decision, with those patients requiring relatively less resources to achieve substantial benefit receiving priority for admission. Thus, the triage system should maximise the benefits obtained from ICU resources available for the community. Where possible, practical examples of what the consensus group agreed would be considered appropriate practice under specified South African circumstances were provided, to assist clinicians with practical decision-making. It must be stressed that this guideline is not intended to be prescriptive for individual hospital or regional practice, and hospitals and regions are encouraged to develop specified local guidelines with locally relevant examples. The guideline should be reviewed and revised if appropriate within 5 years. Conclusion. In recognition of the absolute need to limit patient access to ICU because of the lack of sufficient intensive care resources in public hospitals, this guideline has been developed to guide policy-making and assist frontline triage decision-making in SA. This document is not a complete plan for quality practice, but rather a template to support frontline clinicians, guide administrators and inform the public regarding appropriate triage decision-making.

Oral features in Kabuki make-up Syndrome.

AIM: Kabuki make-up Syndrome is so named because of the characteristic facies of the affected patient. The face is similar to a Kabuki actor's mask. The main aim of this report was to describe the oral features in Kabuki Syndrome, focusing on the tooth anomalies. PATIENTS AND METHODS: Five subjects with Kabuki Syndrome, identified by the Child Neuropsychiatric Clinic of the University of Sassari, Italy, were enrolled. Their medical records were reviewed and oral and dental examinations were completed. The diagnosis was based upon the typical pattern of malformations and dysmorphic features reviewed by Matsumoto and Niikawa. RESULTS: All patients showed typical characteristics of the Syndrome such as a long palpebral fissure, lower palpebral eversion, arched eyebrows, short nasal septum, prominent and large ears, fingertip pads, mental retardation, and paramedian elevation of the lower lip. CONCLUSION: Kabuki make-up Syndrome is of unknown origin but a genetic aetiopathogenesis has been proposed. It is extremely rare; in Japan, where it is most frequent, it affects 1:32000 newborns. The typical facies of the syndrome, combined with general medical and dental examinations, are very important for diagnosis confirmation.

Cognition in multiple sclerosis: Between cognitive reserve and brain volume.

BACKGROUND: Several correlations between cognitive impairment (CI), radiologic markers and cognitive reserve (CR) have been documented in MS. OBIECTIVE: To evaluate correlation between CI and brain volume (BV) considering CR as possibile mitigating factor. METHODS: 195 relapsing MS patients underwent a neuropsychological assessment using BICAMS. BV was estimated using SIENAX to obtain normalized volume of brain (NBV), white matter (NWV), gray matter (NGV) and cortical gray matter (CGV). CR was estimated using a previously validated tool. RESULTS: Pearson test showed a correlation between the symbol digit modality test (SDMT) score and NBV (r=0.38; p<0.000) NGV(r=0.31; p<0.000), CGV (r=0.35; p<0.000) and CRI score(r=0.42; p<0.000). Linear regression (dependent variable:SDMT) showed a relationship with CR scores (p=0.000) and NGV(p<0.000). A difference was detected between cognitive impaired and preserved patients regarding mean of NBV(p=0.002), NGV(p=0.007), CGV(p=0.002) and CR Scores (p=0.007). Anova showed a association between the presence of CI (dependent variable) and the interaction term CRIQ × CGV (p=0.004) whit adjustment for age and disability evaluated by EDSS. CONCLUSIONS: Our study shows a correlation between cognition and BV, in particular gray matter volume. Cognitive reserve is also confirmed as an important element playing a role in the complex interaction to determine the cognitive functions in MS.

A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides.

BACKGROUND: Signal transduction by growth factor receptor protein-tyrosine kinases is generally initiated by autophosphorylation on tyrosine residues following ligand binding. Phosphotyrosines within activated receptors form binding sites for the Src homology 2 (SH2) domains of cytoplasmic signalling proteins. One such protein, Shc, is tyrosine phosphorylated in response to a large number of growth factors and cytokines. Phosphorylation of Shc on tyrosine residue Y317 allows binding to the SH2 domain of Grb2, and hence stimulation of the Ras pathway. Shc is therefore implicated as an adaptor protein able to couple normal and oncogenic protein-tyrosine kinases to Ras activation. Shc itself contains an SH2 domain at its carboxyl terminus, but the function of the amino-terminal half of the protein is unknown. RESULTS: We have found that the Shc amino-terminal region binds to a number of tyrosine-phosphorylated proteins in v-src-transformed cells. This domain also bound directly to the activated epidermal growth factor (EGF) receptor. A phosphotyrosine (pY)-containing peptide modeled after the Shc-binding site in polyoma middle T antigen (LLSNPTpYSVMRSK) was able to compete efficiently with the activated EGF receptor for binding to the Shc amino terminus. This competition was dependent on phosphorylation of the tyrosine residue within the peptide, and was abrogated by deletion of the leucine residue at position -5. The Shc amino-terminal domain also bound to the autophosphorylated nerve growth factor receptor (Trk), but bound significantly less well to a mutant receptor in which tyrosine Y490 in the receptor's Shc-binding site had been substituted by phenylalanine. CONCLUSION: These data implicate the amino-terminal region of Shc in binding to activated receptors and other tyrosine-phosphorylated proteins. Binding appears to be specific for phosphorylated tyrosine residues within the sequence NPXpY, which is conserved in many Shc-binding sites. The Shc amino-terminal region bears only very limited sequence identify to known SH2 domains, suggesting that it represents a new class of phosphotyrosine-binding modules. Consistent with this view, the amino-terminal Shc domain is highly conserved in a Drosophila Shc homologue. Binding of Shc to activated receptors through its amino terminus could leave the carboxy-terminal SH2 domain free for other interactions. In this way, Shc may function as an adaptor protein to bring two tyrosine-phosphorylated proteins together.

Inflammatory myofibroblastic tumor of the nasal cavity.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor with a variable natural history and biologic behavior, ranging from completely benign to malignant with fatal outcome. We report a case of benign IMT in the left nasal cavity with radiologic features mimicking angiofibroma. We also demonstrate the hypervascular nature of this disease on angiography and the contribution of preoperative embolization in assisting surgical excision and minimizing the potential uncontrolled intraoperative bleeding.

Accelerated mammary tumor development in mutant polyomavirus middle T transgenic mice expressing elevated levels of either the Shc or Grb2 adapter protein.

The Grb2 and Shc adapter proteins play critical roles in coupling activated growth factor receptors to several cellular signaling pathways. To assess the role of these molecules in mammary epithelial development and tumorigenesis, we have generated transgenic mice which individually express the Grb2 and Shc proteins in the mammary epithelium. Although mammary epithelial cell-specific expression of Grb2 or Shc accelerated ductal morphogenesis, mammary tumors were rarely observed in these strains. To explore the potential role of these adapter proteins in mammary tumorigenesis, mice coexpressing either Shc or Grb2 and a mutant form of polyomavirus middle T (PyV mT) antigen in the mammary epithelium were generated. Coexpression of either Shc or Grb2 with the mutant PyV mT antigen resulted in a dramatic acceleration of mammary tumorigenesis compared to parental mutant PyV mT strain. The increased rate of tumor formation observed in these mice was correlated with activation of the epidermal growth factor receptor family and mitogen-activated protein kinase pathway. These observations suggest that elevated levels of the Grb2 or Shc adapter protein can accelerate mammary tumor progression by sensitizing the mammary epithelial cell to growth factor receptor signaling.