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1.  Alpha-1 proteinase inhibitors for the treatment of alpha-1 antitrypsin deficiency: safety, tolerability, and patient outcomes 
Alpha-1 antitrypsin (AAT) deficiency remains an underrecognized genetic disease with predominantly pulmonary and hepatic manifestations. AAT is derived primarily from hepatocytes; however, macrophages and neutrophils are secondary sources. As the natural physiological inhibitor of several proteases, most importantly neutrophil elastase (NE), it plays a key role in maintaining pulmonary protease–antiprotease balance. In deficient states, unrestrained NE activity promotes damage to the lung matrix, causing structural defects and impairing host defenses. The commonest form of AAT deficiency results in a mutated Z AAT that is abnormally folded, polymerized, and aggregated in the liver. Consequently, systemic levels are lower, resulting in diminished pulmonary concentrations. Hepatic disease occurs due to liver aggregation of the protein, while lung destruction ensues from unopposed protease-mediated damage. In this review, we will discuss AAT deficiency, its clinical manifestations, and augmentation therapy. We will address the safety and tolerability profiles of AAT replacement in the context of patient outcomes and cost-effectiveness and outline future directions for work in this field.
PMCID: PMC4321641
alpha-1; augmentation; deficiency; replacement; emphysema
2.  The association between dental and periodontal diseases and sickle cell disease. A pilot case-control study 
The Saudi Dental Journal  2014;27(1):40-43.
This is a pilot case-control study conducted to investigate the prevalence of dental caries and periodontal disease and examine the possible association between oral health deterioration and SCD severity in a sample of Saudi SCD patients residing in the city of Al-Qatif, Eastern Province, Saudi Arabia.
Materials and methods
Dental examination to determine the Decayed, Missing and Filled Teeth index (DMFT), Community Periodontal Index (CPI), and plaque index system were recorded for 33 SCD patients and 33 age and sex-matched controls in the Al-Qatif Central Hospital, Qatif, Saudi Arabia. Self-administered surveys used to assess socio-economic status; oral health behaviors for both SCD patients and controls were recorded. In addition, the disease severity index was established for all patients with SCD. SPSS data analysis software package version 18.0 was used for statistical analysis. Numerical variables were described as mean with a standard deviation.
Decayed teeth were significantly more in individuals with ages ranging from 18 to 38 years with SCD compared to the control group (p = 0.036) due to oral hygiene negligence. The mean number of filled teeth was significantly lower in individuals with SCD when compared to the control group (p = 0.015) due to the lack of appropriate and timely treatment reflected in the survey responses of SCD patients as 15.2% only taking oral care during hospitalization. There were differences between the cases and controls in the known caries risk factors such as income level, flossing, and brushing habit. The DMFT, CPI, and plaque index systems did not differ significantly between the SCD patients and the control group.
Data suggest that patients with SCD have increased susceptibility to dental caries, with a higher prevalence of tooth decay and lower prevalence of filled teeth. Known caries risk factors influenced oral health more markedly than did factors related to SCD.
PMCID: PMC4273253  PMID: 25544813
Sickle cell disease; Dental caries; Periodontal
3.  Physician user satisfaction with an electronic medical records system in primary healthcare centres in Al Ain: a qualitative study 
BMJ Open  2014;4(11):e005569.
To explore physician satisfaction with an electronic medical records (EMR) system, to identify and explore the main limitations of the system and finally to submit recommendations to address these limitations.
A descriptive qualitative study that entailed three focus group interviews was performed among physicians using open-ended questions. The interviews were audiotaped, documented and transcribed verbatim. The themes were explored and analysed in different categories.
The study was conducted in primary healthcare centres (PHC) in Al Ain, United Arab Emirates (UAE).
A total of 23 physicians, all using the same EMR system, attended one of three focus groups held in PHC in Al Ain Medical District. Each focus group consisted of 7–9 physicians working in PHC as family medicine specialists, residents or general practitioners.
Primary outcome measure
Physician satisfaction with the EMR system.
Key themes emerged and were categorised as physician-dependent, patient-related and system-related factors. In general, physicians were satisfied with the EMR system in spite of initial difficulties with implementation. Most participants identified that the long time required to do the documentation affected their practice and patient communication. Many physicians expressed satisfaction with the orders and results of laboratory and radiology functions and they emphasised that this was the strongest point in the EMR. They were also satisfied with the electronic prescription function, stating that it reduced errors and saved time.
Physicians are satisfied with the EMR and have a positive perception regarding the application of the system. Several themes emerged during this study that need to be considered to enhance the EMR system. Further studies need to be conducted among other healthcare practitioners and patients to explore their attitude and perception about the EMR.
PMCID: PMC4225459  PMID: 25377010
EMR; Electronic health records; physician satisfaction; computerized health information
4.  Interventions to improve outpatient referrals from primary care to secondary care 
The primary care specialist interface is a key organisational feature of many health care systems. Patients are referred to specialist care when investigation or therapeutic options are exhausted in primary care and more specialised care is needed. Referral has considerable implications for patients, the health care system and health care costs. There is considerable evidence that the referral processes can be improved.
To estimate the effectiveness and efficiency of interventions to change outpatient referral rates or improve outpatient referral appropriateness.
Search methods
We conducted electronic searches of the Cochrane Effective Practice and Organisation of Care (EPOC) group specialised register (developed through extensive searches of MEDLINE, EMBASE, Healthstar and the Cochrane Library) (February 2002) and the National Research Register. Updated searches were conducted in MEDLINE and the EPOC specialised register up to October 2007.
Selection criteria
Randomised controlled trials, controlled clinical trials, controlled before and after studies and interrupted time series of interventions to change or improve outpatient referrals. Participants were primary care physicians. The outcomes were objectively measured provider performance or health outcomes.
Data collection and analysis
A minimum of two reviewers independently extracted data and assessed study quality.
Main results
Seventeen studies involving 23 separate comparisons were included. Nine studies (14 comparisons) evaluated professional educational interventions. Ineffective strategies included: passive dissemination of local referral guidelines (two studies), feedback of referral rates (one study) and discussion with an independent medical adviser (one study). Generally effective strategies included dissemination of guidelines with structured referral sheets (four out of five studies) and involvement of consultants in educational activities (two out of three studies). Four studies evaluated organisational interventions (patient management by family physicians compared to general internists, attachment of a physiotherapist to general practices, a new slot system for referrals and requiring a second ‘in-house’ opinion prior to referral), all of which were effective. Four studies (five comparisons) evaluated financial interventions. One study evaluating change from a capitation based to mixed capitation and fee-for-service system and from a fee-for-service to a capitation based system (with an element of risk sharing for secondary care services) observed a reduction in referral rates. Modest reductions in referral rates of uncertain significance were observed following the introduction of the general practice fundholding scheme in the United Kingdom (UK). One study evaluating the effect of providing access to private specialists demonstrated an increase in the proportion of patients referred to specialist services but no overall effect on referral rates.
Authors’ conclusions
There are a limited number of rigorous evaluations to base policy on. Active local educational interventions involving secondary care specialists and structured referral sheets are the only interventions shown to impact on referral rates based on current evidence. The effects of ‘in-house’ second opinion and other intermediate primary care based alternatives to outpatient referral appear promising.
PMCID: PMC4164370  PMID: 18843691
*Medicine [organization & administration; standards]; *Outpatients; *Practice Guidelines as Topic; *Primary Health Care [economics; organization & administration; standards]; *Specialization; Controlled Clinical Trials as Topic; Economics, Medical; Family Practice [economics; organization & administration; standards]; Information Dissemination; Referral and Consultation [economics; organization & administration; *standards]; Humans
5.  Physiological levels of lipoxin A4 inhibit ENaC and restore airway surface liquid height in cystic fibrosis bronchial epithelium 
Physiological Reports  2014;2(8):e12093.
In cystic fibrosis (CF), the airway surface liquid (ASL) is depleted. We previously demonstrated that lipoxin A4 (LXA4) can modulate ASL height (ASLh) through actions on Cl− transport. Here, we report novel effects of lipoxin on the epithelial Na+ channel ENaC in this response. ASL dynamics and ion transport were studied using live‐cell confocal microscopy and short‐circuit current measurements in CF (CuFi‐1) and non‐CF (NuLi‐1) cell cultures. Low physiological concentrations of LXA4 in the picomolar range produced an increase in ASLh which was dependent on inhibition of an amiloride‐sensitive Na+ current and stimulation of a bumetanide‐sensitive Cl− current. These ion transport and ASLh responses to LXA4 were blocked by Boc‐2 an inhibitor of the specific LXA4 receptor ALX/FPR2. LXA4 affected the subcellular localization of its receptor and enhanced the localization of ALX/FPR2 at the apical membrane of CF cells. Our results provide evidence for a novel effect of low physiological concentrations of LXA4 to inhibit airway epithelial Na+ absorption that results in an ASL height increase in CF airway epithelia.
LXA4 induced apical membrane ALX/FPR2 localization in CuFi‐1 monolayers. LXA4 induced an apical increase of ALX/FPR2 (green) expression (B). Primary rabbit anti‐ALX/FPR2 antibody and secondary Alexa‐Fluor 488 anti‐rabbit were used to label the ALX/FPR2 receptor. Localization of the receptor at the apical surface is shown in the merged fluorochrome images in yellow (A). Rhodamine‐phalloidin was used to stain f‐actin and DAPI used to stain the nuclei (C).
PMCID: PMC4246599  PMID: 25107986
Cystic fibrosis; ENaC; lipoxin A4
6.  Study of Leptin and Adiponectin as Disease Markers in Subjects with Obstructive Sleep Apnea 
Disease Markers  2014;2014:706314.
Background. Published studies showed conflicting results of the associations between adiponectin and leptin levels and obstructive sleep apnoea (OSA). In obese patients, plasma leptin is elevated and adiponectin is decreased, and we postulate that these adipokines could be potential markers of clinical and metabolic perturbations in patients with OSA. Methods. 147 patients with suspected OSA had polysomnography to determine the Respiratory Disturbance Index (RDI). We measured fasting plasma glucose (FPG), fasting serum insulin, plasma leptin, adiponectin, and full lipid profile. Patients were classified on the basis of the RDI, degree of adiposity, and insulin resistance (IR) (homeostasis model assessment of insulin resistance (HOMAIR)). Results. 28.6% of subjects had normal polysomnography, 34.8% had mild OSA, 19.6% had moderate OSA, and 17% had severe OSA. Obesity was more prevalent in subjects with moderate-severe OSA (47%). Adiponectin decreased significantly (P = 0.041) with increasing severity of OSA. Though BMI was significantly higher in subjects with severe OSA, paradoxically, leptin was lowest in those subjects independent of gender dimorphism. Conclusions. Adiponectin is an independent marker of disease severity in patients with OSA. The paradoxical decrease in circulating leptin, which suggests impaired secretion, deserves further studies as a potential marker of severe OSA.
PMCID: PMC4058890  PMID: 24982545
7.  Amelioration of azoxymethane induced-carcinogenesis by reducing oxidative stress in rat colon by natural extracts 
Azoxymethane (AOM) is a potent carcinogenic agent commonly used to induce colon cancer in rats; the cytotoxicity of AOM is considered to mediate oxidative stress. This study investigated the chemopreventive effect of three natural extracts [pomegranate peel extract (PomPE), papaya peel extract (PapPE) and seaweed extract (SE)] against AOM-induced oxidative stress and carcinogenesis in rat colon.
Eighty Sprague–Dawley rats (aged 4 weeks) were randomly divided into 8 groups (10 rats/group). Control group was fed a basal diet; AOM-treated group was fed a basal diet and received AOM intraperitonial injections for two weeks at a dose of 15 mg/kg bodyweight, whereas the other six groups were received oral supplementation of PomPE, PapPE or SE, in the presence or absence of AOM injection. All animals were continuously fed ad-libitum until aged 16 weeks, then all rats were sacrificed and the colon tissues were examined microscopically for pathological changes and aberrant crypt foci (ACF) development, genotoxicity (induced micronuclei (MN) cells enumeration), and glutathione and lipid peroxidation.
Our results showed that AOM-induced ACF development and pathological changes in the colonic mucosal tissues, increased bone marrow MN cells and oxidative stress (glutathione depletion, lipid peroxidation) in rat colonic cells. The concomitant treatment of AOM with PomPE, PapPE or SE significantly ameliorated the cytotoxic effects of AOM.
The results of this study provide in-vivo evidence that PomPE, PapPE and SE reduced the AOM-induced colon cancer in rats, through their potent anti-oxidant activities.
PMCID: PMC3932801  PMID: 24533833
Azoxymethane; Oxidative stress; Colon cancer
8.  Procedural and clinical utility of transulnar approach for coronary procedures following failure of radial route: Single centre experience 
To assess the feasibility and safety of transulnar approach whenever transradial access fails.
Radial access for coronary procedures has gained sound recognition. However, the method is not always successful.
Between January 2010 and June 2013, diagnostic with or without percutaneous coronary intervention (PCI) was attempted in 2804 patients via the radial approach. Transradial approach was unsuccessful in 173 patients (6.2%) requiring crossover to either femoral (128 patients, 4.6%) or ulnar approach (45 patients, 1.6%). Patients who had undergone ulnar approach constituted our study population. Selective forearm angiography was performed after ulnar sheath placement. We documented procedural characteristics and major adverse cardio-cerebrovascular events.
Radial artery spasm was the most common cause of crossover to the ulnar approach (64.4%) followed by failure to puncture the radial artery (33.4%). Out of 45 patients (82.2%), 37 underwent successful ulnar approach. The eight failed cases (17.8%) were mainly due to absent or weak ulnar pulse (75%). PCI was performed in 17 cases (37.8%), of which 8 patients underwent emergency interventions. Complications included transient numbness, non-significant hematoma, ulnar artery perforation, and minor stroke in 15.5%, 13.3%, 2.2% and 2.2%, respectively. No major cardiac-cerebrovascular events or hand ischemia were noted.
Ulnar approach for coronary diagnostic or intervention procedures is a feasible alternative whenever radial route fails. It circumvents crossover to the femoral approach. Our study confirms satisfactory success rate of ulnar access in the presence of adequate ulnar pulse intensity and within acceptable rates of complications.
PMCID: PMC4062755  PMID: 24954986
Coronary procedures; Ulnar; Radial; Femoral approach; Alternative; Feasible; MACCE
10.  Assessment of Truflex™ articulating stylet versus conventional rigid Portex™ stylet as an intubation guide with the D-blade of C-Mac™ videolaryngoscope during elective tracheal intubation: study protocol for a randomized controlled trial 
Trials  2013;14:298.
A variety of videolaryngoscopes with angulated blade have been recently introduced into clinical practice. They provide an indirect view of the glottic structures in normal and challenging clinical settings. Despite the very good visualization of the laryngeal structures by these devices, the insertion and advancement of the endotracheal tube may be prolonged and occasionally fail as it does not conform to the enhanced angulation of the blade. To overcome this handicap, it is recommended to use a pre-shaped, styleted tracheal tube during intubation. Unfortunately, these malleable rigid stylets permit only a fixed shape to the advancing endotracheal tube. This may necessitate withdrawal of endotracheal tube-stylet assembly for reshaping, before undertaking a new attempt. This may cause soft tissue injury and hemodynamic disturbance.
This single-blinded randomized clinical trial aims to overcome these handicaps using a novel method of dynamically changing the shape of the advancing endotracheal tube by Truflex™ articulating stylet as per need during D-blade C-Mac™ videolaryngoscopy.
One hundred and fifty four patients between 18 and 60 years of age belonging to either sex undergoing tracheal intubation under uniform general anesthetic technique will be randomly divided into Portex™ malleable stylet group and Truflex™ articulating stylet group. The primary efficacy variable of success/failure between the two groups will be analyzed using the chi square test. For comparison of intubation times and the Intubation Difficulty Score, ANOVA will be used. Primary efficacy endpoint results will be successful or failed tracheal intubation in the first attempt, total intubation time and the intubation difficulty score. Secondary efficacy endpoints will be overall user satisfaction graded from 1 to 10 (1 = very poor, 10 = excellent), Cormack and Lehane’s grading, glotticoscopy time and ETT negotiation time and total number of intubation attempts. Result of safety endpoints will include dental and airway trauma, hemodynamic disturbances, arrhythmias or cardiac arrest.
Trial registration
Current Controlled Trials ISRCTN57679531; Date of registration 12/02/2013
PMCID: PMC3848553  PMID: 24041300
Videolaryngoscope; Tracheal intubation; Truflex stylet
11.  Aspergillus-Associated Airway Disease, Inflammation, and the Innate Immune Response 
BioMed Research International  2013;2013:723129.
Aspergillus moulds exist ubiquitously as spores that are inhaled in large numbers daily. Whilst most are removed by anatomical barriers, disease may occur in certain circumstances. Depending on the underlying state of the human immune system, clinical consequences can ensue ranging from an excessive immune response during allergic bronchopulmonary aspergillosis to the formation of an aspergilloma in the immunocompetent state. The severest infections occur in those who are immunocompromised where invasive pulmonary aspergillosis results in high mortality rates. The diagnosis of Aspergillus-associated pulmonary disease is based on clinical, radiological, and immunological testing. An understanding of the innate and inflammatory consequences of exposure to Aspergillus species is critical in accounting for disease manifestations and preventing sequelae. The major components of the innate immune system involved in recognition and removal of the fungus include phagocytosis, antimicrobial peptide production, and recognition by pattern recognition receptors. The cytokine response is also critical facilitating cell-to-cell communication and promoting the initiation, maintenance, and resolution of the host response. In the following review, we discuss the above areas with a focus on the innate and inflammatory response to airway Aspergillus exposure and how these responses may be modulated for therapeutic benefit.
PMCID: PMC3736487  PMID: 23971044
12.  A preliminary comparison of total skin electron treatment techniques to demonstrate the application of a mid-torso phantom for measurement of dose penetration 
The British Journal of Radiology  2011;84(1008):1125-1130.
In the UK, the treatment of patients with mycosis fungoides using total skin electron (TSE) beam therapy is undertaken using a number of different irradiation techniques. As part of a review of these techniques, a comparative set of measurements would be useful to determine how the techniques differ in terms of dose distribution. A dose penetration intercomparison method that could be used as part of such a study is presented here.
The dose penetrations for six treatment techniques currently or recently used in four centres in the UK were measured. The variation of dose with skin depth was measured in a WT1 solid water mid-torso phantom. The phantom is portable and suitable to be used in all the techniques. It is designed to hold four small radiochromic film dosemeters to investigate the variation in dose around the mid-torso. For each treatment technique, the phantom was irradiated using the clinical set-up.
The phantom performed well and was able to measure dose penetration and the uniformity of penetration for several treatment techniques.
These preliminary results demonstrate that there is some variation in dose distribution between different TSE treatment techniques and that the phantom could be used in a more comprehensive intercomparison. The results are not intended to demonstrate comprehensively the range of penetration that can be achieved in clinical practice as, for one of the treatment techniques, the penetration is customised for the extent of the disease.
PMCID: PMC3473835  PMID: 21304004
13.  Lipoxin A4 Stimulates Calcium-Activated Chloride Currents and Increases Airway Surface Liquid Height in Normal and Cystic Fibrosis Airway Epithelia 
PLoS ONE  2012;7(5):e37746.
Cystic Fibrosis (CF) is a genetic disease characterised by a deficit in epithelial Cl− secretion which in the lung leads to airway dehydration and a reduced Airway Surface Liquid (ASL) height. The endogenous lipoxin LXA4 is a member of the newly identified eicosanoids playing a key role in ending the inflammatory process. Levels of LXA4 are reported to be decreased in the airways of patients with CF. We have previously shown that in normal human bronchial epithelial cells, LXA4 produced a rapid and transient increase in intracellular Ca2+. We have investigated, the effect of LXA4 on Cl− secretion and the functional consequences on ASL generation in bronchial epithelial cells obtained from CF and non-CF patient biopsies and in bronchial epithelial cell lines. We found that LXA4 stimulated a rapid intracellular Ca2+ increase in all of the different CF bronchial epithelial cells tested. In non-CF and CF bronchial epithelia, LXA4 stimulated whole-cell Cl− currents which were inhibited by NPPB (calcium-activated Cl− channel inhibitor), BAPTA-AM (chelator of intracellular Ca2+) but not by CFTRinh-172 (CFTR inhibitor). We found, using confocal imaging, that LXA4 increased the ASL height in non-CF and in CF airway bronchial epithelia. The LXA4 effect on ASL height was sensitive to bumetanide, an inhibitor of transepithelial Cl− secretion. The LXA4 stimulation of intracellular Ca2+, whole-cell Cl− currents, conductances and ASL height were inhibited by Boc-2, a specific antagonist of the ALX/FPR2 receptor. Our results provide, for the first time, evidence for a novel role of LXA4 in the stimulation of intracellular Ca2+ signalling leading to Ca2+-activated Cl− secretion and enhanced ASL height in non-CF and CF bronchial epithelia.
PMCID: PMC3360607  PMID: 22662206
14.  Emerging Burden of Frail Young and Elderly Persons in Oman 
Recent improvements in health and an increased standard of living in Oman have led to a reduction in environment-related and infectious diseases. Now the country is experiencing an epidemiological transition characterised by a baby boom, youth bulge and increasing longevity. Common wisdom would therefore suggest that Omanis will suffer less ill health. However, a survey of literature suggests that chronic non-communicable diseases are unexpectedly becoming common. This is possibly fuelled by some socio-cultural patterns specific to Oman, as well as the shortcomings of the ‘miracle’ of health and rapid modernisation. Unfortunately, such new diseases do not spare younger people; a proportion of them will need the type of care usually reserved for the elderly. In addition, due to their pervasive and refractory nature, these chronic non-communicable diseases seem impervious to the prevailing ‘cure-oriented’ health care system. This situation therefore calls for a paradigm shift: a health care system that goes beyond a traditional cure-orientation to provide care services for the chronically sick of all ages.
PMCID: PMC3327563  PMID: 22548135
Chronic disease; Non-communicable diseases; Transition, demographic; Disability; Burden of illness; Oman
15.  Pleural Fluid Analysis: Standstill or a Work in Progress? 
Pulmonary Medicine  2012;2012:716235.
Pleural fluid analysis yields important diagnostic information in pleural effusions in combination with clinical history, examination, and radiology. For more than 30 years, the initial and most pragmatic step in this process is to determine whether the fluid is a transudate or an exudate. Light's criteria remain the most robust in separating the transudate-exudate classification which dictates further investigations or management. Recent studies have led to the evaluation and implementation of a number of additional fluid analyses that may improve the diagnostic utility of this method. This paper discusses the current practice and future direction of pleural fluid analysis in determining the aetiology of a pleural effusion. While this has been performed for a few decades, a number of other pleural characteristics are becoming available suggesting that this diagnostic tool is indeed a work in progress.
PMCID: PMC3289839  PMID: 22448326
16.  An Overlooked Complication of Vancomycin Induced Acute Flaccid Paralysis in a Child with Acute Leukemia: A Case Report 
Oman Medical Journal  2011;26(4):283-284.
Vancomycin is a glycopeptide antibiotic which is commonly used to treat methicillin-resistant staphylococcal infections. It is commonly used in pediatric oncology wards for children with febrile neutropenia. We report a very rare side effect of vancomycin induced myopathy in a child with acute lymphoblastic leukemia. To the best of our knowledge, this is the first case reported from Oman.
PMCID: PMC3191713  PMID: 22043437
Vancomycin; Flaccid Paralysis; Acute Leukaemia
17.  Radical Muslim doctors and what they mean for the NHS 
BMJ : British Medical Journal  2008;336(7648):834.
PMCID: PMC2292336  PMID: 18403550
18.  Percutaneous Endoscopic Colostomy: A New Technique for the Treatment of Recurrent Sigmoid Volvulus 
Sigmoid volvulus is a common cause of large bowel obstruction in western countries and Africa. It accounts for 25% of the patients admitted to the hospital for large bowel obstruction. The acute management of sigmoid volvulus is sigmoidoscopic decompression. However, the recurrence rate can be as high as 60% in some series. Recurrent sigmoid volvulus in elderly patients who are not fit for definitive surgery is difficult to manage. The percutaneous endoscopic placement of two percutaneous endoscopic colostomy tube placement is a simple and relatively safe procedure. The two tubes should be left open to act as vents for the colon from over-distending. In our opinion, this aspect is key to its success as it keeps the sigmoid colon deflated until adhesions form between the colon and the abdominal wall.
PMCID: PMC3016501  PMID: 20339184
Sigmoid volvulus; recurrent sigmoid volvulus; PEC
19.  The Syk Protein Tyrosine Kinase Is Essential for Fcγ Receptor Signaling in Macrophages and Neutrophils 
Molecular and Cellular Biology  1998;18(7):4209-4220.
The cytoplasmic protein tyrosine kinase Syk has two amino-terminal SH2 domains that engage phosphorylated immunoreceptor tyrosine-based activation motifs in the signaling subunits of immunoreceptors. Syk, in conjunction with Src family kinases, has been implicated in immunoreceptor signaling in both lymphoid and myeloid cells. We have investigated the role of Syk in Fcγ receptor (FcγR)-dependent and -independent responses in bone marrow-derived macrophages and neutrophils by using mouse radiation chimeras reconstituted with fetal liver cells from Syk−/− embryos. Chimeric mice developed an abdominal hemorrhage starting 2 to 3 months after transplantation that was ultimately lethal. Syk-deficient neutrophils derived from the bone marrow were incapable of generating reactive oxygen intermediates in response to FcγR engagement but responded normally to tetradecanoyl phorbol acetate stimulation. Syk-deficient macrophages were defective in phagocytosis induced by FcγR but showed normal phagocytosis in response to complement. The tyrosine phosphorylation of multiple cellular polypeptides, including the FcγR γ chain, as well as Erk2 activation, was compromised in Syk−/− macrophages after FcγR stimulation. In contrast, the induction of nitric oxide synthase in macrophages stimulated with lipopolysaccharide and gamma interferon was not dependent on Syk. Surprisingly, Syk-deficient macrophages were impaired in the ability to survive or proliferate on plastic petri dishes. Taken together, these results suggest that Syk has specific physiological roles in signaling from FcγRs in neutrophils and macrophages and raise the possibility that in vivo, Syk is involved in signaling events other than those mediated by immunoreceptors.
PMCID: PMC109005  PMID: 9632805
20.  Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade. 
Molecular and Cellular Biology  1995;15(3):1162-1168.
Cellular growth control requires the coordination and integration of multiple signaling pathways which are likely to be activated concomitantly. Mitogenic signaling initiated by thyrotropin (TSH) in thyroid cells seems to require two distinct signaling pathways, a cyclic AMP (cAMP)-dependent signaling pathway and a Ras-dependent pathway. This is a paradox, since activated cAMP-dependent protein kinase disrupts Ras-dependent signaling induced by growth factors such as epidermal growth factor and platelet-derived growth factor. This inhibition may occur by preventing Raf-1 protein kinase from binding to Ras, an event thought to be necessary for the activation of Raf-1 and the subsequent activation of the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinases (MEKs) and MAP kinase (MAPK)/ERKs. Here we report that serum-stimulated hyperphosphorylation of Raf-1 was inhibited by TSH treatment of Wistar rat thyroid cells, indicating that in this cell line, as in other cell types, increases in intracellular cAMP levels inhibit activation of downstream kinases targeted by Ras. Ras-stimulated expression of genes containing AP-1 promoter elements was similarly inhibited by TSH. On the other hand, stimulation of thyroid cells with TSH resulted in stimulation of DNA synthesis which was Ras dependent but both Raf-1 and MEK independent. We also show that Ras-stimulated DNA synthesis required the use of this kinase cascade in untreated quiescent cells but not in TSH-treated cells. These data suggest that in TSH-treated thyroid cells, Ras might be able to signal through effectors other than the well-studied cytoplasmic kinase cascade.
PMCID: PMC230338  PMID: 7862110
21.  Differential regulation of cellular activities by GTPase-activating protein and NF1. 
Molecular and Cellular Biology  1993;13(4):2497-2503.
The regulation of the GTPase activity of the Ras proteins is thought to be a key element of signal transduction. Ras proteins have intrinsic GTPase activity and are active in signal transduction when bound to GTP but not following hydrolysis of GTP to GDP. Three cellular Ras GTPase-activating proteins (Ras-gaps) which increase the GTPase activity of wild-type (wt) Ras but not activated Ras in vitro have been identified: type I and type II GAP and type I NF1. Mutations of wt Ras resulting in lowered intrinsic GTPase activity or loss of response to cellular Ras-gap proteins are thought to be the primary reason for the transforming properties of the Ras proteins. In vitro assays show type I and type II GAP and the GAP-related domain of type I NF1 to have similar biochemical properties with respect to activation of the wt Ras GTPase, and it appears as though both type I GAP and NF1 can modulate the GTPase function of Ras in cells. Here we report the assembling of a full-length coding clone for type I NF1 and the biological effects of microinjection of Ras and Ras-gap proteins into fibroblasts. We have found that type I GAP, type II GAP, and type I NF1 show markedly different biological activities in vivo. Coinjection of type I GAP or type I NF1, but not type II GAP, with wt Ras abolished the ability of wt Ras to induce expression from an AP-1-controlled reporter gene. We also found that serum-stimulated DNA synthesis was reduced by prior injection of cells with type I GAP but not type II GAP or type I NF1. These results suggest that type I GAP, type II GAP, and type I NF1 may have different activities in vivo and support the hypothesis that while type I forms of GAP and NF1 may act as negative regulators of wt Ras, they may do so with differential efficiencies.
PMCID: PMC359570  PMID: 8455625

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