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1.  Tooth Wear Prevalence and Sample Size Determination : A Pilot Study 
Tooth wear is the non-carious loss of tooth tissue, which results from three processes namely attrition, erosion and abrasion. These can occur in isolation or simultaneously. Very mild tooth wear is a physiological effect of aging. This study aims to estimate the prevalence of tooth wear among 16-year old Malay school children and determine a feasible sample size for further study. Fifty-five subjects were examined clinically, followed by the completion of self-administered questionnaires. Questionnaires consisted of socio-demographic and associated variables for tooth wear obtained from the literature. The Smith and Knight tooth wear index was used to chart tooth wear. Other oral findings were recorded using the WHO criteria. A software programme was used to determine pathological tooth wear. About equal ratio of male to female were involved. It was found that 18.2% of subjects have no tooth wear, 63.6% had very mild tooth wear, 10.9% mild tooth wear, 5.5% moderate tooth wear and 1.8 % severe tooth wear. In conclusion 18.2% of subjects were deemed to have pathological tooth wear (mild, moderate & severe). Exploration with all associated variables gave a sample size ranging from 560 – 1715. The final sample size for further study greatly depends on available time and resources.
PMCID: PMC3341919  PMID: 22589636
pilot study; tooth wear; prevalence and sample size determination
2.  Comparison of Plateletpheresis on the Fenwal Amicus and Fresenius Com.Tec Cell Separators 
A variety of apheresis devices are now available on the market for plateletapheresis. We compared two apheresis instruments (Fenwal Amicus and Fresenius COM.TEC) with regard to processing time, platelet (PLT) yield and efficiency, and white blood cell (WBC) content.
Material and Methods
Donors undergoing plateletpheresis were randomly separated into two groups (either the Amicus or the COM.TEC cell separator).
In the pre-apheresis setting, 32 plateletpheresis procedures performed with each instrument revealed no significant differences in donors’ sex, age, weight, height and total blood volume between the two groups. However, the pre-apheresis PLT count was higher with the COM.TEC than with the Amicus (198 × 103/μl vs. 223 × 103/μl; p = 0.035). The blood volume processed to reach a target PLT yield of ≥3.3 × 1011 was higher in the COM.TEC compared to the Amicus (3,481 vs. 2,850 ml; p < 0.001). The median separation time was also significantly longer in the COM.TEC than in the Amicus (61 vs. 44 min; p < 0.001). 91 and 88% of the PLT products collected with the Amicus and the COM.TEC, respectively, had a PLT count of >3.3 × 1011 (p = 0.325). All products obtained with both instruments had WBC counts lower than 5 ↔ 106, as required. There was no statistical difference with regard to collection efficiency between the devices (55 ± 15 vs. 57 ± 15%; p = 0.477). However, the collection rate was significantly higher with the Amicus compared to the COM.TEC instrument (0.077 ± 0.012 × 1011 vs. 0.057 ± 0.008 × 1011 PLT/min; p < 0.001).
Both instruments collected platelets efficiently. Additionally, consistent leukoreduction was obtained with both instruments; however, compared with the COM.TEC instrument, the Amicus reached the PLT target yield more quickly.
PMCID: PMC3076329  PMID: 21512626
Plateletpheresis; Apheresis; Amicus; COM.TEC; Cell separator
3.  OS-1: Prevalence of Oral Lesions and Dentition Status among Non Smoking Diabetes Patients Attending HUSM Diabetic Clinic 
To determine the prevalence of oral mucosal lesions and dentition status among non smoking diabetes patients attending the Diabetic Clinic at Hospital Universiti Sains Malaysia (HUSM).
Patients and Method:
This cross sectional case-control study involved 300 diabetic case and 300 non-diabetic control subjects. Data was collected from November 2007 till March 2008. Demographic information, duration and type of diabetes, glycosylated hemoglobin values (HbAc), medical complications, history and current use of medication was obtained from medical records. Detail oral examination of the oral cavity was done based on international criteria and WHO codes. The number of remaining teeth and presence of dentures were also noted.
There were more females in cases (67.7%) and controls (57.7%). Mean age in both groups was comparable. A higher percentage of subjects were in the 40–59 years age group. Most had type II diabetes (94.3%). About 42.3% had diabetes within the last five years followed by 35.5% who had diabetes between 5–10 years duration and 22.3% had diabetes for more than ten years. Most diabetic subjects were on oral treatment (64.3%) and had poor metabolic control (41.7%). About 10.7% had some form of diabetes complications. The most prevalent oral lesions among diabetics were fissured tongue (29%), denture stomatitis (13.7%), geographic tongue (3.3%) and frictional keratosis (3.0%). About one third of subjects in both groups use dentures. Diabetics have significantly higher prevalence of geographic tongue (p=0.050) and denture stomatitis (p= 0.026). They have a lower mean number of remaining teeth compared to non-diabetics (p<0.001).
Discussion and Conclusion:
Having less mean number of remaining teeth and a higher prevalence of oral lesions among diabetics is a worrying outcome. Thus diabetic patients need intensive dental care and attention to minimize the disease burden.
PMCID: PMC3481260
4.  The changing patterns of bladder cancer in Egypt over the past 26 years 
Cancer causes & control : CCC  2008;19(4):421-429.
To evaluate temporal changes in histopathological types of bladder cancer and to assess associated changes in demographic, epidemiologic, and lifestyle risk factors.
We abstracted data from all available medical records from the National Cancer Institute of Cairo University (NCI-Cairo). Six calendar years representing 5-year periods between 1980 and 2005 were evaluated. Information on demographics, schistosomal infection, clinical symptoms of bladder cancer, and tumor pathology was abstracted.
During this 26-year period, important changes in the frequency of histopathological types of bladder cancer occurred. We found a statistically significant association between time period of diagnosis and histopathological type. Patients diagnosed in 2005 had a sixfold higher odds associated with transitional cell carcinoma compared to those patients diagnosed in 1980 (odds ratio (OR) 6.00 (95% CI 4.00–8.97)).
These data strongly suggest that the histopathological profile of bladder cancer in Egypt has changed significantly over the past 26 years. Historically, squamous cell carcinoma was the predominant form of bladder cancer in Egypt; however transitional cell carcinoma has become the most frequent type. These results corroborate findings from a few small-scale hospital-based studies which conclude that the etiology of bladder cancer in Egypt has changed significantly over the past 26 years.
PMCID: PMC4274945  PMID: 18188671
Bladder cancer; Schistosomiasis; Histopathology; Epidemiologic trends; Egypt
5.  Depressive Symptoms and Diabetes 
PMCID: PMC3904750  PMID: 19001617
6.  Novel linear triaryl guanidines, N-substituted guanidines and potential prodrugs as antiprotozoal agents 
European journal of medicinal chemistry  2008;43(12):10.1016/j.ejmech.2008.02.008.
A series of triaryl guanidines and N-substituted guanidines designed to target the minor groove of DNA were synthesized and evaluated as antiprotozoal agents. Selected carbamate prodrugs of these guanidines were assayed for their oral efficacy. The linear triaryl bis-guanidines 6a,b were prepared from their corresponding diamines 4a,b through the intermediate BOC protected bis-guanidines 5a,b followed by acid catalyzed deprotection. The N-substituted guanidino analogues 9c–f were obtained in three steps starting by reacting the diamines 4a,b with ethyl iso-thiocyanatoformate to give the carbamoyl thioureas 7a,b. Subsequent condensation of 7a,b with various amines in the presence of EDCI provided the carbamoyl N-substituted guanidine intermediates 8a–f which can also be regarded as potential prodrugs for the guanidino derivatives. Compounds 9c–f were obtained via the base catalyzed decarbamoylation of 8a–f. The DNA binding affinities for the target dicationic bis-guanidines were assessed by ΔTm values. In vitro antiprotozoal screening of the new compounds showed that derivatives 6a, 9c and 9e possess high to moderate activity against Trypanosoma brucei rhodesiense (T.b.r.) and Plasmodium falciparum (P.f.). While the prodrugs did not yield cures upon oral administration in the antitrypanosomal STIB900 mouse model, compounds 8a and 8c prolonged the survival of the treated mice.
PMCID: PMC3815585  PMID: 18455271
Antiprotozoan; Bis-guanidines; DNA binding; Triaryl guanidines
7.  Primary paraspinal hydatid cyst treated with puncture, aspiration, injection and re-aspiration (PAIR) technique: a case report 
European Spine Journal  2008;18(Suppl 2):165-167.
Hydatid disease is a parasitic tapeworm infection that usually involves liver and lungs. Primary skeletal muscle hydatid cyst without liver and lung involvement is rare. En bloc resection without inducing rupture and spreading the daughter cyst is recommended treatment strategy and accepted to be curative for intramuscular hydatid cyst. We report a case of primary hydatid cyst of the erector spinae muscle which was treated successfully with ultrasonography guided puncture, aspiration, injection of 95% ethanol and re-aspiration (PAIR) technique.
PMCID: PMC2899571  PMID: 18696124
Hydatid cyst; Skeletal muscle; Percutaneous treatment
8.  Low Tissue Inhibitor of Metalloproteinases 3 and High Matrix Metalloproteinase 14 Levels Defines a Subpopulation of Highly Invasive Foam-Cell Macrophages 
An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo.
Methods and Results
In vivo generated rabbit FCM exhibited 84% reduced TIMP-3 protein compared to nonfoamy macrophages, and immunocytochemistry revealed a TIMP-3 negative subset (28%). Strikingly, only TIMP-3 negative FCM invaded a synthetic basement membrane, and invasion was inhibited by exogenous TIMP-3. TIMP-3 negative FCM also had increased proliferation and apoptosis rates compared to TIMP-3 positive cells, which were retarded by exogenous TIMP-3; this also reduced gelatinolytic activity. TIMP-3 negative FCM were found at the base of advanced rabbit plaques and in the rupture-prone shoulders of human plaques. To explain the actions of low TIMP-3 we observed a 26-fold increase in MT1-MMP (MMP-14) protein in FCM. Adding an MT1-MMP neutralizing antibody reduced foam-cell invasion, apoptosis, and gelatinolytic activity. Furthermore, MT1-MMP overexpressing and TIMP-3 negative FCM were found at the same locations in atherosclerotic plaques.
These results demonstrate that TIMP-3 is downregulated in a distinct subpopulation of FCM which have increased MMP-14. These cells are highly invasive and have increased proliferation and apoptosis, all properties expected to destabilise atherosclerotic plaques.
PMCID: PMC2851011  PMID: 18566294
atherosclerosis; tissue inhibitors of matrix metalloproteinases; macrophages; foam cells; plaque vulnerability
9.  American Society of Clinical Oncology Policy Statement: The Role of the Oncologist in Cancer Prevention and Risk Assessment 
Journal of Clinical Oncology  2008;27(6):986-993.
Oncologists have a critical opportunity to utilize risk assessment and cancer prevention strategies to interrupt the initiation or progression of cancer in cancer survivors and individuals at high risk of developing cancer. Expanding knowledge about the natural history and prognosis of cancers positions oncologists to advise patients regarding the risk of second malignancies and treatment-related cancers. In addition, as recognized experts in the full spectrum of cancer care, oncologists are afforded opportunities for involvement in community-based cancer prevention activities.
Although oncologists are currently providing many cancer prevention and risk assessment services to their patients, economic barriers exist, including inadequate or lack of insurance, that may compromise uniform patient access to these services. Additionally, insufficient reimbursement for existing and developing interventions may discourage patient access to these services.
The American Society of Clinical Oncology (ASCO), the medical society representing cancer specialists involved in patient care and clinical research, is committed to supporting oncologists in their wide-ranging involvement in cancer prevention. This statement on risk assessment and prevention counseling, although not intended to be a comprehensive overview of cancer prevention describes the current role of oncologists in risk assessment and prevention; provides examples of risk assessment and prevention activities that should be offered by oncologists; identifies potential opportunities for coordination between oncologists and primary care physicians in prevention education and coordination of care for cancer survivors; describes ASCO's involvement in education and training of oncologists regarding prevention; and proposes improvement in the payment environment to encourage patient access to these services.
PMCID: PMC2668639  PMID: 19075281
10.  Age, Tumor Size and Relative Survival of Patients With Localized Renal Cell Carcinoma: A Surveillance, Epidemiology and End Results Analysis 
The Journal of urology  2008;181(2):506-511.
Recent data demonstrate that age may be a significant independent prognostic variable following treatment for renal cell carcinoma. We analyzed data from the SEER (Surveillance, Epidemiology and End Results) database to evaluate the relative survival of patients treated surgically for localized renal cell carcinoma as related to tumor size and patient age.
Materials and Methods
Patients in the SEER database with localized renal cell carcinoma were stratified into cohorts by age and tumor size. Three and 5-year relative survival, the ratio of observed survival in the cancer population to the expected survival of an age, sex and race matched cancer-free population, was calculated with SEER-Stat. Brown's method was used for hypothesis testing.
A total of 8,578 patients with surgically treated, localized renal cell carcinoma were identified. While 3 and 5-year survival for patients with small (less than 4 cm) renal cell carcinoma was no different from that of matched cancer-free controls, patients treated for large (greater than 7 cm) localized renal cell carcinoma experienced decreased 5-year relative survival across all age groups. Therefore, age was not a significant predictor of relative survival for patients with small (less than 4 cm) or large (greater than 7 cm) tumors. However, a statistically significant trend toward lower relative survival with increasing age was demonstrated in patients with medium size tumors (4 to 7 cm). Hypothesis testing confirmed these findings.
These data suggest that relative survival is high in patients with tumors less than 4 cm and lower in patients with tumors larger than 7 cm regardless of age. However, increasing age may be related to worse outcomes in patients with tumors 4 to 7 cm. The cause of this observation warrants further investigation.
PMCID: PMC2703466  PMID: 19084868
kidney neoplasms; mortality
11.  Mechanisms associated with tolerance to flooding during germination and early seedling growth in rice (Oryza sativa) 
Annals of Botany  2008;103(2):197-209.
Background and Aims
Flooding slows seed germination, imposes fatalities and delays seedling establishment in direct-seeded rice. This study describes responses of contrasting rice genotypes subjected to flooding or low oxygen stress during germination and discusses the basis of tolerance shown by certain cultivars.
In one set of experiments, dry seeds were sown in soil and either watered normally or flooded with 10 cm of water. Seedling survival and shoot and root growth were assessed and seed portions of germinating seedlings were assayed for soluble sugars and starch concentrations. The whole germinating seedlings were assayed for amylase and peroxidase activities and for ethylene production. Activities of enzymes associated with anaerobic respiration were examined and gene expression was analysed separately with seeds germinating under different amounts of dissolved oxygen in dilute agar.
Key Results
Flooding during germination reduced survival but to a lesser extent in tolerant genotypes. Starch concentration in germinating seeds decreased while sugar concentration increased under flooding, but more so in tolerant genotypes. Amylase activity correlated positively with elongation (r = 0·85 for shoot and 0·83 for root length) and with plant survival (r = 0·92). Tolerant genotypes had higher amylase activity and higher RAmy3D gene expression. Ethylene was not detected in seeds within 2 d after sowing, but increased thereafter, with a greater increase in tolerant genotypes starting 3 d after sowing. Peroxidase activity was higher in germinating seeds of sensitive genotypes and correlated negatively with survival.
Under low oxygen stress, tolerant genotypes germinate, grow faster and more seedlings survive. They maintain their ability to use stored starch reserves through higher amylase activity and anaerobic respiration, have higher rates of ethylene production and lower peroxidase activity as germinating seeds and as seedlings. Relevance of these traits to tolerance of flooding during germination and early growth is discussed.
PMCID: PMC2707318  PMID: 19001425
Amylase; anoxia; crop establishment; direct-seeded rice; ethylene; flooding; germination; hypoxia; Oryza sativa
12.  Development of submergence-tolerant rice cultivars: the Sub1 locus and beyond 
Annals of Botany  2008;103(2):151-160.
Background and Aims
Submergence is a recurring problem in the rice-producing rainfed lowlands of south and south-east Asia. Developing rice cultivars with tolerance of submergence and with agronomic and quality traits acceptable to farmers is a feasible approach to address this problem. The objectives of this study were to (a) develop mega varieties with Sub1 introgression that are submergence tolerant, (b) assess the performance of Sub1 in different genetic backgrounds, (c) determine the roles of the Sub1A and Sub1C genes in conferring tolerance, and (d) assess the level of tolerance in F1 hybrids heterozygous for the Sub1A-1-tolerant allele.
Tolerant varieties were developed by marker-assisted backcrossing through two or three backcrosses, and their performance was evaluated to determine the effect of Sub1 in different genetic backgrounds. The roles of Sub1A and Sub1C in conferring the tolerant phenotype were further investigated using recombinants identified within the Sub1 gene cluster based on survival and gene expression data.
Key Results
All mega varieties with Sub1 introgression had a significantly higher survival rate than the original parents. An intolerant Sub1C allele combined with the tolerant Sub1A-1 allele did not significantly reduce the level of tolerance, and the Sub1C-1 expression appeared to be independent of the Sub1A allele; however, even when Sub1C-1 expression is completely turned off in the presence of Sub1A-2, plants remained intolerant. Survival rates and Sub1A expression were significantly lower in heterozygotes compared with the homozygous tolerant parent.
Sub1 provided a substantial enhancement in the level of tolerance of all the sensitive mega varieties. Sub1A is confirmed as the primary contributor to tolerance, while Sub1C alleles do not seem important. Lack of dominance of Sub1 suggests that the Sub1A-1 allele should be carried by both parents for developing tolerant rice hybrids.
PMCID: PMC2707316  PMID: 18974101
Oryza sativa; Sub1; marker-assisted backcrossing; mega varieties; submergence tolerance; recombinant; hybrid; abiotic stress
13.  Adaptation to flooding in upland and lowland ecotypes of Cyperus rotundus, a troublesome sedge weed of rice: tuber morphology and carbohydrate metabolism 
Annals of Botany  2008;103(2):295-302.
Background and aims
In recent years, Cyperus rotundus has become a problem weed in lowland rice (Oryza sativa) grown in rotation with vegetables in the Philippines. As the growth of C. rotundus is commonly suppressed by prolonged flooding, the ability of the weed to grow vigorously in flooded as well as upland conditions suggests that adapted ecotypes occur in these rotations. Studies were conducted to elucidate the mechanisms that permit C. rotundus to tolerate flooded soil conditions.
Upland and lowland ecotypes of C. rotundus were compared in terms of growth habit, carbohydrate reserves and metabolism, and activities of enzymes involved in alcoholic fermentation – alcohol dehydrogenase (ADH) and pyruvate decarboxylase (PDC).
Key Results
The lowland ecotype has much larger tubers than the upland ecotype. Prior to germination, the amylase activity and total non-structural carbohydrate content in the form of soluble sugars were greater in the tubers of lowland plants than in those of upland C. rotundus. At 24 h after germination in hypoxic conditions, PDC and ADH activities in the lowland plants increased, before decreasing at 48 h following germination. In contrast, ADH and PDC activities in the upland plants increased from 24 to 48 h after germination.
Tolerance of lowland C. rotundus of flooding may be attributed to large carbohydrate content and amylase activity, and the ability to maintain high levels of soluble sugars in the tubers during germination and early growth. This is coupled with the modulation of ADH and PDC activities during germination, possibly to control the use of carbohydrate reserves and sustain substrate supply in order to avoid starvation and death of seedlings with prolonged flooding.
PMCID: PMC2707299  PMID: 18515404
Anoxia; ethanol fermentation; flooding tolerance; nutsedge; Cyperus rotundus; Pasteur effect; weed ecology
14.  Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve 
To determine whether intraocular pressure (IOP) elevation triggers mitochondrial fission and ultrastructural changes and alters optic atrophy type 1 (OPA1) expression and distribution in the optic nerve (ON) of glaucomatous DBA/2J mice.
IOP in the eyes of DBA/2J mice was measured and mitochondrial structural changes were assessed by conventional EM and EM tomography. Cytochrome c oxidase IV subunit 1 (COX), OPA1 and Dnm1, a rat homologue of dynamin-related protein-1, mRNA were measured by Taqman qPCR. COX and OPA1 protein distribution was assessed by immunocytochemistry and Western blot.
Excavation of the optic nerve head (ONH), axon loss, and COX reduction were evident in 10 month-old glaucomatous ONH of eyes with >20 mmHg IOP elevation. EM analysis showed mitochondrial fission, matrix swelling, substantially reduced cristae volume, and abnormal cristae depletion in 10 month-old glaucomatous ONH axons. The mean length of mitochondrial cross section in these axons decreased from 916.6 ± 768.4 nm in 3 month-old mice to 582.87 ± 303.3 nm in 10 month-old glaucomatous mice (P<0.001). Moderate reductions of COX mRNA were observed in the 10 month-old DBA/2J mice optic nerve heads. Larger reductions of OPA1 immunoreactivity and gene expression were coupled with larger increases of Dnm1 gene expression in 10 month-old glaucomatous ONH. Subcellular fractionation analysis indicates increased release of both OPA1 and cytochrome c from mitochondria in 10 month-old glaucomatous ONs.
IOP elevation may directly damage mitochondria in the ONH axons by promoting reduction of COX, mitochondrial fission and cristae depletion, alterations of OPA1 and Dnm1 expression, and induction of OPA1 release. Thus, interventions to preserve mitochondria may be useful for protecting ON degeneration in glaucoma.
PMCID: PMC2688012  PMID: 18469184
15.  Restorative Effects of Uridine Plus Docosahexaenoic Acid in a Rat Model of Parkinson’s Disease 
Neuroscience research  2008;62(3):206-209.
Administering uridine-5’-monophosphate (UMP) and docosahexaenoic acid (DHA) increases synaptic membranes (as characterized by pre-and post-synaptic proteins) and dendritic spines in rodents. We examined their effects on rotational behavior and dopaminergic markers in rats with partial unilateral 6-hydroxydopamine (6-OHDA)-induced striatal lesions. Rats receiving UMP, DHA, both, or neither, daily, and intrastriatal 6-OHDA 3 days after treatment onset, were tested for d-amphetamine-induced rotational behavior and dopaminergic markers after 24 and 28 days, respectively. UMP/DHA treatment reduced ipsilateral rotations by 57% and significantly elevated striatal dopamine, tyrosine hydroxylase (TH) activity, TH protein and Synapsin-1 on the lesioned side. Hence, giving uridine and DHA may partially restore dopaminergic neurotransmission in this model of Parkinson’s Disease.
PMCID: PMC2592845  PMID: 18761383
Parkinson’s Disease; Uridine; Docosahexaenoic Acid; Dopamine; Tyrosine Hydroxylase Activity; Synapse
16.  Human peroxiredoxin PrxI is an ortholog of yeast Tsa1, capable of suppressing genome instability and protecting against cell death in Saccharomyces cerevisiae 
Cancer research  2008;68(4):1055-1063.
The peroxiredoxins (Prxs) are conserved antioxidant proteins that utilize cysteine as the primary site of oxidation during the reduction of peroxides. Many organisms have more than one isoform of Prx. Deletion of TSA1, one of five Prxs in yeast Saccharomyces cerevisiae, results in accumulation of a broad spectrum of mutations including gross chromosomal rearrangements. Deletion of TSA1 is synthetically lethal with mutations in RAD6 and several key genes involved in DNA double-strand break repair. Here we have examined the function of human peroxiredoxins PrxI and PrxII, which share a high degree of sequence identity with Tsa1, by expressing them in S. cerevisiae cells under control of the native TSA1 promoter. We found that expression of PrxI, but not PrxII, was capable of complementing a tsa1Δ mutant for a variety of defects including genome instability, the synthetic lethality observed in rad6Δ tsa1Δ and rad51Δ tsa1Δ double mutants and mutagen sensitivity. Moreover, expression of either Tsa1 or PrxI prevented Bax-induced cell death. These data indicate that PrxI is an ortholog of Tsa1. PrxI and Tsa1 appear to act on the same substrates in vivo and share similar mechanisms of function. The observation that PrxI is involved in suppressing genome instability and protecting against cell death potentially provides a better understanding of the consequences of PrxI dysfunction in human cells. The S. cerevisiae system described here could provide a sensitive tool to uncover the mechanisms that underlie the function of human Prxs.
PMCID: PMC2761232  PMID: 18281480
peroxiredoxin; oxidative stress; genome instability; S. cerevisiae
17.  Resuscitating the Microcirculation in Sepsis: The Central Role of Nitric Oxide, Emerging Concepts for Novel Therapies, and Challenges for Clinical Trials 
Microcirculatory dysfunction is a critical element of the pathogenesis of severe sepsis and septic shock. In this Bench-to-Bedside review, we present: (1) the central role of the microcirculation in the pathophysiology of sepsis; (2) new translational research techniques of in vivo videomicroscopy for assessment of microcirculatory flow in human subjects; (3) clinical investigations that reported associations between microcirculatory dysfunction and outcome in septic patients; (4) the potential role of novel agents to "rescue" the microcirculation in sepsis; (5) current challenges facing this emerging field of clinical investigation; and (6) a framework for the design of future clinical trials aimed to determine the impact of novel agents on microcirculatory flow and organ failure in patients with sepsis. We specifically focus this review on the central role and vital importance of the nitric oxide molecule in maintaining microcirculatory homeostasis and patency, especially when the microcirculation sustains an insult (as with sepsis), and we present the scientific rationale for clinical trials of exogenous nitric oxide administration to treat microcirculatory dysfunction and augment microcirculatory blood flow in early sepsis therapy.
PMCID: PMC2727641  PMID: 18439194
microcirculation; sepsis; severe sepsis; septic shock; resuscitation; endothelium; nitric oxide
18.  Host and microbial risk factors and pathophysiology of fatal Rickettsia conorii infection in Portuguese patients 
The Journal of infectious diseases  2008;198(4):576-585.
The pathophysiologic mechanisms of severity of Mediterranean spotted fever (MSF) and the host and microbial risk factors for a fatal outcome are incompletely determined.
In a prospective study of 140 patients with documented identification of the causative rickettsial strain admitted to 13 Portuguese hospitals during 1994−2006, univariate and multivariate analyses determined the risk factors for a fatal outcome.
Seventy one (51%) patients were infected with Rickettsia conorii Malish strain and 69 (49%) with Israeli spotted fever (ISF) strain. Patients were admitted to ICU (29%), hospitalized as routine inpatients (67%), or managed as outpatients (4%). Deaths occurred in 29 (21%) adults. Fatal outcome was significantly more likely for patients with ISF strain infection, and alcoholism was a risk factor. The pathophysiology of a fatal outcome involved significantly greater incidence of petechial rash, gastrointestinal symptoms, confusion/obtundation, dehydration, tachypnea, hepatomegaly, leukocytosis, coagulopathy, azotemia, hyperbilirubinemia, and elevated hepatic enzymes and creatine kinase. Some but not all these were observed more often in ISF strain-infected patients.
Although fatalities and similar clinical manifestations occurred with both strains, ISF strain was more virulent than Malish strain. Multivariate analysis revealed that acute renal failure and hyperbilirubinemia were most strongly associated with a fatal outcome.
PMCID: PMC2614375  PMID: 18582199
Rickettsia conorii; alcoholism; Israeli spotted fever strain; Malish strain; eschar
19.  The transforming mutation E17K/AKT1 is not a major event in B-cell-derived lymphoid leukaemias 
British Journal of Cancer  2008;99(3):488-490.
Despite the major role of the AKT/PKB family of proteins in the regulation of many growth and survival mechanisms in the cell, and the increasing evidence suggesting that AKT disruption could play a key role in many human malignancies, no major mutations of AKT genes had been reported, until very recently when Carpten et al reported a novel transforming mutation (E17K) in the pleckstrin homology domain of the AKT1 gene in solid tumours. Several laboratories are now screening for this mutation in different malignancies, and, recently, the mutation was described by Malanga et al in 1.9% of lung cancer patients. Considering the importance of the PI3K/AKT pathway in mediating survival and antiapoptotic signals in the B-cell types of chronic lymphocytic leukaemia (CLL) and acute lymphoblastic leukaemia (ALL), we sequenced the AKT1 exon 3 for the above mentioned mutation in 87 specimens, representing 45 CLLs, 38 ALLs and 4 prolymphocytic leukaemia (PLL) cases, which are all of B-cell origin. Our results show that the mutation E17K/AKT1 was not detected in the pleckstrin homology domain of AKT1 of the investigated cases. We conclude that this mutation is not a major event in B-cell-derived lymphoid leukaemias.
PMCID: PMC2527790  PMID: 18665177
AKT1; lymphoid leukaemia; mutation
21.  A Class III PDZ Binding Motif in the Myotilin and FATZ Families Binds Enigma Family Proteins: a Common Link for Z-Disc Myopathies▿  
Molecular and Cellular Biology  2008;29(3):822-834.
Interactions between Z-disc proteins regulate muscle functions and disruption of these interactions results in muscle disorders. Mutations in Z-disc components myotilin, ZASP/Cypher, and FATZ-2 (calsarcin-1/myozenin-2) are associated with myopathies. We report here that the myotilin and the FATZ (calsarcin/myozenin) families share high homology at their final C-terminal five amino acids. This C-terminal E[ST][DE][DE]L motif is present almost exclusively in these families and is evolutionary conserved. We show by in vitro and in vivo studies that proteins from the myotilin and FATZ (calsarcin/myozenin) families interact via this novel type of class III PDZ binding motif with the PDZ domains of ZASP/Cypher and other Enigma family members: ALP, CLP-36, and RIL. We show that the interactions can be modulated by phosphorylation. Calmodulin-dependent kinase II phosphorylates the C terminus of FATZ-3 (calsarcin-3/myozenin-3) and myotilin, whereas PKA phosphorylates that of FATZ-1 (calsarcin-2/myozenin-1) and FATZ-2 (calsarcin-1/myozenin-1). This is the first report of a binding motif common to both the myotilin and the FATZ (calsarcin/myozenin) families that is specific for interactions with Enigma family members.
PMCID: PMC2630697  PMID: 19047374
22.  Effect of thyroid hormone on the distribution and activity of Na, K-ATPase in ventricular myocardium 
Employing detergent-free sucrose density gradient fractionation method we isolated cholesterol rich lighter membrane fractions containing ~ 10% of protein, ~ 30% of cholesterol in membranes of ventricular myocardium. Cholesterol- rich lighter membrane fractions contain > 70% of Na, K-ATPase, and caveolins 1 and 3, and < 10% of β-actin. Treatment of hypothyroid rats with T3 increased the relative abundance of both α1 and β1 Na, K-ATPase subunits in total membranes by 4–5-fold (with no change in caveolin 3), and resulted in 1.9-fold increase in enzyme activity. T3 induced Na, K-ATPase subunits were preferentially distributed to the lighter fractions (#s 4, 5 and 6); and increased abundance of α1 and β1 were 34% to 70% and 43% to 68% respectively. We conclude that the activity of Na, K-ATPase is not uniform in cardiac membranes, and while a significant amount of Na, K-ATPase is present in cardiac cholesterol-rich membrane fractions, the intrinsic activity is significantly less than the enzyme present in relatively cholesterol-poor membranes.
PMCID: PMC2474788  PMID: 18457653
Na; K-ATPase; cholesterol; rafts; detergent resistant membranes; membrane fractionation; caveolar membranes
23.  Pilocarpine improves recognition of nestmates in young honey bees 
Neuroscience letters  2008;439(2):178-181.
Honey bees can distinguish nestmates from non-nestmates, directing aggressive responses toward non-nestmates and rarely attacking nestmates. Here we provide evidence that treatment with pilocarpine, a muscarinic agonist, significantly reduced the number of aggressive responses directed toward nestmates. By contrast, treatment with scopolamine, a muscarinic antagonist, significantly increased attacks on nestmates. Locomotor activity was not altered by these pharmacological treatments. When interpreted in light of known cholinergic pathways in the insect brain, our results provide the first evidence that cholinergic signaling via muscarinic receptors plays a role in olfaction-based social behavior in honey bees.
PMCID: PMC2517128  PMID: 18514413
acetylcholine; Apis mellifera; kin recognition; muscarinic receptor; pilocarpine; scopolamine
24.  A male phenotype (XY) hermaphrodite treated for seminoma, fathered a healthy child by IVF–ICSI technique 
To report a successful delivery of a healthy infant fathered by an infertile 46, XY true hermaphrodite who suffered from a seminoma.
Case report
IVF unit in University hospital
Male 41 years (true hermaphrodite), his wife 35 years
Main Outcome Measures
Laboratory, pathology tests and ultrasound tests
The above patient treated and cured from seminoma, the couple had in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) using frozen testicular sperm and had a healthy baby.
This is the first case report of a successful delivery of a healthy infant fathered by an infertile 46, XY true hermaphrodite who suffered from a seminoma. Once treated and cured, the couple had IVF and ICSI using frozen testicular sperm and had a healthy baby.
PMCID: PMC2596674  PMID: 18648929
Hermaphrodite; Seminoma; IVF; ICSI
25.  Use of glycated hemoglobin (HbA1C) and impaired glucose tolerance in the screening of undiagnosed diabetes in the Malaysian population 
Although HbA1C is widely accepted as a useful index of mean blood glucose in type 2 diabetic patients its usefulness as screening test for diabetes has been controversial. The present study was undertaken to determine whether the level of HbA1C predicted diabetes in a prediabetic group of subjects. Plasma lipids, oral glucose tolerance, HbA1C was determined in 90 normal control subjects, 57 offspring of one type 2 diabetes mellitus parent and 11 diagnosed type 2 diabetes mellitus individuals. The mean age of participants was 44.5 yrs (not significantly different amongst the three groups) and the mean body mass index was 26.8 (not significantly different amongst the three groups). Two hours after a 75 g glucose challenge, the offspring had a significantly higher plasma glucose level (mean = 7.1 mmol/L, p value = 0.002) than the normals. Similarly the HbA1C values were higher in the offspring than in the normals (mean = 5.78%, p value = 0.016). Besides the significantly higher values for oral glucose tolerance test and HbA1C, the diabetics also were significantly higher for triglycerides (mean = 2.25mmol/L), total cholesterol (mean = 6.24mmol/L) and systolic blood pressure (mean = 138.45mm Hg) than the offspring (P value = 0.031, 0.006, 0.010) and the normals (P value = 0.026, 0.018, 0.002) respectively. The mean values of diastolic blood pressure, LDL cholesterol and HDL cholesterol were not significantly different amongst the three groups.
PMCID: PMC3453455  PMID: 23105763
Diabetes mellitus; HbA1C; Prediabetic; Fasting blood glucose; Insulin resistance

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