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1.  Integrins and cAMP mediate netrin-induced growth cone collapse 
Brain research  2013;1537:10.1016/j.brainres.2013.08.045.
Growth cones integrate a remarkably complex concert of chemical cues to guide axons to their appropriate destinations. Recent work suggests that integrins contribute to axon guidance by interacting with a wide range of extracellular molecules including axon guidance molecules, by mechanisms that are not fully understood. Here, we describe an interaction between integrins and netrin-1 in growth cones that contributes to growth cone collapse. Our data show that netrin-1 causes growth cone collapse in a substratum-specific manner and is integrin-dependent. Netrin-1 causes collapse of cultured chick dorsal root ganglion (DRG) growth cones extending on high levels of laminin-1 (LN) but not growth cones extending on low levels of LN or on fibronectin. Blocking integrin function significantly decreases netrin-induced growth cone collapse on high LN. Netrin-1 and integrins interact on growth cones; netrin-1 causes integrin activation, a conformational shift to a high ligand-affinity state. Netrin-1 directly binds to integrin α3 and α6 peptides, further suggesting a netrin-integrin interaction. Interestingly, our data reveal netrin-1 increases growth cone levels of cAMP in a substratum-specific manner and that netrin-induced growth cone collapse requires increased cAMP in combination with integrin activation. Manipulations that either decrease cAMP levels or integrin activation block netrin-induced collapse. These results imply a common mechanism for growth cone collapse and novel interactions between integrins, netrin-1 and cAMP that contribute to growth cone guidance.
PMCID: PMC3833899  PMID: 24001590
axon guidance; netrin-1; laminin; integrin activation; cyclic AMP; regeneration
2.  Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. 
Journal of Clinical Investigation  1994;94(3):1277-1288.
Pulses of growth hormone (GH) release in acromegaly may arise from hypothalamic regulation or from random events intrinsic to adenomatous tissue. To distinguish between these possibilities, serum GH concentrations were measured at 5-min intervals for 24 h in acromegalic men and women with active (n = 19) and inactive (n = 9) disease and in normal young adults in the fed (n = 20) and fasted (n = 16) states. Daily GH secretion rates, calculated by deconvolution analysis, were greater in patients with active acromegaly than in fed (P < 0.05) but not fasted normal subjects. Significant basal (nonpulsatile) GH secretion was present in virtually all active acromegalics but not those in remission or in fed and fasted normal subjects. A recently introduced scale- and model-independent statistic, approximate entropy (ApEn), was used to test for regularity (orderliness) in the GH data. All but one acromegalic had ApEn values greater than the absolute range in normal subjects, indicating reduced orderliness of GH release; ApEn distinguished acromegalic from normal GH secretion (fed, P < 10(-12); fasted, P < 10(-7)) with high sensitivity (95%) and specificity (100%). Acromegalics in remission had ApEn scores larger than those of normal subjects (P < 0.0001) but smaller than those of active acromegalics (P < 0.001). The coefficient of variation of successive incremental changes in GH concentrations was significantly lower in acromegalics than in normal subjects (P < 0.001). Fourier analysis in acromegalics revealed reduced fractional amplitudes compared to normal subjects (P < 0.05). We conclude that GH secretion in acromegaly is highly irregular with disorderly release accompanying significant basal secretion.
PMCID: PMC295213  PMID: 8083369
3.  Examining the Value of Lexical Retrieval Treatment in Primary Progressive Aphasia: Two Positive Cases 
Brain and language  2013;127(2):145-156.
Individuals with primary progressive aphasia (PPA) suffer a gradual decline in communication ability as a result of neurodegenerative disease. Language treatment shows promise as a means of addressing these difficulties but much remains to be learned with regard to the potential value of treatment across variants and stages of the disorder. We present two cases, one with semantic variant of PPA and the other with logopenic PPA, each of whom underwent treatment that was unique in its focus on training self-cueing strategies to engage residual language skills. Despite differing language profiles and levels of aphasia severity, each individual benefited from treatment and showed maintenance of gains as well as generalization to untrained lexical items. These cases highlight the potential for treatment to capitalize on spared cognitive and neural systems in individuals with PPA, improving current language function as well as potentially preserving targeted skills in the face of disease progression.
PMCID: PMC4026252  PMID: 23871425
primary progressive aphasia; rehabilitation; treatment; naming; lexical retrieval; logopenic variant; semantic dementia
4.  Predicting response and survival in chemotherapy-treated triple-negative breast cancer 
British Journal of Cancer  2014;111(8):1532-1541.
In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC).
Gene expression and clinical–pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated.
Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55–81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival.
The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.
PMCID: PMC4200088  PMID: 25101563
breast cancer; genomics; subtypes; intrinsic; basal like; chemotherapy; neoadjuvant
Chemosphere  2012;90(2):459-463.
The objective of this research was to examine the potential for intercalation of trichloroethene (TCE) by clay minerals associated with aquifer sediments. Sediment samples were collected from a field site in Tucson, AZ. Two widely used Montmorillonite specimen clays were employed as controls. X-ray diffraction, conducted with a controlled-environment chamber, was used to characterize smectite interlayer d-spacing for three treatments (bulk air-dry sample, sample mixed with synthetic groundwater, sample mixed with TCE-saturated synthetic groundwater). The results show that the d-spacing measured for the samples treated with TCE-saturated synthetic groundwater are larger (~26%) than those of the untreated samples for all field samples as well as the specimen clays. These results indicate that TCE was intercalated by the clay minerals, which may have contributed to the extensive elution tailing observed in prior miscible-displacement experiments conducted with this sediment.
PMCID: PMC3548623  PMID: 22921434
Smectite; montmorillonite; clay; sorption; X-ray diffraction
6.  Mapping the subcellular distribution of alpha-synuclein in neurons using genetically encoded probes for correlated light and electron microscopy: Implications for Parkinson’s disease pathogenesis 
Modifications to the gene encoding human alpha-synuclein have been linked to development of Parkinson’s disease. The highly conserved structure of alpha-synuclein suggests a functional interaction with membranes, and several lines of evidence point to a role in vesicle-related processes within nerve terminals. Using recombinant fusions of human alpha-synuclein including new genetic tags developed for correlated LM and EM (the tetracysteine-biarsenical labeling system or the new fluorescent protein for EM, MiniSOG), we determined the distribution of alpha-synuclein when over-expressed in primary neurons at supramolecular and cellular scales, in three dimensions (3D). We observed specific association of alpha-synuclein with a large and otherwise poorly characterized membranous organelle system of the presynaptic terminal, as well as with smaller vesicular structures within these boutons. Furthermore, alpha-synuclein was localized to multiple elements of the protein degradation pathway, including multivesicular bodies in the axons and lysosomes within neuronal cell bodies. Examination of synapses in brains of transgenic mice over-expressing human alpha-synuclein revealed alterations of the presynaptic endomembrane systems similar to our findings in cell culture. 3D electron tomographic analysis of enlarged presynaptic terminals in several brain areas revealed that these terminals were filled with membrane-bounded organelles, including tubulo-vesicular structures similar to what observed in vitro. We propose that alpha-synuclein over-expression is associated with hypertrophy of membrane systems of the presynaptic terminal previously shown to have a role in vesicle recycling. Our data support the conclusion that alpha- synuclein is involved in processes associated with the sorting, channeling, packaging and transport of synaptic material destined for degradation.
PMCID: PMC3711410  PMID: 23392688
7.  Treatment for apraxia of speech in nonfluent variant primary progressive aphasia 
Behavioural neurology  2013;26(0):77-88.
There is a growing body of literature examining the utility of behavioral treatment in primary progressive aphasia (PPA). There are, however, no studies exploring treatment approaches to improve speech production in individuals with apraxia of speech (AOS) associated with the nonfluent variant of PPA. The purpose of this study was to examine a novel approach to treatment of AOS in nonfluent PPA. We implemented a treatment method using structured oral reading as a tool for improving production of multisyllabic words in an individual with mild AOS and nonfluent variant PPA. Our participant showed a reduction in speech errors during reading of novel text that was maintained at one year post-treatment. Generalization of improved speech production was observed on repetition of words and sentences and the participant showed stability of speech production over time in connected speech. Results suggest that oral reading treatment may offer an efficient and effective means of addressing multisyllabic word production in AOS associated with nonfluent PPA, with lasting and generalized treatment effects.
PMCID: PMC3651677  PMID: 22713405
apraxia of speech; treatment; speech therapy; nonfluent PPA; primary progressive aphasia
8.  Serial Analysis of the Gut and Respiratory Microbiome in Cystic Fibrosis in Infancy: Interaction between Intestinal and Respiratory Tracts and Impact of Nutritional Exposures 
mBio  2012;3(4):e00251-12.
Pulmonary damage caused by chronic colonization of the cystic fibrosis (CF) lung by microbial communities is the proximal cause of respiratory failure. While there has been an effort to document the microbiome of the CF lung in pediatric and adult patients, little is known regarding the developing microflora in infants. We examined the respiratory and intestinal microbiota development in infants with CF from birth to 21 months. Distinct genera dominated in the gut compared to those in the respiratory tract, yet some bacteria overlapped, demonstrating a core microbiota dominated by Veillonella and Streptococcus. Bacterial diversity increased significantly over time, with evidence of more rapidly acquired diversity in the respiratory tract. There was a high degree of concordance between the bacteria that were increasing or decreasing over time in both compartments; in particular, a significant proportion (14/16 genera) increasing in the gut were also increasing in the respiratory tract. For 7 genera, gut colonization presages their appearance in the respiratory tract. Clustering analysis of respiratory samples indicated profiles of bacteria associated with breast-feeding, and for gut samples, introduction of solid foods even after adjustment for the time at which the sample was collected. Furthermore, changes in diet also result in altered respiratory microflora, suggesting a link between nutrition and development of microbial communities in the respiratory tract. Our findings suggest that nutritional factors and gut colonization patterns are determinants of the microbial development of respiratory tract microbiota in infants with CF and present opportunities for early intervention in CF with altered dietary or probiotic strategies.
While efforts have been focused on assessing the microbiome of pediatric and adult cystic fibrosis (CF) patients to understand how chronic colonization by these microbes contributes to pulmonary damage, little is known regarding the earliest development of respiratory and gut microflora in infants with CF. Our findings suggest that colonization of the respiratory tract by microbes is presaged by colonization of the gut and demonstrated a role of nutrition in development of the respiratory microflora. Thus, targeted dietary or probiotic strategies may be an effective means to change the course of the colonization of the CF lung and thereby improve patient outcomes.
PMCID: PMC3428694  PMID: 22911969
9.  Genome Sequence of Edwardsiella ictaluri 93-146, a Strain Associated with a Natural Channel Catfish Outbreak of Enteric Septicemia of Catfish 
Journal of Bacteriology  2012;194(3):740-741.
Edwardsiella ictaluri is the cause of extensive mortalities and economic losses to the channel catfish industry of the southeast United States. Here we report the complete genome of Edwardsiella ictaluri 93-146. Whole-genome sequence analysis of E. ictaluri provides a tool for understanding the genomic regions specific to the species and the Edwardsiella genus.
PMCID: PMC3264089  PMID: 22247535
10.  Low levels of realized seed and pollen gene flow and strong spatial genetic structure in a small, isolated and fragmented population of the tropical tree Copaifera langsdorffii Desf 
Heredity  2010;106(1):134-145.
Over the past century, the Brazilian Atlantic forest has been reduced to small, isolated fragments of forest. Reproductive isolation theories predict a loss of genetic diversity and increases in inbreeding and spatial genetic structure (SGS) in such populations. We analysed eight microsatellite loci to investigate the pollen and seed dispersal patterns, genetic diversity, inbreeding and SGS of the tropical tree Copaifera langsdorffii in a small (4.8 ha), isolated population. All 112 adult trees and 128 seedlings found in the stand were sampled, mapped and genotyped. Seedlings had significantly lower levels of genetic diversity (A=16.5±0.45, mean±95% s.e.; He=0.838±0.006) than did adult trees (A=23.2±0.81; He=0.893±0.030). Parentage analysis did not indicate any seed immigration (mseeds=0) and the pollen immigration rate was very low (mpollen=0.047). The average distance of realized pollen dispersal within the stand was 94 m, with 81% of the pollen travelling <150 m. A significant negative correlation was found between the frequency and distance of pollen dispersal (r=−0.79, P<0.01), indicating that short-distance pollinations were more frequent. A significant SGS for both adults (∼50 m) and seedlings (∼20 m) was also found, indicating that most of the seeds were dispersed over short distances. The results suggested that the spatial isolation of populations by habitat fragmentation can restrict seed and pollen gene flow, increase SGS and affect the genetic diversity of future generations.
PMCID: PMC3183851  PMID: 20372183
Copaifera langsdorffii; tropical trees; microsatellite loci; seed dispersal; pollen dispersal; spatial genetic structure
11.  The logopenic variant of primary progressive aphasia 
Current opinion in neurology  2010;23(6):633-637.
The aim of this review is to explore the evolution of the logopenic variant of primary progressive aphasia as a distinct clinical entity and to outline recent advances that have clarified its clinical characteristics, neural underpinnings and potential genetic and pathological bases. This is particularly relevant as researchers attempt to identify clinico-pathological relationships in subtypes of primary progressive aphasia in hopes of utilizing language phenotype as a marker of underlying disease.
Recent findings
Recent work has served to refine and expand upon the clinical phenotype of the logopenic variant. Logopenic patients show a unique pattern of spared and impaired language processes that reliably distinguish this syndrome from other variants of progressive aphasia. Specifically, they exhibit deficits in naming and repetition in the context of spared semantic, syntactic and motor speech abilities. Further, there is a growing body of evidence indicating a possible link between the logopenic variant phenotype and specific pathological and genetic correlates.
Findings indicate that the logopenic variant is a distinct subtype of progressive aphasia that may hold value as a predictor of underlying pathology. Additional research, however, is warranted in order to further clarify the cognitive-linguistic profile and to confirm its relation to certain pathological and genetic processes.
PMCID: PMC3201824  PMID: 20852419
logopenic progressive aphasia; primary progressive aphasia; logopenic variant; Alzheimer’s disease
12.  P32 - A Case of Multicentric Giant Cell Tumours with 25-Year Follow Up 
Giant cell tumour of bone (GCT) is a relatively rare benign bone tumour more frequent in young people (20–40 years). Histologically, two cell types are represented, stromal cells of osteoblastic origin and a distinctive osteoclast-like population probably of monocytic origin. GCTs can be aggressive and they recur locally in up to 50% of cases; up to 5% of GCTs metastasise to the lungs and spontaneous transformation to a high-grade malignancy occurs in 1–3% of patients. The aetiology of GCT is not known, and no risk factors have been recognised, although familial clustering of both Paget’s disease and GCT has been reported.
GCTs account for approximately 3–5% of primary bone tumours. GCT is rarely multicentric and usually occurs at the epiphyses of long bones, but may also affect other bones.
There are few randomised, prospective clinical trials available to guide clinical management of GCT. Recent developments have led to evaluation of newer therapeutic agents, including biphosphonates and denosumab, with encouraging results. We report the case of a 66-year-old woman affected by GCT. In 1985 the patient, then 41 years old, presented a cystic lesion on her left tibia, which was removed surgically. This lesion relapsed two years later. Therefore the patient was hospitalised and received a diagnosis of “multicentric giant cell bone lesions” (limb-girdle, sternum, mandible, ribs), confirmed by histological examination. These lesions showed hyperactivity on bone scintigraphy. Plain radiographs demonstrated destructive lytic lesions. Blood and urinary examinations showed markedly elevated levels of bone alkaline phosphatase and urine pyridinoline and there was persistent bone pain. In 1993 normocalcaemic primary hyperparathyroidism was diagnosed and an adenoma was removed, with no relapse of the disease. Subsequently the patient started clodronate therapy, i.v., followed by alendronate-neridronate per os and clodronate i.m. for about nine years. Biphosphonate therapy caused a modest and transient decrease in bone indexes. Initial bone lesions were unchanged on computed tomography 25 years after diagnosis, but new bone lesions had appeared. MEN1 gene and CasR analyses were negative.
This is a rare case of a patient affected by multicentric giant cell tumours with a 25-year follow up. A slow progression of the lesion is documented, as well as the absence of significant effect of biphosphonate therapy.
PMCID: PMC3213768
13.  3D Head Shape Quantification for Infants with and without Deformational Plagiocephaly 
We developed and tested three dimensional (3-D) indices for quantifying severity of deformational plagiocephaly (DP).
We evaluated the extent to which infants with and without DP (as determined by clinic referral and two experts’ ratings) could be correctly classified.
Infants ages 4–11 months, including 154 with diagnosed DP and 100 infants without a history of DP or other craniofacial condition. After excluding participants with discrepant expert ratings, data from 90 infants with DP and 50 infants without DP were retained.
Two-dimensional histograms of surface normal vector angles were extracted from 3-D mesh data and used to compute the severity scores below.
Outcome measures
Left Posterior Flattening Score (LPFS), Right Posterior Flattening Score (RPFS), Asymmetry Score (AS), Absolute Asymmetry Score (AAS) and an approximation of a previously described 2-D measure, the Oblique Cranial Length Ratio (aOCLR). Two-dimensional histograms localized the posterior flatness for each participant.
We fit receiver operating characteristic curves and calculated the area under the curves (AUC) to evaluate the relative accuracy of DP classification using the above measures.
The AUC statistics were: AAS=91%; LPFS=97%, RPFS=91%; AS=99%, and aOCLR=79%.
Novel 3-D-based plagiocephaly posterior severity scores provided better sensitivity and specificity in the discrimination of plagiocephalic and typical head shapes than the 2-D measurements provided by a close approximation of OCLR. These indices will allow for more precise quantification of the DP phenotype in future studies on the prevalence of this condition, which may lead to improved clinical care.
PMCID: PMC2899494  PMID: 20590458
plagiocephaly; head shape
14.  Enamel matrix proteins; old molecules for new applications 
Emdogain® (enamel matrix derivative, EMD) is well recognized in periodontology, where it is used as a local adjunct to periodontal surgery to stimulate regeneration of periodontal tissues lost to periodontal disease. The biological effect of EMD is through stimulation of local growth factor secretion and cytokine expression in the treated tissues, inducing a regenerative process that mimics odontogenesis. The major (>95%) component of EMD is Amelogenins (Amel). No other active components have so far been isolated from EMD, and several studies have shown that purified amelogenins can induce the same effect as the complete EMD. Amelogenins comprise a family of highly conserved extracellular matrix proteins derived from one gene. Amelogenin structure and function is evolutionary well conserved, suggesting a profound role in biomineralization and hard tissue formation. A special feature of amelogenins is that under physiological conditions the proteins self-assembles into nanospheres that constitute an extracellular matrix. In the body, this matrix is slowly digested by specific extracellular proteolytic enzymes (matrix metalloproteinase) in a controlled process, releasing bioactive peptides to the surrounding tissues for weeks after application. Based on clinical and experimental observations in periodontology indicating that amelogenins can have a significant positive influence on wound healing, bone formation and root resorption, several new applications for amelogenins have been suggested. New experiments now confirm that amelogenins have potential for being used also in the fields of endodontics, bone regeneration, implantology, traumatology, and wound care.
PMCID: PMC2825346  PMID: 19627527
amelogenins; bone formation; endodontics; implantology; wound healing
15.  Nurse-led follow-up of patients after oesophageal or gastric cardia cancer surgery: a randomised trial 
British Journal of Cancer  2008;100(1):70-76.
Between January 2004 and February 2006, 109 patients after intentionally curative surgery for oesophageal or gastric cardia cancer were randomised to standard follow-up of surgeons at the outpatient clinic (standard follow-up; n=55) or by regular home visits of a specialist nurse (nurse-led follow-up; n=54). Longitudinal data on generic (EuroQuol-5D, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30) and disease-specific quality of life (EORTC QLQ-OES18), patient satisfaction and costs were collected at baseline and at 6 weeks and 4, 7 and 13 months afterwards. We found largely similar quality-of-life scores in the two follow-up groups over time. At 4 and 7 months, slightly more improvement on the EQ-VAS was noted in the nurse-led compared with the standard follow-up group (P=0.13 and 0.12, respectively). Small differences were also found in patient satisfaction between the two groups (P=0.14), with spouses being more satisfied with nurse-led follow-up (P=0.03). No differences were found in most medical outcomes. However, body weight of patients of the standard follow-up group deteriorated slightly (P=0.04), whereas body weight of patients of the nurse-led follow-up group remained stable. Medical costs were lower in the nurse-led follow-up group (€2600 vs €3800), however, due to the large variation between patients, this was not statistically significant (P=0.11). A cost effectiveness acceptability curve showed that the probability of being cost effective for costs per one point gain in general quality-of-life exceeded 90 and 75% after 4 and 13 months of follow-up, respectively. Nurse-led follow-up at home does not adversely affect quality of life or satisfaction of patients compared with standard follow-up by clinicians at the outpatient clinic. This type of care is very likely to be more cost effective than physician-led follow-up.
PMCID: PMC2634677  PMID: 19066612
oesophageal cancer surgery; follow-up; quality of life; patient satisfaction; costs
16.  MUTYH Associated Polyposis (MAP) 
Current Genomics  2008;9(6):420-435.
MUTYH Associated Polyposis (MAP), a Polyposis predisposition caused by biallelic mutations in the Base Excision Repair (BER) gene MUTYH, confers a marked risk of colorectal cancer (CRC). The MAP phenotype is difficult to distinguish from other hereditary CRC syndromes. Especially from Familial Adenomatous Polyposis (FAP) and to a lesser extend Lynch Syndrome, which are caused by germline mutations in the APC and Mismatch Repair (MMR) genes, respectively.
Here we review research findings regarding MUTYH interactions, genotypic and phenotypic characteristics of MAP, as well as surveillance and treatment of the disease. The applied papers, published between 1/1 2002- 1/2 2008, were found through PubMed.
The exact role of MUTYH in CRC tumorgenesis is still uncertain, although MAP tumors show distinct molecular features, including somatic G:C>T:A transversions in the APC gene. Furthermore, cooperation between the BER and the MMR systems exists, as MUTYH interacts with MMR gene-products. Possibly, monoallelic defects in both pathways are of significance to CRC development.
Specific MUTYH variants are found to be characteristic in distinct ethnic populations, which could facilitate future genetic screening. Knowledge concerning functional consequences of many MUTYH germline mutations remains sparse. Most thoroughly investigated are the two most common MUTYH variants, Y179C and G396D, both generating dysfunctional gene products.
Phenotypic features of MAP include: development of 10-100 colorectal adenomas, debuting at 46-47 years, often CRC at time of clinical diagnosis, and in some, development of extracolonic manifestations.
PMCID: PMC2691665  PMID: 19506731
Colorectal cancer; MUTYH associated polyposis; The MUTYH gene; base excision repair; (Attenuated) familial adenomatous polyposis; lynch syndrome.
17.  ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial 
Cardiovascular Drugs and Therapy  2007;21(4):269-279.
ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction.
PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months.
In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07).
Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD.
PMCID: PMC2039813  PMID: 17657599
ACE inhibition; brachial reactivity; endothelial function; cardiovascular disease prevention; atherosclerosis; coronary heart disease
18.  Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma 
Gut  2004;53(10):1494-1498.
Background: Identification of risk factors for the development of hepatocellular carcinoma (HCC) is important for HCC surveillance in chronic hepatitis B virus (HBV) infection. Our aim was to study the independent risk factors and effect of HBV genotypes on HCC development in a prospective longitudinal cohort of chronic hepatitis B patients.
Patients and methods: Chronic hepatitis B patients recruited since 1997 were prospectively followed up for the development of HCC. HCC was diagnosed by a combination of α fetoprotein, imaging, and histology. Liver cirrhosis was defined as ultrasonic features of cirrhosis together with hypersplenism, ascites, varices, and/or encephalopathy.
Results: In total, 426 patients were followed up for 1664 person years; median 225 (range 12–295) weeks. Forty nine (11%) patients had underlying clinical liver cirrhosis. A total of 242 (57%) and 179 (42%) patients had HBV genotypes C and B, respectively. Twenty five patients developed HCC in a median follow up of 121 (range 14–236) weeks. The overall incidence of HCC was 1502 cases per 100 000 person years. On multivariate analysis, clinical liver cirrhosis and HBV genotype C infection were independently associated with HCC development, with an adjusted relative risk of 10.24 (95% confidence interval (CI) 4.39–23.89; p<0.001) and 2.84 (95% CI 1.05–7.72; p = 0.040), respectively. Patient age, sex, hepatitis B e antigen (HBeAg) status, alanine aminotransferase (ALT) levels, and basal core promoter mutations did not predict HCC development. Patients infected with HBV genotype C tended to have persistently positive HBeAg or fluctuating HBeAg status and higher ALT levels during the follow up period.
Conclusion: Genotype C HBV infection is an independent risk factor for HCC development in addition to liver cirrhosis.
PMCID: PMC1774221  PMID: 15361502
hepatitis B; genotype; hepatocellular carcinoma; liver cirrhosis; basal core promoter mutations
19.  Evaluating the role of human papillomaviruses in conjunctival neoplasia 
British Journal of Cancer  2006;94(3):446-449.
Mucosal, cutaneous and Epidermodysplasia verruciformis (EV)-related human papillomaviruses (HPVs) were searched by broad-spectrum PCR in 86 conjunctival neoplasia biopsies and 63 conjunctival non-neoplastic control tissue from Ugandan subjects. Seven different EV-related HPV types, including a putative new HPV, and two mucosal HPVs were detected in 25% (14 out of 56) of HIV-positive, in 10% (three out of 30) of HIV-negative conjunctival neoplasia samples, and rarely (0–1.6%) in control subjects. The absence of high-risk HPVs and the low detection frequency of EV-related HPV types in more advanced tumour stages (10%) raise doubts about their role in conjunctival carcinomas.
PMCID: PMC2361142  PMID: 16404433
conjunctiva squamous cell carcinoma; conjunctival intraepithelial neoplasia; papillomavirus; human immunodeficiency virus; Uganda
20.  Expression of the proapoptotic protein Bid is an adverse prognostic factor for radiotherapy outcome in carcinoma of the cervix 
British Journal of Cancer  2005;92(3):449-458.
The Bcl-2 family of apoptotic regulators is thought to play an essential role in cancer development and influence the sensitivity of tumour cells to radiotherapy. Bid is an abundantly expressed Bcl-2 family protein playing a central role in various pathways of apoptosis by integrating and converging signals at the mitochondria. The relevance of apoptotic modulation by Bcl-2 and related proteins in tumour development and radiation response for human tumours remains undefined. Therefore, a study was made regarding the expression of Bid in patients with locally advanced cervix carcinoma who received radiotherapy. Bid expression was assessed using immunohistochemistry in pretreatment archival biopsies from 98 patients. The data were correlated with clinicopathologic characteristics and treatment outcome. Pretreatment tumour radiosensitivity data were available for 60 patients. Strong Bid expression was associated with a patient age less than the median of 52 years (P=0.034) and poor metastasis-free survival. In multivariate analysis, after allowing for stage, Bid expression was a significant prognostic factor for both disease-specific and metastasis-free survival (P=0.026). It is concluded that strong tumour Bid expression is associated with poor outcome following radiotherapy regardless of intrinsic tumour cell radiosensitivity, and is adverse prognostic for disease-specific and metastasis-free survival in younger patients.
PMCID: PMC2362081  PMID: 15685241
Bcl-2 family; cervix carcinoma; prognosis; metastasis; radiotherapy
21.  Induction of Systemic and Mucosal Cross-Clade Neutralizing Antibodies in BALB/c Mice Immunized with Human Immunodeficiency Virus Type 1 Clade A Virus-Like Particles Administered by Different Routes of Inoculation 
Journal of Virology  2005;79(11):7059-7067.
We have recently developed a candidate human immunodeficiency virus type 1 (HIV-1) vaccine model, based on virus-like particles (VLPs) expressing gp120 from a Ugandan HIV-1 isolate of clade A (HIV-VLPAs), which shows the induction of neutralizing antibodies as well as cytotoxic T lymphocytes (CTL) in BALB/c mice by intraperitoneal (i.p.) administration. In the present study, immunization experiments based on a multiple-dose regimen have been performed with BALB/c mice to compare different routes of administration. i.p. and intranasal (i.n.), but not oral, administration induce systemic as well as mucosal (vaginal and intestinal) immunoglobulin G (IgG) and IgA responses. These immune sera exhibit >50% ex vivo neutralizing activity against both autologous and heterologous primary isolates. Furthermore, the administration of HIV-VLPAs by the i.n. immunization route induces a specific CTL activity, although at lower efficiency than the i.p. route. The HIV-VLPAs represent an efficient strategy to stimulate both arms of immunity; furthermore, the induction of specific humoral immunity at mucosal sites, which nowadays represent the main port of entry for HIV-1 infection, is of great interest. All these properties, and the possible cross-clade in vivo protection, could make these HIV-VLPAs a good candidate for a mono- and multicomponent worldwide preventive vaccine approach not restricted to high-priority regions, such as sub-Saharan countries.
PMCID: PMC1112107  PMID: 15890945
22.  Topographic Changes in SARS Coronavirus–infected Cells at Late Stages of Infection 
Emerging Infectious Diseases  2004;10(11):1907-1914.
Scanning electron and atomic force microscopy was used for the first time to view the maturation of SARS-CoV at the cell surface.
Scanning electron and atomic force microscopy was used for the first time to view the maturation of the severe acute respiratory syndrome–associated coronavirus at the cell surface. The surface form of the cells at advanced infection displayed prolific pseudopodia that, in addition to the rest of the plasma membrane, were also active sites of virus release. High magnification of the maturing virus particles showed a rosette appearance with short knoblike spikes under both the scanning electron and atomic force microscopes. The final expulsion step of the maturing virus particles seemed to result in some disruptions to the plasma membrane. The cytoskeletal network along the edge of the infected cells was enhanced and could be involved in transporting and expelling the progeny virus particles. Thickening of the actin filaments at the cell edge provided the bending force to extrude the virus particles.
PMCID: PMC3328989  PMID: 15550199
SARS coronavirus replication; atomic force microscopy; scanning electron microscopy; research
23.  How Plants Cope with Water Stress in the Field? Photosynthesis and Growth 
Annals of Botany  2002;89(7):907-916.
Plants are often subjected to periods of soil and atmospheric water deficit during their life cycle. The frequency of such phenomena is likely to increase in the future even outside today’s arid/semi‐arid regions. Plant responses to water scarcity are complex, involving deleterious and/or adaptive changes, and under field conditions these responses can be synergistically or antagonistically modified by the superimposition of other stresses. This complexity is illustrated using examples of woody and herbaceous species mostly from Mediterranean‐type ecosystems, with strategies ranging from drought‐avoidance, as in winter/spring annuals or in deep‐rooted perennials, to the stress resistance of sclerophylls. Differences among species that can be traced to different capacities for water acquisition, rather than to differences in metabolism at a given water status, are described. Changes in the root : shoot ratio or the temporary accumulation of reserves in the stem are accompanied by alterations in nitrogen and carbon metabolism, the fine regulation of which is still largely unknown. At the leaf level, the dissipation of excitation energy through processes other than photosynthetic C‐metabolism is an important defence mechanism under conditions of water stress and is accompanied by down‐regulation of photochemistry and, in the longer term, of carbon metabolism.
PMCID: PMC4233809  PMID: 12102516
Carbon assimilation; high temperature stress; Lupinus; photosynthesis; Quercus ilex; Quercus suber; stomatal functioning; Vitis vinifera; water‐stress, xanthophyll cycle
24.  Regulation of the Phosphate Stress Response in Rhizobium meliloti by PhoB 
Applied and Environmental Microbiology  1997;63(12):4978-4981.
Alkaline phosphatase activity and phosphate transport rates in Rhizobium meliloti increased significantly when medium phosphate levels decreased to approximately 10 (mu)M. Both responses were abolished in a Tn5:: phoB mutant, but the mutant could be complemented by a plasmid that contained cloned R. meliloti phoB. The PhoB(sup-) mutant had a normal symbiosis phenotype under growth conditions that supplied either limiting or nonlimiting levels of phosphate to the host plant Medicago sativa, suggesting that induction of genes by PhoB was not required for normal symbiotic function.
PMCID: PMC1389314  PMID: 16535758
25.  Expression of the thyroid hormone receptor gene, erbAalpha, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. 
Nucleic Acids Research  1997;25(21):4296-4300.
The erbAalpha gene encodes two alpha-thyroid hormone receptor isoforms, TRalpha1 and TRalpha2, which arise from alternatively processed mRNAs, erbAalpha1 (alpha1) and erb alpha2 (alpha2). The splicing and alternative polyadenylation patterns of these mRNAs resemble that of mRNAs encoding different forms of immunoglobulin heavy chains, which are regulated at the level of alternative processing during B cell differentiation. This study examines the levels of erbAalpha mRNA in eight B cell lines representing four stages of differentiation in order to determine whether regulation of the alternatively processed alpha1 and alpha2 mRNAs parallels the processing of immunoglobulin heavy chain mRNAs. Results show that the pattern of alpha1 and alpha2 mRNA expression is clearly different from that observed for immunoglobulin heavy chain mRNAs. B cell lines display characteristic ratios of alpha1/alpha2 mRNA at distinct stages of differentiation. Furthermore, expression of an overlapping gene, Rev-ErbAalpha (RevErb), was found to correlate strongly with an increase in the ratio of alpha1/alpha2 mRNA. These results suggest that alternative processing of erbAalpha mRNAs is regulated by a mechanism which is distinct from that regulating immunoglobulin mRNA. The correlation between RevErb and erbAalpha mRNA is consistent with negative regulation of alpha2 via antisense interactions with the complementary RevErb mRNA.
PMCID: PMC147039  PMID: 9336460

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