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1.  A gluten-free diet lowers NKG2D and ligand expression in BALB/c and non-obese diabetic (NOD) mice 
The interplay between diet and immune parameters which could affect type 1 diabetes (T1D) pathogenesis is not sufficiently clarified. Intestinal up-regulation of the activating receptor natural killer group 2D (NKG2D) (CD314) and its ligands is a hallmark of coeliac disease. However, the direct effect of gluten on NKG2D expression is not known. We studied, by fluorescence activated cell sorter (lymphoid tissues) and reverse transcription–quantitative polymerase chain reaction (intestine and pancreatic islets), if a gluten-free diet (GF diet) from 4 weeks of age or a gluten-free diet introduced in breeding pairs (SGF diet), induced changes in NKG2D expression on DX5+(CD49b) natural killer (NK) cells, CD8+ T cells and in intestinal and islet levels of NKG2D and ligands in BALB/c and non-obese diabetic (NOD) mice. Gluten-free NOD mice had lower insulitis (P < 0·0001); reduced expression of NKG2D on DX5+ NK cells in spleen and auricular lymph nodes (P < 0·05); and on CD8+ T cells in pancreas-associated lymph nodes (P = 0·04). Moreover, the level of CD71 on DX5+ NK cells and CD8+ T cells (P < 0·005) was markedly reduced. GF and SGF mice had reduced expression of NKG2D and DX5 mRNA in intestine (P < 0·05). Differences in intestinal mRNA expression were found in mice at 8, 13 and 20 weeks. Intestinal expression of NKG2D ligands was reduced in SGF mice with lower expression of all ligands. In isolated islets, a SGF diet induced a higher expression of specific NKG2D ligands. Our data show that a gluten-free diet reduces the level of NKG2D and the expression of NKG2D ligands. These immunological changes may contribute to the lower T1D incidence associated with a gluten-free diet.
PMCID: PMC4226590  PMID: 24673402
coeliac disease; gluten; gluten-free diet; NKG2D; type 1 diabetes
2.  Association Between Antiretroviral Exposure and Renal Impairment Among HIV-Positive Persons With Normal Baseline Renal Function: the D:A:D Studya 
The Journal of Infectious Diseases  2013;207(9):1359-1369.
Background. Several antiretroviral agents (ARVs) are associated with chronic renal impairment, but the extent of such adverse events among human immunodeficiency virus (HIV)–positive persons with initially normal renal function is unknown.
Methods. D:A:D study participants with an estimated glomerular filtration rate (eGFR) of ≥90 mL/min after 1 January 2004 were followed until they had a confirmed eGFR of ≤70 mL/min (the threshold below which we hypothesized that renal interventions may begin to occur) or ≤60 mL/min (a value indicative of moderately severe chronic kidney disease [CKD]) or until the last eGFR measurement during follow-up. An eGFR was considered confirmed if it was detected at 2 consecutive measurements ≥3 months apart. Predictors and eGFR-related ARV discontinuations were identified using Poisson regression.
Results. Of 22 603 persons, 468 (2.1%) experienced a confirmed eGFR of ≤70 mL/min (incidence rate, 4.78 cases/1000 person-years of follow-up [95% confidence interval {CI}, 4.35–5.22]) and 131 (0.6%) experienced CKD (incidence rate, 1.33 cases/1000 person-years of follow-up [95% CI, 1.10–1.56]) during a median follow-up duration of 4.5 years (interquartile range [IQR], 2.7–6.1 years). A current eGFR of 60–70 mL/min caused significantly higher rates of discontinuation of tenofovir (adjusted incidence rate ratio [aIRR], 1.72 [95% CI, 1.38–2.14]) but not other ARVs compared with a current eGFR of ≥90 mL/min. Cumulative tenofovir use (aIRR, 1.18/year [95% CI, 1.12–1.25]) and ritonavir-boosted atazanavir use (aIRR, 1.19/year [95% CI, 1.09–1.32]) were independent predictors of a confirmed eGFR of ≤70 but were not significant predictors of CKD whereas ritonavir-boosted lopinavir use was a significant predictor for both end points (aIRR, 1.11/year [95% CI, 1.05–1.17] and 1.22/year [95% CI, 1.16–1.28], respectively). Associations were unaffected by censoring for concomitant ARV use but diminished after discontinuation of these ARVs.
Conclusions. Tenofovir, ritonavir-boosted atazanavir, and ritonavir-boosted lopinavir use were independent predictors of chronic renal impairment in HIV-positive persons without preexisting renal impairment. Increased tenofovir discontinuation rates with decreasing eGFR may have prevented further deteriorations. After discontinuation, the ARV-associated incidence rates decreased.
PMCID: PMC3610424  PMID: 23382571
HIV; eGFR; ART; tenofovir; atazanavir; lopinavir; chronic kidney disease; nephrotoxicity
3.  Effects of LPS and dietary free fatty acids on MCP-1 in 3T3-L1 adipocytes and macrophages in vitro 
Nutrition & Diabetes  2014;4(3):e113-.
High levels of free fatty acids (FFA) have been suggested to be one of the underlying mechanisms for adipose tissue (AT) inflammation and dysfunction in obesity. Human AT produces several adipokines including monocyte chemoattractant protein-1 (MCP-1), which are involved in the pathogenesis of obesity-mediated inflammation.
In this study, we investigated the effects of lipopolysaccharide (LPS) and a panel of dietary FFA on MCP-1 gene and protein expression in adipocytes and macrophages. Furthermore, we investigated whether the effect of LPS and FFA were mediated through the toll-like receptor 4 (TLR4).
3T3-L1 adipocytes and THP-1 macrophages were incubated for 24 h with the following FFA: monounsaturated fatty acid (oleic acid), saturated fatty acid (palmitic acid) and trans fatty acid (elaidic acid; 500 μM) with and without LPS (2 ng ml−1), and MCP-1 and TLR4 mRNA expression and MCP-1 protein secretion was determined.
The results showed that LPS significantly increased MCP-1 and TLR4 expression and MCP-1 secretion in 3T3-L1 adipocytes, and that the MCP-1 expression was blocked by a TLR4 inhibitor (CLI095). The effects of the various FFA on MCP-1 mRNA expression and protein secretion in the adipocytes showed no significant changes either alone or in combination with LPS. In macrophages, palmitic acid increased MCP-1 mRNA expression by 1.8-fold (P<0.05), but oleic acid and elaidic acid had no effects.
In conclusion, in 3T3-L1 adipocyte, the TLR4-agonist, LPS, stimulates the proinflammatory chemokine MCP-1. The different classes of FFA did not induce MCP-1 mRNA expression or protein secretion in the adipocytes, but the saturated FFA, palmitic acid, induced MCP-1 mRNA expression in macrophages, possibly because of the higher expression level of TLR4 in the macrophages than the adipocytes. Our results indicate that FFA may induce AT inflammation through proinflammatory stimulation of macrophages.
PMCID: PMC3974034  PMID: 24662749
4.  First detection of livestock-associated meticillin-resistant Staphylococcus aureus CC398 in bulk tank milk in the United Kingdom, January to July 2012 
Livestock-associated meticillin-resistant Staphylococcus aureus belonging to clonal complex 398 (LA-MRSA CC398) is an important cause of zoonotic infections in several countries, but there is only a single published report of this lineage from the United Kingdom (UK). Here, we describe the isolation of LA-MRSA CC398 from bulk tank milk from five geographically dispersed farms in the UK. Our findings suggest that LA-MRSA CC398 is established in livestock in the UK. Awareness of the potential occupational risks and surveillance in other food-producing animal species should be promoted.
PMCID: PMC3867000  PMID: 23241232
5.  Metabolism of Hyperpolarized [1-13C]Pyruvate in the Isolated Perfused Rat Lung – An Ischemia Study 
NMR in biomedicine  2012;25(10):1113-1118.
We report studies of the effect of ischemia on the metabolic activity of the intact, perfused lung, and its restoration after a period of reperfusion. Two groups of rat lungs were studied using hyperpolarized 1-13C pyruvate to compare the rate of lactate labeling, differing only in the temporal ordering of ischemic and normoxic acquisitions. In both cases, a several-fold increase in lactate labeling was observed immediately after a 25-minute ischemia event as was its reversal back to the baseline after 30–40 minutes of resumed perfusion (n=5, p < 0.025 for both comparisons). These results were corroborated by 31P spectroscopy, and correspond well to measured changes in lactate pool size determined by 1H spectroscopy of freeze-clamped specimens.
PMCID: PMC3399019  PMID: 22311307
Hyperpolarization; lung metabolism; multinuclear MRI
6.  NeuroD1 regulation of migration accompanies the differential sensitivity of neuroendocrine carcinomas to TrkB inhibition 
Oncogenesis  2013;2(8):e63-.
The developmental transcription factor NeuroD1 is anomalously expressed in a subset of aggressive neuroendocrine tumors. Previously, we demonstrated that TrkB and neural cell adhesion molecule (NCAM) are downstream targets of NeuroD1 that contribute to the actions of neurogenic differentiation 1 (NeuroD1) in neuroendocrine lung. We found that several malignant melanoma and prostate cell lines express NeuroD1 and TrkB. Inhibition of TrkB activity decreased invasion in several neuroendocrine pigmented melanoma but not in prostate cell lines. We also found that loss of the tumor suppressor p53 increased NeuroD1 expression in normal human bronchial epithelial cells and cancer cells with neuroendocrine features. Although we found that a major mechanism of action of NeuroD1 is by the regulation of TrkB, effective targeting of TrkB to inhibit invasion may depend on the cell of origin. These findings suggest that NeuroD1 is a lineage-dependent oncogene acting through its downstream target, TrkB, across multiple cancer types, which may provide new insights into the pathogenesis of neuroendocrine cancers.
PMCID: PMC3759124  PMID: 23958853
NeuroD1; neuroendocrine; TrkB; migration
7.  Marked Subchondral Bandlike Osteopenia on Radiography after Trauma and Inactivity: A Report of four Cases 
Case Reports in Orthopedics  2013;2013:234278.
We report about four cases of marked subchondral osteopenia on followup radiography after trauma and prolonged disuse. This localized form of disuse osteopenia has not been reported in details beside the followup imaging of talar neck fractures, where it is known as the “Hawkins sign.” Due to its unique morphology, it can be easily recognized as a benign finding in posttraumatic followup imaging and can be morphologically distinguished from severe complications like complex regional pain syndrome type 1 (Sudeck's disease) or periarticular osteopenia in infectious arthritis. It is important for the radiologist and orthopaedic surgeon to be aware of this form of disuse osteopenia in the proper clinical context.
PMCID: PMC3638522  PMID: 23691391
8.  Analysis of Reserve Capacity and Subsequent Stenting in a Case of Subacute Occlusion of the Internal Carotid Artery 
Clinical Neuroradiology  2012;23(3):225-229.
While acute internal carotid artery (ICA) occlusions are increasingly being treated with carotid angioplasty and stenting (CAS), the utility of CAS in subacute stages is unclear.
Case Report
A 65-year-old patient with an acute left ICA occlusion and pre-existing occlusion on the right side presented with dysarthria and central right-sided facial palsy. Carbon dioxide (CO2) reactivity within the left hemisphere was markedly reduced. Due to acute deterioration despite maximal conservative therapy CAS was performed 8 days after the initial event with an excellent result and symptoms subsided.
CAS in subacute ICA occlusion is possible. Patients should be selected carefully. Assessment of cerebrovascular CO2 reactivity might provide valuable information.
PMCID: PMC3739872  PMID: 22960936
9.  Measurements of the persistent singlet state of N2O in blood and other solvents–Potential as a magnetic tracer 
Magnetic Resonance in Medicine  2011;66(4):1177-1180.
The development of hyperpolarized tracers has been limited by short nuclear polarization lifetimes. The dominant relaxation mechanism for many hyperpolarized agents in solution arises from intramolecular nuclear dipole-dipole coupling modulated by molecular motion. It has been previously demonstrated that nuclear spin relaxation due to this mechanism can be removed by storing the nuclear polarization in long-lived, singlet-like states. In the case of N2O, storing the polarization of the nitrogen nuclei has been shown to substantially increase the polarization lifetime. The feasibility of utilizing N2O as a tracer is investigated by measuring the singlet-state lifetime of the N2O when dissolved in a variety of solvents including whole blood. Comparison of the singlet lifetime to longitudinal relaxation and between protonated and deuterated solvents is consistent with the dominance of spin-rotation relaxation, except in the case of blood.
PMCID: PMC3380434  PMID: 21928358
Singlet States; Long Lived States; Nitrous Oxide; Hyperpolarized Tracer
10.  Histamine Immunoreactive Axons in the Macaque Retina 
The goal of these experiments was to identify the neurotransmitter in centrifugal axons of the macaque retina.
Macaca mulatta, retinas and optic nerves were fixed overnight in carbodiimide and labeled with an antiserum to histamine with the use of an immunofluorescence technique.
Several large histamine-immunoreactive axons ran from the optic nerve head to the peripheral retina, where they branched extensively and terminated in the inner plexiform layer, occasionally alongside retinal blood vessels. Other axons that emerged from the optic nerve head ran in the optic fiber layer to the central retina, circled the fovea, and then returned to the optic disc. These may be the source of histamine-immunoreactive axons that have been observed in central visual areas. No labeled cell bodies were present in the retina. Because perikarya in die posterior hypothalamus are the only known source of histamine in the primate central nervous system and because neurons there can be retrogradely labeled from the cut optic nerve, the histamine-immunoreactive axons must have originated there.
Centrifugal axons in the macaque retina are part of the system of axons containing histamine that originate in the hypothalamus and project throughout the brain. Because the activity of these neurons is highest during the morning, histamine might play a role in preparing the retina to operate in daylight. The contacts of histamine-immunoreactive axons with blood vessels suggest that histamine may also play a role in regulating the retinal microvasculature.
PMCID: PMC3342641  PMID: 9950609
11.  Use of the Frank Sequence in Pulsed EPR 
The Frank polyphase sequence has been applied to pulsed EPR of triarylmethyl radicals at 256 MHz (9.1 mT magnetic field), using 256 phase pulses. In EPR, as in NMR, use of a Frank sequence of phase steps permits pulsed FID signal acquisition with very low power microwave/RF pulses (ca. 1.5 mW in the application reported here) relative to standard pulsed EPR. A 0.2 mM aqueous solution of a triarylmethyl radical was studied using a 16 mm diameter cross loop resonator to isolate the EPR signal detection system from the incident pulses.
PMCID: PMC3107679  PMID: 21371924
Correlation spectroscopy; Frank sequence; NMR; EPR; low power; multi-pulse EPR
12.  Mild cognitive impairment in Parkinson disease 
Neurology  2010;75(12):1062-1069.
In studies of mild cognitive impairment (MCI) in Parkinson disease (PD), patients without dementia have reported variable prevalences and profiles of MCI, likely to be due to methodologic differences between the studies.
The objective of this study was to determine frequency and the profile of MCI in a large, multicenter cohort of well-defined patients with PD using a standardized analytic method and a common definition of MCI.
A total of 1,346 patients with PD from 8 different cohorts were included. Standardized analysis of verbal memory, visuospatial, and attentional/executive abilities was performed. Subjects were classified as having MCI if their age- and education-corrected z score on one or more cognitive domains was at least 1.5 standard deviations below the mean of either control subjects or normative data.
A total of 25.8% of subjects (95% confidence interval [CI] 23.5–28.2) were classified as having MCI. Memory impairment was most common (13.3%; 11.6–15.3), followed by visuospatial (11.0%; 9.4–13.0) and attention/executive ability impairment (10.1%; 8.6–11.9). Regarding cognitive profiles, 11.3% (9.7–13.1) were classified as nonamnestic single-domain MCI, 8.9% (7.0–9.9) as amnestic single-domain, 4.8% (3.8–6.1) as amnestic multiple-domain, and 1.3% (0.9–2.1) as nonamnestic multiple-domain MCI. Having MCI was associated with older age at assessment and at disease onset, male gender, depression, more severe motor symptoms, and advanced disease stage.
MCI is common in patients with PD without dementia, affecting a range of cognitive domains, including memory, visual-spatial, and attention/executive abilities. Future studies of patients with PD with MCI need to determine risk factors for ongoing cognitive decline and assess interventions at a predementia stage.
= amnestic multiple-domain MCI;
= amnestic single-domain MCI;
= confidence interval;
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= mild cognitive impairment;
= Mini-Mental State Examination;
= nonamnestic multiple-domain MCI;
= nonamnestic single-domain MCI;
= Parkinson disease;
= Parkinson's Disease Cognitive Rating Scale;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC2942065  PMID: 20855849
13.  Choice of psychological coping in laryngectomized, head and neck squamous cell carcinoma patients versus multiple sclerosis patients 
To be treated for cancer must be a frightening experience. Yet quality of life (QoL) of successfully treated cancer patients seems to be relatively similar in comparison with QoL of a general population, with psychological coping partly responsible for this finding. When measuring choice of coping, the nature of coping score levels constituting appropriate scores, and whether score levels rely on the context of the disease has not been settled. We have studied the COPE coping responses as related to disease in successfully treated head and neck squamous cell carcinoma (HNSCC) patient groups (general and laryngectomized), as well as compared to multiple sclerosis (MS) patients. The COPE response patterns have also been compared to the Beck depression inventory (BDI) scores. Age and gender of patients were not directly associated with choice of coping. Within the problem-focused coping indexes, the coping index “active coping” was reported to be most utilized among HNSCC patients, whereas “coping by suppression” and “coping by social support” were most utilized among MS patients. Emotional-focused coping was most prevalent among HNSCC patients and lowest among the MS patients. Level of avoidance coping was similar between the groups. The coping of the general HNSCC patients differed most from the MS patients. An association was shown between increased coping efforts and lowered mood. In particular, avoidance coping was associated with lowered mood. These associations were stronger among the MS patients than HNSCC patients. Drinking to cope was most prevalent among the laryngectomized group, and was correlated with BDI scores in all groups. Furthermore, adequate coping seems to be to limit avoidance coping and promote coping by acceptance. The response pattern of the COPE inventory seems to be valid among HNSCC and MS patients.
PMCID: PMC3087083  PMID: 21085978
Neoplasms; Head and neck cancer; Multiple sclerosis; Psychological coping; Drinking to cope; Depression
14.  Insomnia in Parkinson's disease: frequency and progression over time 
To examine the development of nocturnal sleeping problems in patients with Parkinson's disease (PD) over an 8‐year period and to study the clinical and demographic correlates of insomnia.
231 patients were included in a population‐based prevalence study in 1993, and re‐examined in 1997 and 2001. At all study visits, we applied semi‐structured interviews to obtain information on clinical and demographic data, as well as on nocturnal sleeping problems. Standardised rating scales of parkinsonism, depression and cognitive impairment were used. The relationship between insomnia and demographic and clinical variables was analysed using population‐averaged logistic regression models for correlated data. 231 patients were included at baseline, 142 were available for re‐evaluation in 1997 and 89 patients in 2001.
Most nocturnal sleeping problems varied little in prevalence over time, whereas problems related to turning in bed and vivid dreaming or nightmares increased. Insomnia was present in 54–60% of the patients at each of the three study visits and varied considerably in individual patients over time. The presence of insomnia was closely related to disease duration, higher Montgomery–Åsberg Depression Rating Scale scores and female sex.
Insomnia is a highly frequent complaint in patients with PD. It fluctuates over time in individual patients, and its origin seems to be multifactorial. Physicians should be aware of the high prevalence of insomnia in patients with PD and should examine their patients for a possible coexisting depression.
PMCID: PMC2117851  PMID: 17098844
15.  Tandem aneurysms of an internal mammary-aortocoronary bypass graft 
Netherlands Heart Journal  2009;17(7-8):300-302.
Graft aneurysms following aortocoronary surgery are a rare occurrence in clinical practice. Reported cases have mostly involved saphenous vein grafts. Here we report the rare finding of a tandem aneurysm of an internal mammary artery graft which was incidentally detected 17 years following bypass surgery. (Neth Heart J 2009;17:300-2.19789701)
PMCID: PMC2743822  PMID: 19789701
aneurysm; coronary artery bypass grafting; internal mammary artery; spiral computed tomography
16.  Phylogenetic Analysis of Members of the Phycodnaviridae Virus Family, Using Amplified Fragments of the Major Capsid Protein Gene▿  
Applied and Environmental Microbiology  2008;74(10):3048-3057.
Algal viruses are considered ecologically important by affecting host population dynamics and nutrient flow in aquatic food webs. Members of the family Phycodnaviridae are also interesting due to their extraordinary genome size. Few algal viruses in the Phycodnaviridae family have been sequenced, and those that have been have few genes in common and low gene homology. It has hence been difficult to design general PCR primers that allow further studies of their ecology and diversity. In this study, we screened the nine type I core genes of the nucleocytoplasmic large DNA viruses for sequences suitable for designing a general set of primers. Sequence comparison between members of the Phycodnaviridae family, including three partly sequenced viruses infecting the prymnesiophyte Pyramimonas orientalis and the haptophytes Phaeocystis pouchetii and Chrysochromulina ericina (Pyramimonas orientalis virus 01B [PoV-01B], Phaeocystis pouchetii virus 01 [PpV-01], and Chrysochromulina ericina virus 01B [CeV-01B], respectively), revealed eight conserved regions in the major capsid protein (MCP). Two of these regions also showed conservation at the nucleotide level, and this allowed us to design degenerate PCR primers. The primers produced 347- to 518-bp amplicons when applied to lysates from algal viruses kept in culture and from natural viral communities. The aim of this work was to use the MCP as a proxy to infer phylogenetic relationships and genetic diversity among members of the Phycodnaviridae family and to determine the occurrence and diversity of this gene in natural viral communities. The results support the current legitimate genera in the Phycodnaviridae based on alga host species. However, while placing the mimivirus in close proximity to the type species, PBCV-1, of Phycodnaviridae along with the three new viruses assigned to the family (PoV-01B, PpV-01, and CeV-01B), the results also indicate that the coccolithoviruses and phaeoviruses are more diverged from this group. Phylogenetic analysis of amplicons from virus assemblages from Norwegian coastal waters as well as from isolated algal viruses revealed a cluster of viruses infecting members of the prymnesiophyte and prasinophyte alga divisions. Other distinct clusters were also identified, containing amplicons from this study as well as sequences retrieved from the Sargasso Sea metagenome. This shows that closely related sequences of this family are present at geographically distant locations within the marine environment.
PMCID: PMC2394928  PMID: 18359826
17.  Long-term efficacy and safety of insulin detemir compared to Neutral Protamine Hagedorn insulin in patients with Type 1 diabetes using a treat-to-target basal–bolus regimen with insulin aspart at meals: a 2-year, randomized, controlled trial 
Diabetic Medicine   2008;25(4):442-449.
This 24-month, multi-national, open-label, parallel group trial investigated the long-term efficacy and safety of insulin detemir and Neutral Protamine Hagedorn insulin in combination with mealtime insulin aspart in patients with Type 1 diabetes using a treat-to-target concept.
Patients were randomized 2 : 1 to detemir (n = 331) or NPH (n = 166) groups. Basal insulin was initiated once daily (evening) and titrated individually based on self-measured plasma glucose (PG) levels, aiming for pre-breakfast and pre-dinner targets ≤ 6.0 mmol/l. A second basal morning dose could be added according to pre-defined criteria.
After 24 months, superiority of glycated haemoglobin (HbA1c) was achieved with detemir compared to NPH (detemir 7.36%, NPH 7.58%, mean difference −0.22% points) [95% confidence interval (CI) −0.41 to −0.03%], with reductions of 0.94% and 0.72% points, respectively. Fasting PG (FPGlab) was also lower with detemir (detemir 8.35 mmol/l, NPH 9.43 mmol/l; P = 0.019). Twenty-two per cent of patients treated with detemir reached an HbA1c ≤ 7.0% in the absence of confirmed hypoglycaemia during the last month of treatment vs. 13% on NPH (P = 0.019). Risk of major and nocturnal hypoglycaemia was 69% and 46% lower with detemir than with NPH (P < 0.001), respectively; patients treated with detemir gained less weight (detemir 1.7 kg, NPH 2.7 kg; P = 0.024). The overall safety profile was similar in the two groups and treatment with detemir did not result in any unexpected findings.
Long-term treatment with the insulin analogues detemir + aspart was superior to NPH + aspart in reducing HbA1c, with added benefits of less major and nocturnal hypoglycaemia and less weight gain.
Diabet. Med. 25, 442–449 (2008)
PMCID: PMC2327220  PMID: 18387078
insulin analogues; glycaemic control; hypoglycaemia; Type 1 diabetes; HbA1c
18.  A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes 
Diabetologia  2008;51(3):408-416.
This 52-week multinational, randomised, open-label, parallel-group, non-inferiority trial compared clinical outcomes following supplementation of oral glucose-lowering drugs with basal insulin analogues detemir and glargine in type 2 diabetic patients.
Insulin-naive adults (n = 582, HbA1c 7.5–10.0%, BMI ≤ 40.0 kg/m2) were randomised 1:1 to receive insulin detemir or glargine once daily (evening) actively titrated to target fasting plasma glucose (FPG) ≤ 6.0 mmol/l. An additional morning insulin detemir dose was permitted if pre-dinner plasma glucose (PG) was >7.0 mmol/l after achieving FPG < 7.0 mmol/l. Due to labelling restrictions, no second glargine dose was allowed.
Baseline HbA1c decreased from 8.6 to 7.2 and 7.1% (NS) with detemir and glargine, respectively. FPG improved from 10.8 to 7.1 and 7.0 mmol/l (NS), respectively. With detemir, 45% of participants completed the study on once daily dosing and 55% on twice daily dosing, with no difference in HbA1c. Overall, 52% of participants achieved HbA1c ≤ 7.0%: 33% (detemir) and 35% (glargine) without hypoglycaemia. Within-participant variability for self-monitored FPG and pre-dinner PG did not differ by insulin treatment, nor did the relative risk of overall or nocturnal hypoglycaemia. Modest reductions in weight gain were seen with detemir vs glargine in completers (3.0 vs 3.9 kg, p = 0.01) and in the intention-to-treat population (2.7 vs 3.5 kg, p = 0.03), primarily related to completers on once-daily detemir. Mean daily detemir dose was higher (0.78 U/kg [0.52 with once daily dosing, 1.00 U/kg with twice daily dosing]) than glargine (0.44 IU/kg). Injection site reactions were more frequent with detemir (4.5 vs 1.4%).
Supplementation of oral agents with detemir or glargine achieves clinically important improvements in glycaemic control with low risk of hypoglycaemia. Non-inferiority was demonstrated for detemir using higher insulin doses (mainly patients on twice daily dosing); weight gain was somewhat reduced with once daily insulin detemir. ID no.: NCT00283751.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0911-x) contains supplementary material, which is available to authorised users.
PMCID: PMC2235909  PMID: 18204830
Body weight; Fasting plasma glucose; Glucose variability; Glucose control; Hypoglycaemia; Insulin detemir; Insulin glargine; Insulin supplementation; Oral glucose-lowering agents; Type 2 diabetes
19.  TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis 
British Journal of Cancer  2006;95(8):1114-1120.
Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of four inhibitors of the matrix metalloproteinases, which are capable of degrading most components of the extracellular matrix. However, in recent years, TIMP-1 has been recognised as a multifunctional protein, playing a complex role in cancer. In this regard, several studies have demonstrated an antiapoptotic effect of TIMP-1 in a number of different cell types. Since chemotherapy works by inducing apoptosis in cancer cells, we raised the hypothesis that TIMP-1 promotes resistance against chemotherapeutic drugs. In order to investigate this hypothesis, we have established TIMP-1 gene-deficient and TIMP-1 wild-type fibrosarcoma cells from mouse lung tissue. We have characterised these cells with regard to TIMP-1 genotype, TIMP-1 expression, malignant transformation and sensitivity to chemotherapy-induced apoptosis. We show that TIMP-1 gene deficiency increases the response to chemotherapy considerably, confirming that TIMP-1 protects the cells from apoptosis. This is to our knowledge the first study investigating TIMP-1 and chemotherapy-induced apoptosis employing a powerful model system comprising TIMP-1 gene-deficient cells and their genetically identical wild-type controls. For future studies, this cell system can be used to uncover the mechanisms and signalling pathways involved in the TIMP-1-mediated inhibition of apoptosis as well as to investigate the possibility of using TIMP-1 inhibitors to optimise the effect of conventional chemotherapy.
PMCID: PMC2360707  PMID: 17047657
TIMP-1; apoptosis; chemotherapy; fibrosarcoma cells
20.  Continued improvement of clinical outcome and cost effectiveness following intravascular ultrasound guided PCI: insights from a prospective, randomised study 
Heart  2003;89(9):1043-1049.
Objective: To investigate in a prospective randomised study both long term clinical effects and cost effectiveness of percutaneous coronary interventions (PCI) with or without intravascular ultrasound (IVUS) guidance.
Methods: 108 male patients with stable angina referred for PCI of a significant coronary lesion were randomly assigned to IVUS guided PCI or conventional PCI. Individual accumulated costs of the entire follow up period were calculated and compared in the randomisation groups. Effectiveness of treatment was measured by freedom from major adverse cardiac events.
Results: Cost effectiveness of IVUS guided PCI that was noted at six months was maintained and even accentuated at long term follow up (median 2.5 years). The cumulated cost level was found to be lower for the IVUS guided group, with a cumulated cost of &163 672 in the IVUS guided group versus &313 706 in the coronary angiography group (p = 0.01). Throughout the study, mean cost per day was lower in the IVUS guided PCI group (&2.7 v &5.2; p = 0.01). In the IVUS group, 78% were free from major adverse cardiac events versus 59% in the coronary angiography group (p = 0.04) with an odds ratio of 2.5 in favour of IVUS guidance.
Conclusion: IVUS guidance results in continued improvement of long term clinical outcome and cost effectiveness. The results of this study suggest that IVUS guidance may be used more liberally in PCI.
PMCID: PMC1767812  PMID: 12923023
intravascular ultrasonography; percutaneous coronary intervention; cost effectiveness
21.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
PMCID: PMC1738667  PMID: 12933921
22.  Primary amyloid tumour of the breast: a case report 
Journal of Clinical Pathology  2002;55(8):634-635.
A case of primary amyloid tumour of the breast is reported with a brief review of the literature. The tumour was mammographically suspicious of carcinoma. Fine needle aspiration cytology yielded clumps of amorphous material surrounded by giant cells and lymphocytes. Subsequent histology showed nodular amyloid associated with osseous metaplasia and giant cell reaction. There are 13 cases of amyloid tumour of the breast reported in the literature and in four of these fine needle aspiration had been undertaken.
PMCID: PMC1769737  PMID: 12147664
breast; tumour; fine needle aspiration cytology; osseous metaplasia; amyloid
23.  Donepezil for cognitive impairment in Parkinson's disease: a randomised controlled study 
Objective: To study the safety and efficacy of the cholinesterase inhibitor donepezil in patients with Parkinson's disease (PD) and cognitive impairment.
Methods: This was a double blind, randomised and placebo controlled, crossover study in which 14 patients with PD and cognitive impairment received donepezil (5 or 10 mg per day) or matching placebo during two sequential periods lasting 10 weeks each. The primary outcome measures were the mini mental state examination (MMSE) score, the clinician's interview based impression of change plus caregiver input (CIBIC+) score, and the motor subscale of the unified Parkinson's disease rating scale (UPDRS).
Results: Two patients on donepezil (14%) dropped out after one and four weeks of the first treatment period because of peripheral cholinergic side effects, otherwise the adverse effects were few and not severe. Carryover or residual effects were not observed. Parkinsonism did not increase during donepezil treatment. After 10 weeks of treatment, the mean MMSE score was increased by 2.1(SD 2.7) points on donepezil and 0.3 (SD 3.2) points on placebo, and the CIBIC+ score was 3.3 (SD 0.9) on donepezil and 4.1 (SD 0.8) on placebo. Statistical analysis of the repeated measurements and crossover study design showed significant effects of donepezil compared with placebo for MMSE (p=0.013) and CIBIC+ (p=0.034). Five (42%) patients on donepezil and two (17%) on placebo were rated as improved on the basis of the CIBIC+ score.
Conclusions: Donepezil improves cognition, and seems to be well tolerated and not to worsen parkinsonism in patients with cognitive impairment.
PMCID: PMC1737925  PMID: 12023410
24.  Health related quality of life in Parkinson's disease: a prospective longitudinal study 
OBJECTIVES—To examine the change over time in health related quality of life (HRQL) in a community based cohort of patients with Parkinson's disease.
METHODS—One hundred and eleven patients were evaluated for HRQL in 1993 and then again in a follow up study 4 years later. The patients included in the study in 1993 were derived from a prevalence study of patients with Parkinson's disease in the county of Rogaland, Norway. The HRQL was measured by the Nottingham health profile (NHP). At both evaluations clinical and demographic variables were determined during semistructured interviews and by clinical examinations by a neurologist.
RESULTS—During the 4 year follow up period there was a significant increase in NHP scores, reflecting a decreased HRQL, in the dimensions of physical mobility, emotional reactions, pain, and social isolation. In the same time period mean total NHP score increased from 120.0(SD 102.6) to 176.0 (SD 119.4) (p<0.01). There were no clinical or demographic factors found in 1993 that identified patients at higher risk for developing decreased HRQL. Increased UPDRS score (unified Parkinson's disease rating scale) and Hoehn and Yahr stage during the 4 year study period correlated with increased NHP scores. Even though there was no increase in depressive symptoms or self reported insomnia, these symptoms, together with lower Schwab and England score, were the most important factors for a poor HRQL in 1997.
CONCLUSIONS—Parkinson's disease has a substantial impact on HRQL. Despite modern care, we found a significantly increased distress during the 4 year follow up period. Increased parkinsonism, measured by UPDRS and Hoehn and Yahr stage, correlated with increased stress, not only in the dimension of physical mobility, but also in the areas of pain, social isolation, and emotional reactions. In addition to the clinical examination, HRQL scoring provides valuable information on the total health burden of Parkinson's disease in both cross sectional and longitudinal evaluations, and contributes to a more comprehensive picture of the total disease impact.

PMCID: PMC1763406  PMID: 11032608

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