Decreased gallbladder smooth muscle (GBSM) contractility is a hallmark of cholesterol gallstone disease, but the interrelationship between lithogenicity, biliary stasis and inflammation are poorly understood. We studied a mouse model of gallstone disease to evaluate the development of GBSM dysfunction relative to changes in bile composition and the onset of sterile cholecystitis.
BALB/cJ mice were fed a lithogenic diet for up to 8 weeks, and tension generated by gallbladder muscle strips was measured. Smooth muscle Ca2+ transients were imaged in intact gallbladder.
Lipid composition of bile was altered lithogenically as early as one week, with increased hydrophobicity and cholesterol saturation indexes; however, inflammation was not detectable until the fourth week. Agonist-induced contractility was reduced from weeks 2 through 8. GBSM normally exhibits rhythmic synchronized Ca2+ flashes, and their frequency is increased by carbachol (3μM). After one week, lithogenic diet-fed mice exhibited disrupted Ca2+ flash activity, manifesting as clustered flashes, asynchronous flashes or prolonged quiescent periods. These changes could lead to a depletion of intracellular Ca2+ stores, which are required for agonist-induced contraction, and diminished basal tone of the organ. Responsiveness of Ca2+ transients to carbachol was reduced in mice on the lithogenic diet, particularly after 4-8 weeks, concomitant with appearance of mucosal inflammatory changes.
Conclusions & Inferences
These observations demonstrate that GBSM dysfunction is an early event in the progression of cholesterol gallstone disease and that it precedes mucosal inflammation.
bile composition; cholecystitis; biliary motility; gallbladder emptying
The estimation of phylogenetic relationships and divergence times among a group of organisms is a fundamental first step toward understanding its biological diversification. The time of the most recent or last common ancestor (LCA) of extant platyrrhines is one of the most controversial among scholars of primate evolution. Here we use two molecular based approaches to date the initial divergence of the platyrrhine clade, Bayesian estimations under a relaxed-clock model and substitution rate plus generation time and body size, employing the fossil record and genome datasets. We also explore the robustness of our estimations with respect to changes in topology, fossil constraints and substitution rate, and discuss the implications of our findings for understanding the platyrrhine radiation. Our results suggest that fossil constraints, topology and substitution rate have an important influence on our divergence time estimates. Bayesian estimates using conservative but realistic fossil constraints suggest that the LCA of extant platyrrhines existed at ca. 29 Ma, with the 95% confidence limit for the node ranging from 27–31 Ma. The LCA of extant platyrrhine monkeys based on substitution rate corrected by generation time and body size was established between 21–29 Ma. The estimates based on the two approaches used in this study recalibrate the ages of the major platyrrhine clades and corroborate the hypothesis that they constitute very old lineages. These results can help reconcile several controversial points concerning the affinities of key early Miocene fossils that have arisen among paleontologists and molecular systematists. However, they cannot resolve the controversy of whether these fossil species truly belong to the extant lineages or to a stem platyrrhine clade. That question can only be resolved by morphology. Finally, we show that the use of different approaches and well supported fossil information gives a more robust divergence time estimate of a clade.
•We investigate the role of PPARδ in a model of Parkinson’s disease.•PPARδ is upregulated after the neurotoxin MPTP.•PPARδ antagonism enhances MPP+ toxicity which is reversible by PPARδ agonism.•PPARδ agonism protects against MPTP-toxicity.
Peroxisome proliferator-activated receptor (PPAR)-γ and PPARα have shown neuroprotective effects in models of Parkinson’s disease (PD). The role of the third, more ubiquitous isoform PPARδ has not been fully explored. This study investigated the role of PPARδ in PD using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to model the dopaminergic neurodegeneration of PD. In vitro administration of the PPARδ antagonist GSK0660 (1 μM) increased the detrimental effect of 1-methyl-4-phenylpyridinium iodide (MPP+) on cell viability, which was reversed by co-treatment with agonist GW0742 (1 μM). GW0742 alone did not affect MPP+ toxicity. PPARδ was expressed in the nucleus of dopaminergic neurons and in astrocytes. Striatal PPARδ levels were increased (over two-fold) immediately after MPTP treatment (30 mg/kg for 5 consecutive days) compared to saline-treated mice. PPARδ heterozygous mice were not protected against MPTP toxicity. Intra-striatal infusion of GW0742 (84 μg/day) reduced the MPTP-induced loss of dopaminergic neurons (5036 ± 195) when compared to vehicle-infused mice (3953 ± 460). These results indicate that agonism of PPARδ provides protection against MPTP toxicity, in agreement with the effects of other PPAR agonists.
DMEM, Dulbecco’s Modified Eagle Medium; DMSO, dimethyl sulfoxide; DPBS, Dulbecco’s phosphate-buffered saline; EDTA, ethylenediaminetetraacetic acid; FCS, foetal calf serum; GFAP, glial fibrillary acid protein; IL, interleukin; LDH, lactate dehydrogenase; MAC-1, macrophage antigen complex-1; MPP+, 1-methyl-4-phenylpyridinium iodide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MTT, 3-(4,5-dimethylthizol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PD, Parkinson’s disease; PFA, paraformaldehyde; PPAR, peroxisome proliferator-activated receptor; TH, tyrosine hydroxylase; TNFα, tumour necrosis factor-α; MPP+; neurodegeneration; neuroinflammation; SH-SY5Y; MPTP; PPAR delta
Cerebral blood flow (CBF) increases from rest to ∼60% of peak oxygen uptake (VO2peak) and thereafter decreases towards baseline due to hyperventilation-induced hypocapnia and subsequent cerebral vasoconstriction. It is unknown what happens to CBF in older adults (OA), who experience a decline in CBF at rest coupled with a blunted ventilatory response during VO2peak. In 14 OA (71 ± 10 year) and 21 young controls (YA; 23 ± 4 years), we hypothesized that OA would experience less hyperventilation-induced cerebral vasoconstriction and therefore an attenuated reduction in CBF at VO2peak. Incremental exercise was performed on a cycle ergometer, whilst bilateral middle cerebral artery blood flow velocity (MCA Vmean; transcranial Doppler ultrasound), heart rate (HR; ECG) and end-tidal PCO2 (PETCO2) were monitored continuously. Blood pressure (BP) was monitored intermittently. From rest to 50% of VO2peak, despite greater elevations in BP in OA, the change in MCA Vmean was greater in YA compared to OA (28% vs. 15%, respectively; P < 0.0005). In the YA, at intensities >70% of VO2peak, the hyperventilation-induced declines in both PETCO2 (14 mmHg (YA) vs. 4 mmHg (OA); P < 0.05) and MCA Vmean (−21% (YA) vs. −7% (OA); P < 0.0005) were greater in YA compared to OA. Our findings show (1), from rest-to-mild intensity exercise (50% VO2peak), elevations in CBF are reduced in OA and (2) age-related declines in hyperventilation during maximal exercise result in less hypocapnic-induced cerebral vasoconstriction.
Cerebral blood flow; Humans; Aging; Ventilation; Exercise intensity; Cycling; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
The endoscopic transsphenoidal approach (eTSA) to lesions of the sellar region is typically performed jointly by neurosurgeons and otolaryngologists. Occasionally, the approach is significantly altered by sinonasal disease, anatomic variants, or previous surgery. However, there are no current guidelines that describe which physical or radiological findings should prompt a change in the plan of care. The purpose of this study was to determine the incidence of sinonasal pathology or anatomic variants noted endoscopically or by imaging that altered preoperative or intraoperative management.
A retrospective review was performed of 355 consecutive patients who underwent combined neurosurgery–otolaryngology endoscopic sella approach from August 1, 2007 to April 1, 2011. Our practice in these patients involves preoperative otolaryngology clinical evaluation and MRI review. Intraoperative image guidance is not routinely used in uncomplicated eTSA.
The most common management alteration was the addition of image guidance based on anatomic variants on MRI, which occurred in 81 patients (35.0%). Eight patients (2.9%) were preoperatively treated with antibiotics and surgery was postponed secondary to acute or chronic purulent rhinosinusitis; two (0.7%) required functional endoscopic sinus surgery for medically refractory disease before eTSA. Five patients (1.8%) required anterior septoplasty intraoperatively for severe nasal septal deviation. Two patients (0.7%) had inverted papilloma and one patient had esthesioneuroblastoma identified preoperatively during rigid nasal endoscopy.
This is one of the larger reviews of patients undergoing eTSA for sellar lesions and the only study that describes how intraoperative management may be altered by preoperative sinonasal evaluation. We found a significant incidence of sinonasal pathology and anatomic variants that altered routine operative planning; therefore, a thorough sinonasal evaluation is warranted in these cases.
Endoscopic; image-guided surgery; incidental; preoperative; sella; sinonasal; transsphenoidal
The aim of the present study was to evaluate the use of 2-deoxy-2-(18F)-fluoro-D-glucose (18FDG) positron emission tomography (PET)/computed tomography (CT) in patients with suspected ovarian cancer recurrence and describe the distribution of metastasis. A total of 45 female patients who underwent PET/CT scan due to raised CA-125 levels, clinical suspicion of ovarian cancer recurrence or alterations detected on ultrasound (US), CT or magnetic resonance imaging (MRI) were included in this retrospective study. PET/CT results were compared with histological findings (n=15) or clinical, laboratory and repeated imaging techniques during subsequent follow-up for at least six months (n=30). CA-125 was elevated in 34 patients, 14 patients had clinical symptoms of disease and 23 presented with alterations on US, CT and MRI. A total of 42 patients were confirmed to have ovarian cancer recurrence, all with abnormal findings on PET/CT. Three patients remained free of disease during clinical follow-up, all with normal PET/CT findings. There were 11 patients with raised CA-125 levels and normal conventional imaging, all with positive PET/CT. Among the 11 patients with normal CA-125 levels, eight presented with positive PET/CT scan. Lymph nodes were the most frequent site of relapse of disease, followed by peritoneal implants. Distant sites of metastasis included the liver, spleen, pleura, lung and bone. PET/CT detected unsuspected lesions in 20/45 patients (44.4%). 18FDG PET/CT was a useful tool for evaluating the extent of ovarian cancer recurrence. In the current series, lymph nodes were the most frequent site of relapse of disease, with supradiaphragmatic lymph node metastasis in a large number of cases.
18FDG; PET scan; ovarian neoplasms
To investigate whether circulating levels of fibroblast growth factor 21 (FGF21), which previously has been shown to be elevated in obesity, could predict the development of type 2 diabetes in a 5.4-year, population-based, prospective study.
RESEARCH DESIGN AND METHODS
Baseline plasma FGF21 levels were measured using an enzyme-linked immunosorbent assay in 1,900 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). The prospective association of FGF21 with diabetes development over 5.4 years was analyzed using multiple logistic regression.
At baseline, plasma levels of FGF21 increased progressively with worsening dysglycemia from normal glucose tolerance, through prediabetes, to diabetes (global trend, P < 0.001). Of 1,292 subjects without diabetes at baseline, a high baseline FGF21 level was a strong independent predictor for diabetes development (odds ratio 1.792; P < 0.01), together with waist circumference and fasting plasma glucose levels.
Plasma FGF21 levels were significantly increased in subjects with prediabetes and diabetes and predicted the development of diabetes in humans.
Isotretinoin’s (13-cis RA) full mechanism of action in treating acne is unknown. 13-cis RA induces key genes in sebocytes that are involved in apoptosis. In this study, we report that 13-cis RA up-regulates expression of Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL) within SEB-1 sebocytes.
Treatment with recombinant human TRAIL (rhTRAIL) protein increases TUNEL positive staining in SEB-1 sebocytes. TRAIL siRNA significantly decreases the percentage of TUNEL positive SEB-1 sebocytes in response to 13-cis RA treatment. Furthermore, TRAIL expression increases in the skin of acne patients after one week of isotretinoin therapy compared to baseline. TRAIL expression localized within sebaceous glands. Unlike sebocytes, TRAIL protein expression is not increased in normal human epidermal keratinocytes in response to 13-cis RA, nor does rhTRAIL induce apoptosis in keratinocytes, suggesting that TRAIL is key in the sebocyte-specific apoptotic effects of 13-cis RA.
Taken together, our data suggests that TRAIL, like the neutrophil gelatinase-associated lipocalin is involved in mediating 13-cis RA apoptosis of sebocytes.
isotretinoin; sebaceous gland; acne; TRAIL; apoptosis
A clear-cut need exists for safe and effective alternatives to the use of isotretinoin in severe acne. Lack of data regarding the specifics of isotretinoin’s mechanism of action has hampered progress in this area. Recently the protein neutrophil gelatinase-associated lipocalin (NGAL) has been identified as a mediator of the apoptotic effect of isotretinoin on sebocytes. The goal of this paper is to further establish the clinical relevance of NGAL and to elucidate the factors that induce NGAL expression in sebocytes.
Methods were developed to isolate and quantify skin surface levels of NGAL from normal subjects and acne patients undergoing treatment with isotretinoin. Acne patients were found to have higher skin levels of NGAL compared to normal subjects. Studies in SEB-1 sebocytes indicate that NGAL expression is increased in response to P. acnes and IL-1β. In patients, isotretinoin increases NGAL levels by 2.4-fold on the skin surface and this increase precedes decreases in sebum and P. acnes counts.
These data support the hypothesis that NGAL is an important mediator of the early effects of isotretinoin on the sebaceous glands and provide insights into the mechanisms that regulate NGAL expression in the skin.
Acne; Isotretinoin; NGAL; P. acnes
Adipose tissue inflammation and dysregulated adipokine secretion are implicated in obesity-related insulin resistance and type 2 diabetes. We evaluated the use of serum adiponectin, an anti-inflammatory adipokine, and several proinflammatory adipokines, as biomarkers of diabetes risk and whether they add to traditional risk factors in diabetes prediction.
We studied 1300 non-diabetic subjects from the prospective Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). Serum adiponectin, tumor necrosis factor-alpha receptor 2 (TNF-α R2), interleukin-6 (IL-6), adipocyte–fatty acid binding protein (A-FABP) and high-sensitivity C-reactive protein (hsCRP) were measured in baseline samples.
Seventy-six participants developed diabetes over 5.3 years (median). All five biomarkers significantly improved the log-likelihood of diabetes in a clinical diabetes prediction (CDP) model including age, sex, family history of diabetes, smoking, physical activity, hypertension, waist circumference, fasting glucose and dyslipidaemia. In ROC curve analysis, “adiponectin + TNF-α R2” improved the area under ROC curve (AUC) of the CDP model from 0.802 to 0.830 (P = 0.03), rendering its performance comparable to the “CDP + 2-hour post-OGTT glucose” model (AUC = 0.852, P = 0.30). A biomarker risk score, derived from the number of biomarkers predictive of diabetes (low adiponectin, high TNF-α R2), had similar performance when added to the CDP model (AUC = 0.829 [95% CI: 0.808–0.849]).
The combined use of serum adiponectin and TNF-α R2 as biomarkers provided added value over traditional risk factors for diabetes prediction in Chinese and could be considered as an alternative to the OGTT.
BACKGROUND AND PURPOSE
The neuroanatomic substrate of cognitive deficits in long-term survivors of prematurity with PVL is poorly understood. The thalamus is critically involved in cognition via extensive interconnections with the cerebral cortex. We hypothesized that the thalamus is atrophic (reduced in volume) in childhood survivors of prematurity with neuroimaging evidence of PVL and that the atrophy is associated with selective microstructural abnormalities within its subdivisions.
MATERIALS AND METHODS
We performed quantitative volumetric and DTI measurements of the thalamus in 17 children with neuroimaging evidence of PVL (mean postconceptional age, 5.6 ± 4.0 years) who were born prematurely and compared these with 74 term control children (5.7 ± 3.4 years).
The major findings were the following: 1) a significant reduction in the overall volume of the thalamus in patients with PVL compared with controls (P < .0001), which also correlated with the severity of PVL (P = .001); 2) significantly decreased FA (P = .003) and increased λ⊥ (P = .02) in the thalamus overall and increased axial, radial, and mean diffusivities in the pulvinar (P < .03), suggesting injury to afferent and efferent myelinated axons; and 3) a positive correlation of pulvinar abnormalities with those of the parieto-occipital white matter in periventricular leukomalacia, suggesting that the pulvinar abnormalities reflect secondary effects of damaged interconnections between the pulvinar and parieto-occipital cortices in the cognitive visual network.
There are volumetric and microstructural abnormalities of the thalamus in preterm children with PVL, very likely reflecting neuronal loss and myelinated axonal injury. The selective microstructural damage in the pulvinar very likely contributes to abnormal cognitive visual processing known to occur in such survivors.
The KCNJ11 E23K variant is associated with type 2 diabetes mellitus (T2DM) in cross-sectional studies, but conflicting findings have been reported from prospective studies.
This study aimed to evaluate whether the E23K variant could predict glycaemic progression in a Southern Chinese population.
We performed a long-term prospective study on 1912 subjects from the Hong Kong Cardiovascular Risk Factors Prevalence Study (CRISPS). The KCNJ11 E23K variant was associated with the progression to prediabetes after a median interval of 12 years on multinomial logistic regression analysis, even after adjustment for traditional risk factors (OR 1.29, Page, sex, BMI and fasting plasma glucose [FPG] adjusted = 0.02). Based on Cox proportional hazard regression analysis, the E23K variant also predicted incident prediabetes (HR 1.18, Page, sex, BMI and FPG adjusted = 0.021). However, E23K was not associated with the progression to T2DM in either multinomial or Cox regression analysis, and the association of E23K with glycaemic progression to either prediabetes or T2DM was significant only in unadjusted Cox regression analysis (P = 0.039). In a meta-analysis of eight prospective studies including our own, involving 15680 subjects, the E23K variant was associated with incident T2DM (fixed effect: OR 1.10, P = 4×10−3; random effect: OR 1.11, P = 0.035).
Our study has provided supporting evidence for the role of the E23K variant in glycaemic progression in Chinese, with its effect being more evident in the early stage of T2DM, as the subjects progressed from normal glucose tolerance to prediabetes.
Multielectrodes have been used with great success to simultaneously record the activity of neuronal populations in awake, behaving animals. In particular, there is great promise in the use of this technique to allow the control of neuroprosthetic devices by human patients. However, it is crucial to fully characterize the tissue response to the chronic implants in animal models ahead of the initiation of human clinical trials. Here we evaluated the effects of unilateral multielectrode implants on the motor cortex of rats weekly recorded for 1–6 months using several histological methods to assess metabolic markers, inflammatory response, immediate-early gene (IEG) expression, cytoskeletal integrity and apoptotic profiles. We also investigated the correlations between each of these features and firing rates, to estimate the impact of post-implant time on neuronal recordings. Overall, limited neuronal loss and glial activation were observed on the implanted sites. Reactivity to enzymatic metabolic markers and IEG expression were not significantly different between implanted and non-implanted hemispheres. Multielectrode recordings remained viable for up to 6 months after implantation, and firing rates correlated well to the histochemical and immunohistochemical markers. Altogether, our results indicate that chronic tungsten multielectrode implants do not substantially alter the histological and functional integrity of target sites in the cerebral cortex.
In the 1980s the outlook for patients with the acquired immunodeficiency syndrome (AIDS) and critical illness was poor. Since then several studies of outcome of HIV+ patients on ICU have shown improving prognosis, with anti-retroviral therapy playing a large part. We retrospectively examined intensive care (ICU) admissions in a large HIV unit in London. Between April 2001 and April 2006 43 patients were admitted to the ICU. The mean age of patients was 44 years and 74% were male. Fifty-six percent of admissions were receiving anti-retroviral therapy and 44% had an AIDS defining diagnosis. The median CD4 count was 128 cells/mL and the median APACHE II score was 21. The commonest diagnostic ICU admission category was respiratory disease. This group experienced higher mortality despite slightly lower APACHE II scores, though this did not achieve statistical significance. The follow up period was one year or until April 2007, when data were censored. ICU mortality was 33%, in hospital mortality was 51% and overall mortality at the end of the study period was 67%. Median survival was 1008 days. The CD4 count did not predict long-term survival, although the sample size was too small for this to be conclusive.
The mitogen-activated protein kinase (MAPK) phosphatases or dual specificity phosphatases (DUSPs) are a family of proteins that catalyse the inactivation of MAPK in eukaryotic cells. Little is known of the expression, regulation or function of the DUSPs in human neoplasia.
We used RT–PCR and quantitative PCR (qPCR) to examine the expression of DUSP16 mRNA. The methylation in the DUSP16 CpG island was analysed using bisulphite sequencing and methylation-specific PCR. The activation of MAPK was determined using western blotting with phospho-specific antibodies for extra-cellular signal-related kinase (ERK), p38 and c-Jun N-terminal kinase (JNK). The proliferation of cell lines was assessed using the CellTiter 96 Aqueous One assay.
The expression of DUSP16, which inactivates MAPK, is subject to methylation-dependent transcriptional silencing in Burkitt's Lymphoma (BL) cell lines and in primary BL. The silencing is associated with aberrant methylation in the CpG island in the 5′ regulatory sequences of the gene blocking its constitutive expression. In contrast to BL, the CpG island of DUSP16 is unmethylated in other non-Hodgkin's lymphomas (NHLs) and epithelial malignancies. In BL cell lines, neither constitutive nor inducible ERK or p38 activity varied significantly with DUSP16 status. However, activation of JNK was increased in lines with DUSP16 methylation. Furthermore, methylation in the DUSP16 CpG island blocked transcriptional induction of DUSP16, thereby abrogating a normal physiological negative feedback loop that limits JNK activity, and conferred increased cellular sensitivity to agents, such as sorbitol and anthracycline chemotherapeutic agents that activate JNK.
DUSP16 is a new epigenetically regulated determinant of JNK activation in BL.
DUSP; Epigenetics; HIV; Burkitt's lymphoma
In the absence of widespread access to individualized laboratory monitoring, which forms an integral part of HIV patient management in resource-rich settings, the roll-out of highly active antiretroviral therapy (HAART) in resource-limited settings has adopted a public health approach based on standard HAART protocols and clinical/immunological definitions of therapy failure. The cost-effectiveness of HIV-1 viral load monitoring at the individual level in such settings has been debated, and questions remain over the long-term and population-level impact of managing HAART without it. Computational models that accurately predict virological response to HAART using baseline data including CD4 count, viral load and genotypic resistance profile, as developed by the Resistance Database Initiative, have significant potential as an aid to treatment selection and optimization. Recently developed models have shown good predictive performance without the need for genotypic data, with viral load emerging as by far the most important variable. This finding provides further, indirect support for the use of viral load monitoring for the long-term optimization of HAART in resource-limited settings.
computational modelling; antiretroviral therapy; HIV/AIDS; access
OBJECTIVE—To investigate the relationships of serum adipocyte fatty acid–binding protein (A-FABP) and epidermal fatty acid–binding protein (E-FABP) with renal dysfunction and macrovascular complications in type 2 diabetic patients.
RESEARCH DESIGN AND METHODS—The associations of serum A-FABP and E-FABP with markers of renal function, nephropathy staging, and macrovascular complications were examined in 237 type 2 diabetic patients.
RESULTS—Serum A-FABP and E-FABP correlated significantly with serum creatinine, mean albumin excretion rate, and glomerular filtration rate (all P < 0.001) and were independently associated with diabetic nephropathy staging (P = 0.001 and P < 0.05, respectively). Circulating levels of both types of FABP were increased (P < 0.01) in subjects with macrovascular complications. Serum A-FABP was independently associated with macrovascular complications (odds ratio 2.92 [95% CI 1.42–6.01]; P = 0.004).
CONCLUSIONS—Serum A-FABP and E-FABP might be novel serum biomarkers for evaluating the progression of nephropathy and its cardiovascular risk in type 2 diabetic patients.
OBJECTIVE—To investigate the association between raised blood pressure and dysglycemia.
RESEARCH DESIGN AND METHODS—We studied the association between raised blood pressure and dysglycemia in 1,862 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study cohort. We determined the factors predicting the development of diabetes and hypertension in 1,496 subjects who did not have either condition at baseline.
RESULTS—Diabetes and hypertension were both related to age, obesity indexes, blood pressure, glucose, HDL cholesterol, and triglycerides. Of subjects with diabetes, 58% had raised blood pressure. Of subjects with hypertension, 56% had dysglycemia. BMI and blood glucose 2 h after a 75-g oral glucose load were independent predictors of new-onset diabetes. Age, systolic blood pressure, and 2-h glucose were independent predictors of new-onset hypertension. BMI, systolic blood pressure, and 2-h glucose were independent predictors of the development of diabetes and hypertension together.
CONCLUSIONS—Diabetes and hypertension share common etiological factors. Patients with diabetes or hypertension should be screened and managed for the precursor of the other condition.
We report initial results with single voxel spectroscopy (SVS) using diffusion weighting and localization by adiabatic selective refocusing (LASER) in breast tumors to measure the apparent diffusion coefficient of water (ADCw). This is a quick (30 sec.) and relatively easy method to implement compared to image-based diffusion measurements, and is insensitive to lipid signal contamination. The ADCw and concentration of total choline containing compounds, [tCho], were evaluated for associations with each other and final pathologic diagnosis in 25 subjects. The average (+/- S.D.) ADCw in benign and malignant lesions was 1.96 +/- 0.47 mm2/s and 1.26 +/- 0.29 × 10-3 mm2/s, respectively, p < 0.001. Receiver operating characteristic curve analysis showed an area under the curve of 0.92. Analysis of the single voxel (SV) ADCw and [tCho] showed significant correlation with a R2 of 0.56, p<0.001. Compared to more commonly used image-based methods of measuring water ADC, SV-ADCw is faster, more robust, insensitive to fat, and potentially easier to implement on standard clinical systems.
Atazanavir, an azadipeptide protease inhibitor (PI) with once daily dosing, a lack of insulin resistance, lipid increase, and gastrointestinal toxicities, is approved in combination with other antiretrovirals for the treatment of patients infected with HIV. Unboosted atazanavir is also used in highly active antiretroviral therapy (HAART) naive patients.
The study prospectively followed up an established cohort of patients who received atazanavir, and for whom one year of follow up data were available.
It was found that use of atazanavir in intent to treat and on treatment analyses, maintained and led to virological suppression and increases in CD4 count in both PI naive and experienced patients. Virological failure occurred in 7% of patients and the main toxicity was hyperbilirubinaemia, which led to treatment withdrawal in 2%. Its efficacy and safety profile was similar to that seen in previous randomised studies investigating its use.
These data should provide reassurance for clinicians wishing to introduce a new antiretroviral into an established cohort.
HIV; AIDS; compliance; atazanavir; lipid
Cardiac fibroma is more commonly encountered in patients with Gorlin syndrome than the general population. Mutations of the tumor suppressor gene PTCH1 localized to 9q22.3 are the underlying cause of Gorlin syndrome. In this study, homozygous or heterozygous loss of the PTCH1 locus was identified in three nonsyndromic cardiac fibromas. These data support a somatic role of the PTCH1 tumor suppressor gene in sporadic cardiac fibroma.
Cardiac fibroma is a rare benign tumor that is poorly characterized genetically. Cardiac fibroma is more commonly encountered in patients with Gorlin syndrome (3%) than the general population. Mutations of the tumor suppressor gene PTCH1 are the underlying cause of Gorlin syndrome.
Conventional cytogenetic analysis was performed on a peripheral blood and a cardiac fibroma sample from a 2-week-old male. In addition, FISH studies were performed to assess the copy number of the PTCH1 gene locus (9q22.3) on metaphase and interphase cells from these same specimens using YAC probe 891G1 and on representative paraffin-embedded tissue sections of two additional cardiac fibromas (one arising in a 2-month-old female and the other in a 13-week-old male). None of the patients had Gorlin syndrome.
Karyotypically, the following abnormal chromosomal complement was detected in the 2-week-old male’s cardiac fibroma: 46,XY,del(9)(q22q34). FISH studies revealed homozygous loss of the PTCH1 locus in the cytogenetically analyzed cardiac fibroma and in the cardiac fibroma arising in the 13-week-old male. Heterozygous loss of this locus was identified in the remaining cardiac fibroma from the 2-month-old female. A mutational mechanism other than deletion may be responsible for PTCH1 inactivation on the other locus in this latter patient. Conventional cytogenetic and FISH studies of the peripheral blood sample from the 2-week-old male were normal.
These data support a tumor suppressor gene role for PTCH1 in nonsyndromic or sporadic cardiac fibromas.
Cardiac fibroma; Gorlin syndrome; PTCH1 gene
Small-conductance Ca2• -activated K• (SK) channels play an important role in regulating the frequency and in shaping urinary bladder smooth muscle (UBSM) action potentials, thereby modulating contractility. Here we investigated a role for the SK2 member of the SK family (SK1−3) utilizing: 1) mice expressing • -galactosidase (• -gal) under the direction of the SK2 promoter (SK2 • -gal mice) to localize SK2 expression and 2) mice lacking SK2 gene expression (SK2• /• mice) to assess SK2 function. In SK2 • -gal mice, UBSM staining was observed, but staining was undetected in the urothelium. Consistent with this, urothelial SK2 mRNA was determined to be 4% of that in UBSM. Spontaneous phasic contractions in wild-type (SK2• /•) UBSM strips were potentiated (259% of control) by the selective SK channel blocker apamin (EC50 • 0.16 nM), whereas phasic contractions of SK2• /• strips were unaffected. Nerve-mediated contractions of SK2• /• UBSM strips were also increased by apamin, an effect absent in SK2• /• strips. Apamin increased the sensitivity of SK2• /• UBSM strips to electrical field stimulation, since pretreatment with apamin decreased the frequency required to reach a 50% maximal contraction (vehicle, 21 • 4 Hz, n • 6; apamin, 12 • 2 Hz, n • 7; P & 0.05). In contrast, the sensitivity of SK2• /• UBSM strips was unaffected by apamin. Here we provide novel insight into the molecular basis of SK channels in the urinary bladder, demonstrating that the SK2 gene is expressed in the bladder and that it is essential for the ability of SK channels to regulate UBSM contractility.
bladder; contractility; small-conductance calcium-activated potassium channel; apamin
Background: The CD4 count is a dominant prognostic and predictive factor in HIV infection. This study assessed the utility of the total lymphocyte count (TLC) in place of the CD4 count to predict the development of AIDS defining opportunistic infections (ADOI).
Methods: The Chelsea and Westminster cohort was used to identify those people with a first episode of an ADOI. Corresponding CD4 and TLCs were recorded before diagnosis or at the time of first prescribing prophylaxis; patients without an AIDS defining opportunistic infection were defined as being at "risk" and receiver operating characteristic (ROC) curves were used to display the results of sensitivity and the false positive error rate of total lymphocyte and CD4 count groups.
Results: A significant linear correlation was seen between the log10 CD4 count and log10 TLC (Pearson's correlation coefficient = 0.70, p<0.001). The finer cut off value for TLC where false positive error rate is minimum and sensitivity maximum was 1500–2000 cells/mm3. Patients with TLC 1000–1500 cells/mm3 were estimated to be at 40% increased risk of developing an ADOI. The cut off value for CD4 counts measured 200 cells/mm3 above which the risk developing an ADOI decreased. Patients with a CD4 count of 150–200 cells/mm3 were at a 34% increased risk of developing an ADOI. The area under the ROC curve for TLC was 10% lower than that for CD4 count.
Conclusions: The TLC is minimally less reliable than the CD4 count as a predictor of ADOIs. In the absence of expensive equipment for CD4 measurement, the TLC is a useful test.