Experimental evaluation of dual Multiple Aperture Devices for Fluence Field Modulated X-Ray Computed Tomography.

Acquisition of CT images with comparable diagnostic power can potentially be achieved with lower radiation exposure than the current standard of care through the adoption of hardware-based fluence-field modulation (e.g. dynamic bowtie filters). While modern CT scanners employ elements such as static bowtie filters and tube-current modulation, such solutions are limited in the fluence patterns that they can achieve, and thus are limited in their ability to adapt to broad classes of patient morphology. Fluence-field modulation also enables new applications such as region-of-interest imaging, task specific imaging, reducing measurement noise or improving image quality. The work presented in this paper leverages a novel fluence modulation strategy that uses "Multiple Aperture Devices" (MADs) which are, in essence, binary filters, blocking or passing x-rays on a fine scale. Utilizing two MAD devices in series provides the capability of generating a large number of fluence patterns via small relative motions between the MAD filters. We present the first experimental evaluation of fluence-field modulation using a dual-MAD system, and demonstrate the efficacy of this technique with a characterization of achievable fluence patterns and an investigation of experimental projection data.

A genetic risk score that includes common type 2 diabetes risk variants is associated with gestational diabetes.

OBJECTIVE: Gestational diabetes (GDM) is characterized by maternal glucose intolerance that manifests during pregnancy. Because GDM resembles type 2 diabetes (T2DM), shared genetic predisposition is likely but has not been established. We tested the hypothesis that a genetic risk score (GRS) that included variants known to be associated with T2DM is associated with GDM. STUDY DESIGN: We conducted a case-control study using the Vanderbilt Medical Center biobank (BioVU) and calculated a simple-count GRS using 34 variants previously associated with T2DM or fasting glucose in the general population, or with GDM or glucose intolerance in pregnancy. We assessed the association of the GRS with GDM adjusting for maternal age, parity, and body mass index (BMI) and calculated the area under the curve for the receiver-operating characteristic curve (c-statistic). STUDY POPULATION: Among Caucasian women, we identified 458 cases of GDM and 1538 pregnant controls with normal glucose tolerance. RESULTS: Cases of GDM had a higher number of risk alleles compared to controls (38.9±4.0 vs 37.4±4.0 risk alleles, P=1.6×10-11 ). The GRS was significantly associated with GDM; the adjusted odds ratio associated with each additional risk allele was 1.10 (95% CI: 1.07-1.13, P=6×10-11 ). Clinical variables predicted the risk of GDM (c-statistic 0.67, 95% CI: 0.64-0.70), and adding the GRS modestly improved prediction (0.70, 95% CI: 0.67-0.73). CONCLUSIONS: Among Caucasian women, a GRS that included common T2DM genetic risk variants was associated with increased risk of GDM but showed limited utility in the identification of GDM cases.

The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy.

Statins (HMG-CoA reductase inhibitors) lower low-density lipoprotein cholesterol (LDL-C) and prevent cardiovascular disease. However, there is wide individual variation in LDL-C response. Drugs targeting proprotein convertase subtilin/kexin type 9 (PCSK9) lower LDL-C and will be used with statins. PCSK9 mediates the degradation of LDL receptors (LDLRs). Therefore, a greater LDL-C response to statins would be expected in individuals with PCSK9 loss-of-function (LOF) variants because LDLR degradation is reduced. To examine this hypothesis, the effect of 11 PCSK9 functional variants on statin response was determined in 669 African Americans. One LOF variant, rs11591147 (p.R46L) was significantly associated with LDL-C response to statin (P=0.002). In the three carriers, there was a 55.6% greater LDL-C reduction compared with non-carriers. Another functional variant, rs28362261 (p.N425S), was marginally associated with statin response (P=0.0064).The effect of rs11591147 was present in individuals of European ancestry (N=2388, P=0.054). The therapeutic effect of statins may be modified by genetic variation in PCSK9.

Genetic variation in the alpha1B-adrenergic receptor and vascular response.

The alpha1B (α1B)-adrenergic receptors contribute to vasoconstriction in humans. We tested the hypothesis that variation in the ADRA1B gene contributes to interindividual variability and ethnic differences in adrenergic vasoconstriction. We measured dorsal hand vein responses to increasing doses of phenylephrine in 64 Caucasians and 41 African Americans and genotyped 34 ADRA1B variants. We validated findings in another model of catecholamine-induced vasoconstriction, the increase in mean arterial pressure (ΔMAP) during a cold pressor test (CPT). One ADRA1B variant, rs10070745, present in 14 African-American heterozygotes but not in Caucasians, was associated with a lower phenylephrine ED50 (geometric mean (95% confidence interval), 144 (69-299) ng ml-1) compared with 27 African-American non-carriers (208 (130-334) ng ml-1; P=0.015) and contributed to the ethnic differences in ED50. The same variant was also associated with a greater ΔMAP during CPT (P=0.008). In conclusion, ADRA1B rs10070745 was significantly associated with vasoconstrictor responses after adrenergic stimulation and contributed to the ethnic difference in phenylephrine sensitivity.

HLA-DRB1*0102 is associated with TINU syndrome and bilateral, sudden-onset anterior uveitis but not with interstitial nephritis alone.

BACKGROUND: Tubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the authors performed HLA analysis on subjects with isolated bilateral sudden-onset uveitis (as in the TINU subtype) or with isolated tubulointerstitial nephritis (TIN). METHODS: Patients with sudden onset, anterior, bilateral uveitis not fulfilling a diagnosis of TINU were identified. Pathology reports were reviewed to identify subjects with biopsy-proven TIN. Molecular typing of the HLA-DRB1 gene was performed by the Luminex technology-based sequence-specific oligonucleotide (SSO) hybridisation method (One Lambda, Canoga Park, California). HLA-DRB1 allele frequencies were compared with normal published controls (http://www.ncbi.nlm.nih.gov/projects/gv/mhc/ihwg.cgi dbMHC Europe cohort) and the published TINU cohort (n=18). RESULTS: The authors included 28 subjects with uveitis and 14 with TIN. There was a significantly higher frequency of DRB1*0102 in the isolated uveitis cohort versus in normal controls (10.7% vs 0.6%, respectively, p<0.0001; RR 14.3 (6.9-29.8)). None of the nephritis patients showed this HLA subtype. Another association with HLA-DRB1*08 was seen in the isolated uveitis cohort with an allele frequency of 10.7% versus 2.7% in normal controls (p=0.0019; RR 4.0 (1.8-9.0)). In contrast, the HLA-DRB1*08 was not different from controls in the TINU cohort (allele frequency 2.8%, p=not significant). CONCLUSION: The incidence of HLA-DRB1*0102 is increased in sudden-onset bilateral anterior uveitis, as seen in patients with TINU. The same allele does not appear to occur in increased frequency in patients with isolated TIN. HLA DRB1*0102 might predispose to this subset of uveitis.

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals.

Birdshot chorioretinopathy (BCR), a chronic ocular inflammatory disease with characteristic choroidal lymphocytic infiltrates, has been strongly associated with human leukocyte antigen (HLA)-A29. Although HLA-A29 occurs frequently in all populations, BCR affects only a small percentage of HLA-A29-positive Caucasians, indicating additional susceptibility factors for BCR. Discovery of HLA class I-specific killer cell immunoglobulin-like receptors (KIR) led to a series of epidemiological studies implicating KIR-HLA gene combinations in disease. Here, we characterized KIR-HLA pairs in BCR patients and controls carrying HLA-A*29 as well as controls lacking HLA-A*29. KIR-HLA pairs implicated for weak inhibition (KIR2DL2/3+HLA-C1 and KIR3DL1+HLA-Bw4(T80)) in combination with activating KIR genes associated with autoimmunity (KIR2DS2, 2DS3 and 2DS4) augment the risk of developing BCR in HLA-A*29-positive individuals. The reciprocal association of strong inhibitory pairs (KIR3DL1+HLA-Bw4(I80) and KIR2DL1+HLA-C2) in combination with those implicated in protection from infection (KIR3DS1+HLA-Bw4(I80) and KIR2DS1+HLA-C2) was observed in HLA-A*29-negative controls. These results suggest that a profound effect of KIR2DS2/S3/S4 in the absence of strong inhibition may enhance the activation of natural killer cells and T-cell subsets against intraocular self-antigens, thereby contributing to pathogenesis of BCR.

Immunogenetics of ocular inflammatory disease.

Ocular inflammatory disease comprises of a diverse group of clinical entities that may result from autoimmune processes, infections, or both. While many individual ocular inflammatory diseases are quite rare, ocular inflammation is one of the more common causes of visual disability, including blindness, in the developed world. Better understanding of ocular inflammatory disease is an important step in designing more sophisticated therapies that may help prevent loss of visual function for these patients.

Advancing vaginal drug delivery.

Bacterial vaginosis and vulvovaginal candidiasis are the two most common forms of vaginitis in female patients. Although a variety of effective treatments have been available to eradicate these infections, limitations have lessened the utility of previously available products. Oral therapies are often fraught with systemic adverse reactions, as well as the potential to interact with concomitant medications. Vaginal preparations, although generally perceived as safer, have historically been undesirable for women to use due to their multiple days of dosing; messy, dripping creams; and requisite night-time dosing. Recognising that the therapeutic delivery of the active agent plays a critical role in the overall success of therapy, and attempting to circumvent the weaknesses of traditional vaginal drug delivery while maintaining and even improving safety profiles, a new form of vaginal drug delivery was developed. This unique and proprietary delivery system, with both bioadhesive and sustained release properties, introduces the convenience of a single dose of medication that can be applied at any time, with efficacy rates equivalent to lengthier durations of treatment. This advance in science and technology has now been successfully applied to two products, Gynazole-1(butoconazole nitrate 2%) and Clindesse(clindamycin phosphate 2%) indicated for the treatment of vulvovaginal candidiasis and bacterial vaginosis, respectively, in order to enhance convenience and compliance for the treatment of two very common clinical conditions.

An open-label, two-period, crossover study of the systemic bioavailability in healthy women of clindamycin phosphate from two vaginal cream formulations.

BACKGROUND: A clindamycin phosphate 2% single-dose vaginal cream (CSDVC) formulation has been designed to provide release of clindamycin equivalent to 7 daily doses of a conventional clindamycin phosphate 2% vaginal cream (CVC). OBJECTIVE: The purpose of this study was to compare the systemic bioavailability of clindamycin from 1 dose of CSDVC with that from 1 dose from a 7-day regimen of CVC in healthy women. METHODS: This was a single-center, open-label, randomized, 2-period, 2-sequence crossover study that enrolled healthy, nonpregnant, adult women. Subjects were randomly assigned to receive a single 5-g intravaginal dose of CSDVC or CVC. Blood samples were then collected for 96 hours after study medication administration. Subjects were crossed over after a 14-day washout period, and received a single dose of the other medication. Blood samples were then collected for 96 hours after administration of the second drug. The plasma clindamycin pharmacokinetic profiles were determined, using a validated assay with a lower limit of detection of 0.2 ng/mL, and compared between treatments. RESULTS: The median age of women was 43.5 years(range, 18-66 years), the median weight was 65.0 kg (range, 47.7-91.8 kg), and the median body mass index was 25.4 kg/m2 (range, 19.2-34.7 kg/m(2)). AUC from time 0 to the last detectable concentration (AUCO(0-t)) and from time 0 to infinity (AUCO(0-infinity)) and C(max) were significantly lower with CSDVC than with CVC (geometric means of 98.61 vs 794.21 ng . h/mL for AUCO(0-t), 100.33 vs 809.14 ng . h/mL for AUC(0-infinity), and 3.18 vs 42.27 ng/mL for C(max); all comparisons, P < 0.001 between formulations). Overall bioavailability of clindamycin from CSDVC was approximately 12% of that from CVC, as measured by AUC. The arithmetic mean T(max) was significantly longer with CSDVC (26.4 vs 9.8 hours; P < 0.007). There were 18 adverse events reported during this study. The most common adverse event with each formulation was headache (CSDVC, 10%; CVC, 25%). CONCLUSIONS: Systemic bioavailability of clindamycin was significantly lower and systemic absorption was significantly slower with the CSDVC formulation than with the single dose of 7-day CVC formulation in these healthy volunteers.

Normal p21Ras/MAP kinase pathway expression and function in PBMC from patients with polycystic ovary disease.

Polycystic ovary disease (PCOD) is associated with insulin resistance and increased prevalence of type II diabetes mellitus (T2DM). The p21Ras/MAP kinase is a major intracellular signaling pathway mediating insulin signaling in insulin responsive tissues. The expression, regulation and function of the p21Ras/MAP kinase pathway in PCOD patients were examined. Peripheral blood mononuclear cells (PBMC) were isolated from ten patients with PCOD and ten controls. The expression of p21Ras and its regulatory proteins; hSOS1 and p120GAP were studied. The basal and phytohemaglutinin (PHA) or insulin stimulated phosphorylation of MAP kinase was determined. Expression of p21Ras, and its regulatory proteins hSOS1 and p120GAP were similar in PCOD patients and controls. Basal, PHA and insulin stimulated phosphorylation of MAP kinase, were also comparable in the two groups as well as their PBMC proliferative response. These data indicate that the expression and overall function of the p21Ras/MAP kinase pathway remain intact in non-diabetic patients with PCOD.

The tubulointerstitial nephritis and uveitis syndrome.

The world's medical literature on tubulointerstitial nephritis and uveitis (TINU) syndrome was reviewed, and data on 133 patients with TINU syndrome were identified. The median age of onset was 15 years (range 9-74 years) with a 3:1 female-to-male predominance. Common laboratory abnormalities included elevated Westergren erythrocyte sedimentation rates and elevated urinary beta-2-microglobulin levels. Ocular symptoms preceded systemic symptoms in 21% of cases, and followed systemic symptoms by up to 14 months in 65% of cases. Uveitis involved only the anterior segment in 80% of cases. Uveitis was bilateral at presentation in 77% of cases. Patients were treated with systemic corticosteroids in 80% of cases and with immunosuppressive drugs in 9% of cases. Uveitis recurred or followed a chronic course in 56% of patients and persisted for several years in some cases. Ocular complications (including posterior synechiae, cataracts, and elevated intraocular pressure) were reported in 21% of cases. The visual prognosis appears to be good. Persistent renal dysfunction was reported in 11% of cases, including five patients who required renal dialysis. TINU syndrome is a distinct clinical entity that may be under-recognized and may account for some cases of unexplained chronic or recurrent uveitis. It is important for ophthalmologists, nephrologists, and primary care providers to be familiar with this disorder to ensure early diagnosis and appropriate treatment.

Ischemic maculopathy in patients with acquired immunodeficiency syndrome.

PURPOSE: To describe the characteristics of ischemic maculopathy in patients with human immunodeficiency virus (HIV) infection, as a means of understanding this uncommon disorder more fully. METHODS: This is a multicenter, retrospective review of clinical data available for five HIV-infected patients who were given the diagnosis of ischemic maculopathy. RESULTS: All cases had been diagnosed on the basis of fluorescein angiograms obtained after patients complained of vision loss. Four of the five patients had bilateral macular disease. Visual acuity at presentation in the nine affected eyes ranged from 20/20 to count fingers. Vision loss was gradual in both eyes of one patient and was abrupt in onset in seven eyes. Each of the seven eyes with abrupt vision loss had opacification of the superficial retina and/or intraretinal hemorrhages near the fovea. Fluorescein angiography revealed enlargement of the foveal avascular zone and mild staining of the juxtafoveal vessels in affected eyes. Six eyes had active or clinically inactive cytomegalovirus retinitis at presentation, and a seventh eye developed cytomegalovirus retinitis 2 weeks later. All patients were receiving anticytomegalovirus drugs when they developed visual symptoms. Visual acuity remained stable in five eyes, became worse in two eyes, and improved in two eyes; final visual acuity ranged from 20/25 to count fingers. CONCLUSIONS: Ischemic maculopathy may cause profound and permanent vision loss in HIV-infected individuals. Fluorescein angiography should be considered in all HIV-infected patients with unexplained loss of vision. The pathogenesis of ischemic maculopathy remains unknown.

Relationship between aqueous humor protein level and outflow facility in patients with uveitis.

PURPOSE: To determine whether there is a relationship between the aqueous humor protein level and outflow facility in patients with uveitis. METHODS: Aqueous humor protein levels were determined by laser flare photometry, and outflow facility was determined by Schiotz tonography. RESULTS: Thirty patients with uveitis and 10 control subjects were studied. Outflow facility was lower in patients with uveitis (0.21 +/- 0.12 microl/min x mm Hg) than in control subjects (0.33 +/- 0.05 microl/min x mm Hg, P < 0.001). Patients with uveitis and laser flare photometry results (flare) more than 20 photon units/msec (n = 21) had a lower outflow facility (0.17 +/- 0.07 microl/min x mm Hg) than patients with uveitis and flare less than 20 photon units/msec (n = 9, 0.32 +/- 0.14 microl/min x mm Hg, P = 0.004). Furthermore, no difference was identified between outflow facility in patients with active uveitis (those who had anterior chamber cells) and flare less than 20 photon units/msec and outflow in control subjects. In patients with uveitis, there was a linear correlation between flare and outflow facility (r = -0.50, P = 0.005). There was no relationship between flare measurements and either intraocular pressure or aqueous humor cell levels when scored with a clinical, semiquantitative system. CONCLUSIONS: Outflow facility is significantly reduced in patients with uveitis who have high aqueous humor protein levels. Outflow facility appears to be normal in patients with active uveitis whose flare levels are low, and therefore the association between flare and outflow facility does not appear to be an indirect reflection of elevated anterior chamber cells. It is possible that elevated aqueous humor protein levels contribute to the development of uveitic glaucoma in some individuals by decreasing aqueous humor outflow facility, although a causal relationship cannot be established on the basis of this study.

Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease.

OBJECTIVE: To evaluate the clinical usefulness of tumor necrosis factor (TNF) inhibitors in patients with inflammatory eye disease that is resistant to conventional immunosuppressive therapies. METHODS: Sixteen patients (4 males and 12 females aged 7 to 78 years) who received etanercept (n = 14) or infliximab (n = 2) for either inflammatory eye disease or associated joint disease were studied retrospectively to determine the effect of these medications on their ocular inflammation. RESULTS: Nine cases of uveitis and 7 cases of scleritis were treated. Systemic diagnoses included rheumatoid arthritis (n = 8), juvenile rheumatoid arthritis (n = 3), ankylosing spondylitis (n = 1), and psoriatic spondylarthropathy (n = 1). Three patients had uveitis without associated systemic disease. Although 12 of 12 patients with active articular inflammation (100%) experienced improvement in joint disease, only 6 of 16 with ocular inflammation (38%) experienced improvement in eye disease. Five patients developed inflammatory eye disease for the first time while taking a TNF inhibitor. No patient discontinued treatment because of adverse drug effects. CONCLUSION: TNF inhibitors are well tolerated immunosuppressive medications that may benefit certain subgroups of patients with inflammatory eye disease, but they appear to be more effective in controlling associated inflammatory arthritis.

[Sepsis associated cholestasis in adults].

Hepatic injury presenting as jaundice, hypglycemia, encephalopathy, coagulation disturbances and a significant increase in transaminases in a late well recognized complication of sepsis. Less known is a cholestatic liver injury, which can precede sepsis. This type of early liver injury is characterized by a rise of direct bilirubin and less prominent increase in liver enzymes. Experimental work in animal models demonstrates that sepsis associated cholestasis is mediated by a variety of gram negative bacterial endotoxins and cytokines which interfere with the function of bile acid intracellular transporters. Although sepsis associated cholestasis is quite common, its clinical and prognostic characteristics are not widely appreciated. This often results in performance of unnecessary procedures and delayed diagnosis. Here we review the relevant updated literature regarding the pathophysiological basis of this phenomenon and its clinical presentation and implications.

An association between Vogt-Koyanagi-Harada disease and Guillain-Barré syndrome.

PURPOSE: To describe an association between Vogt-Koyanagi-Harada disease and Guillain-Barré syndrome. METHODS: Case series, describing three patients. RESULTS: In two patients, the disorders had their onsets within 2 weeks of each other; in the third patient, Vogt-Koyanagi-Harada disease occurred after 3 months, as Guillain-Barré syndrome resolved. All three patients had bilateral panuveitis typical of Vogt-Koyanagi-Harada disease. Each also developed well-accepted manifestations of Guillain-Barré syndrome, including paresis of the lower extremities (all patients), paresis of the upper extremities (two patients), paresis of cranial nerves (two patients), areflexia (all patients), and abnormal electromyography findings (two patients). CONCLUSIONS: Vogt-Koyanagi-Harada disease may follow or occur simultaneously with Guillain-Barré syndrome. The fact that these two autoimmune disorders occur together in some patients suggest that they may share common disease mechanisms.

Bloodless surgery.

Doctors and nurses in the forefront of the bloodless medicine and surgery movement say that virtually all hospitals now employ at least some facet of bloodless medicine. Because the strategies generally promote good health and save money, some New Jersey hospitals have even made bloodless medicine a standard of care regardless of patients' religious or moral convictions.