Sleep disordered breathing occurring predominantly in rapid eye movement REM sleep (rapid-eye-movement-related sleep-disordered breathing, REM SDB) is present in 10 to 36% of patients undergoing polysomnography (PSG) for suspected obstructive sleep apnea (O'Connor et al. in Am J Respir Crit Care Med 161:1465-1472, 2000; Resta et al. in J Respir Medicine 99:91-96, 2005; Haba-Rubio et al. in Chest 128:3350-3357, 2005; Juvelekian and Golish, American Academy of Sleep Medicine, abstract, 2004). We hypothesize that REM SDB is an age-related condition in women and, additionally, more prevalent in women than in men. Subjects with REM SDB were identified retrospectively among 1,540 obstructive sleep apnea (OSA) patients with an apnea-hypopnea index (AHI)>>or= 5. Inclusion criteria for REM SDB were age >18, AHI>>or= 5, NREM AHI < 15, and REM AHI/NREM AHI>> 2. PSG data included sleep latency, REM latency, total sleep time (TST), AHI, REM AHI, NREM AHI, and sleep stage percentages. Demographic data and medical and psychiatric histories were also obtained. Statistical comparisons were made between men and women and women older and younger than 55 years, a marker for menopausal status. Two hundred twenty-one subjects fulfilled the criteria for REM SDB, yielding a prevalence of 14.4%. Overall, female apneics had a significantly higher prevalence of REM SDB than did men (24.5 vs 7.9%; p < 0.001). Younger women had a significantly higher prevalence than did older women (27.2 vs 18.6%; p = 0.008); younger men had a significantly higher prevalence of REM SDB than did older men (9.9 vs 4.5%; p = 0.002). Women were significantly older and more obese than were men. Younger women were more likely to be depressed and were significantly more obese than were older women. REM SDB is more prevalent in women than in men and more prevalent in men and women younger than 55 than those older than 55. In this population, women are more obese and older than men, while younger women were more obese than older women. These descriptive distinctions suggest differences in mechanism which may depend on gender and age.

Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness among the elderly population in the industrialized world. One of the typical features of this pathology is the gradual death of retinal pigment epithelial (RPE) cells, which are essential for maintaining photoreceptor functions and survival. The etiology is multifactorial, and oxidative stress is clearly one of the key factors involved in disease pathogenesis (Plafker, Adv. Exp. Med. Biol. 664 (2010) 447-56; Qin, Drug Dev. Res. 68 (2007) 213-225). Recent work has revealed the presence of phosphorylated signaling proteins in the vitreous humour of patients affected by AMD or other retinal diseases. While the location of these signaling proteins is typically the cell membrane or intracellular compartments, vitreous samples were proven to be cell-free (Davuluri et al., Arch. Ophthalmol. 127 (2009) 613-21). To gain a better understanding of how these proteins can be shed into the vitreous, we used reverse phase protein arrays (RPMA) to analyze the protein and phosphoprotein content of exosomes shed by cultured ARPE-19 cells under oxidative stress conditions. Seventy two proteins were shown to be released by ARPE-19 cells and compartmentalized within exosomes. Forty one of them were selectively detected in their post-translationally modified form (i.e., phosphorylated or cleaved) for the first time in exosomes. Sets of these proteins were linked together reflecting activation of pathway units within exosomes. A subset of (phospho)proteins were altered in exosomes secreted by ARPE-19 cells subjected to oxidative stress, compared to that secreted by control/non stressed cells. Stress-altered exosome proteins were found to be involved in pathways regulating apoptosis/survival (i.e, Bak, Smac/Diablo, PDK1 (S241), Akt (T308), Src (Y416), Elk1 (S383), ERK 1/2 (T202/Y204)) and cell metabolism (i.e., AMPKα1 (S485), acetyl-CoA carboxylase (S79), LDHA). Exosomes may thus represent the conduit through which membrane and intracellular signaling proteins are released into the vitreous. Changes in their (phospho)protein content upon stress conditions suggest their possible role in mediating cell-cell signaling during physio-pathological events; furthermore, exosomes may represent a potential source of biomarkers.

BACKGROUND

Premature termination is common among patients treated for depression with either pharmacotherapy or psychotherapy. Yet little is known about factors associated with premature treatment termination among depressed patients.

METHODS

This study examines predictors of, time to, and reasons for dropout from the 12-week acute phase treatment of nonpsychotic adult outpatients, age 18-75, with chronic major depression who were randomly assigned to nefazadone alone (MED), cognitive behavioral analysis system of psychotherapy alone (CBASP) or both treatments (COMB).

RESULTS

Of 681 randomized study participants, 156 were defined as dropouts. Dropout rates were equivalent across the three treatments. Among dropouts, those in COMB remained in treatment (Mean=40 days) significantly longer than those in either MED (Mean=27 days) or CBASP (Mean=28 days). Dropouts attributed to medication side-effects were significantly lower in COMB than in MED, suggesting that the relationship with the psychotherapist may increase patient willingness to tolerate side-effects associated with antidepressant medications. Ethnic or racial minority status, younger age, lower income, and co-morbid anxiety disorders significantly predicted dropout in the full sample. Within treatments, differences between completers and dropouts in minority status and the prevalence of anxiety disorders were most pronounced in MED. Among those receiving CBASP, dropouts had significantly lower therapeutic alliance scores than completers.

CONCLUSIONS

The sample included only individuals with chronic depression.

CONCLUSIONS

Predictors of dropout included baseline patient characteristics, but not early response to treatment. Ethnic and racial minorities and those with comorbid anxiety are at higher risk of premature termination, particularly in pharmacotherapy, and may require modified treatment strategies.

Medulloblastoma (MB) can arise in the cerebellum due to genetic activation of the Sonic Hedgehog (Shh) signaling pathway. During normal cerebellum development, Shh spurs the proliferation of granule neuron precursors (GNP), the precursor cells of MB. Mutations in the Shh receptor gene patched1 (ptc1+/-) lead to increased MB incidence in humans and mice. MB tumorigenesis in mice heterozygous for ptc1+/- shows distinct steps of progression. Most ptc1+/- mice form clusters of preneoplastic cells on the surface of the mature cerebellum that actively transcribe Shh target genes. In approximately 15% of mice, these preneoplastic cells will become fast-growing, lethal tumors. It was previously shown that the loss of function of insulin-like growth factor 2 (igf2) suppresses MB formation in ptc1+/- mice. We found that igf2 is not expressed in preneoplastic lesions but is induced as these lesions progress to more advanced MB tumors. Igf2 is not required for formation of preneoplastic lesions but is necessary for progression to advanced tumors. Exogenous Igf2 protein promoted proliferation of MB precursor cells (GNP) and a MB cell line, PZp53(MED). Blocking igf2 signaling inhibited growth of PZp53(MED) cells, implicating igf2 as a potential clinical target.

Although hypophosphatemia is commonly present in diabetics, little is known about its isolated effects on glucose and insulin metabolism. We therefore investigated glucose metabolism in six nondiabetic subjects with chronic hypophosphatemia. When glucose was infused to maintain a constant hyperglycemic level (125 mg per deciliter [6.9 mmol per liter] above basal levels), the glucose infusion rate was 36 per cent less in the hypophosphatemic group than in controls (4.90 +/- 0.34 mg per kilogram of body weight per minute vs. 7.64 +/- 0.37, P < 0.001), although responses to endogenous insulin were similar. When exogenous insulin was infused at a constant rate to maintain an insulin level about 100 microU per milliliter (718 pmol per liter) above basal levels and glucose was infused as necessary to maintain fasting glucose levels, the infusion rate of glucose was 43 per cent lower in the hypophosphatemic group than in controls (3.80 +/- 0.58 mg per kilogram per minute vs. 6.70 +/- 0.33, P < 0.001), although the clearance rate of insulin was similar in both groups. These results indicate that hypophosphatemia is associated with impaired glucose metabolism in both the hyperglycemic and euglycemic states, and that this associated primarily reflects decreased tissue sensitivity to insulin. (N Engl J Med. 1980; 303; 1259-63.).

The prevalence of obesity has been rising steadily over the last several decades and is currently at unprecedented levels: more than 68% of US adults are considered overweight, and 35% are obese (Flegal et al., JAMA 303:235-241, 2010). This increase has occurred across every age, sex, race, and smoking status, and data indicate that segments of individuals in the highest weight categories (i.e., BMI>> 40 kg/m(2)) have increased proportionately more than those in lower BMI categories (BMI < 35 kg/m(2)). The dramatic rise in obesity has also occurred in many other countries, and the causes of this increase are not fully understood (Hill and Melanson, Med Sci Sports Exerc 31:S515-S521, 1999).

Mediator complex (MED) is an evolutionarily conserved multiprotein, fundamental for growth and survival of all cells. In eukaryotes, the mRNA transcription is dependent on RNA polymerase II that is associated to various molecules like general transcription factors, MED subunits and chromatin regulators. To date, transcriptional machinery dysfunction has been shown to elicit broad effects on cell proliferation, development, differentiation, and pathologic disease induction, including cancer. Indeed, in malignant cells, the improper activation of specific genes is usually ascribed to aberrant transcription machinery. Here, we focus our attention on the correlation of MED subunits with carcinogenesis. To date, many subunits are mutated or display altered expression in human cancers. Particularly, the role of MEDMEDMEDMED subunits as novel diagnostic/prognostic tumour markers to be used in combination with imaging technique in clinical oncology, and to develop novel anti-cancer targets for molecular-targeted therapy.

Noise in MR image data increases the mean signal intensity of image regions due to the usually performed magnitude reconstruction. Diffusion-weighted imaging (DWI) is especially affected by high noise levels for several reasons, and a decreasing SNR at increasing diffusion weighting causes systematic errors when calculating apparent diffusion coefficients (ADCs). Two different methods are presented to correct biased signal intensities due to the presence of complex noise: 1) with Gaussian intensity distribution, and 2) with arbitrary intensity distribution. The performance of the correction schemes is demonstrated by numerical simulations and DWI measurements on two different MR systems with different noise characteristics. These experiments show that noise significantly influences the determination of ADCs. Applying the proposed correction schemes reduced the bias of the determined ADC to less than 10% of the bias without correction. Magn Reson Med 45:448-453, 2001.

Three new human medulloblastoma (MB) cell lines (D384 Med, D425 Med, and D458 Med) and their transplantable xenografts were examined for antigenic expression with antibodies against neuroectodermal antigens, cytoskeletal proteins, neuroendocrine markers, glioma-associated antigens, tenascin, human lymphocyte antigen molecules, epidermal growth factor receptor, and T-cell antigen by indirect immunofluorescence, avidin-biotin complex peroxidase immunohistochemistry, and immunoblot methods. We found that each of the three cell lines expressed vimentin; low-, middle-, and high-molecular-weight neurofilament proteins; and the synaptic vesicle membrane glycoprotein synaptophysin. Each of the cell lines also reacted with antibodies against neural cell adhesion molecules, but none of them were positive for antibodies against glial fibrillary acidic protein, keratin, microtubule-associated protein tau and microtubule-associated protein 2, human lymphocyte antigen-DR, epidermal growth factor receptor, and T-cell antigen. Immunoreactivities with anti-tenascin and anti-glioma-associated antibodies were variable in these cell lines. Anti-human lymphocyte antigen-A,B and anti-beta 2-microglobulin antibodies reacted with xenografts of D384 Med and D425 Med and were weakly positive for a small population of D384 Med cultured cells. In summary, the detection of neurofilament proteins and synaptophysin and the absence of glial fibrillary acidic protein provide strong evidence for a neuronal phenotype of D384 Med, D425 Med, and D458 Med.

BACKGROUND

Advance directives (ADs) are widely regarded as the best available mechanism to ensure that patients' wishes about medical treatment at the end of life are respected. However, observational studies suggest that these discussions often fail to meet their stated goals.

OBJECTIVE

To explore best practices by describing what physicians who are considered expert in the area of end of-life bioethics or medical communication do when discussing ADs with their patients and to explore the ways in which best practices of the expert group might differ in content or style from normative practice derived from primary care physicians' discussions of ADs with their patients collected as part of an earlier study.

METHODS

Nonexperimental, descriptive study of audiotaped discussions.

METHODS

Outpatient primary care practices in the United States.

METHODS

Eighteen internists who have published articles in the areas of bioethics or communication and 48 of their patients. Fifty-six academic internists and 56 of their established patients in 5 practice sites in 2 locations-Durham, NC, and Pittsburgh, Pa. Eligible patients were at least 65 years old or suffered from serious medical illness and had not previously discussed ADs with their physician. Expert clinicians had discretion regarding patient selection, while the internists chose patients according to a predetermined protocol.

METHODS

Coders applied the Roter Interaction Analysis System (RIAS) to audiotapes of the medical visits to describe communication dynamics. In addition, the audiotapes were scored on 21 items reflecting physician performance in specific skills related to AD discussions.

RESULTS

Experts spent close to twice as much time (14.7 vs 8.1 minutes, P<.001) and were less verbally dominant (P<.05) than other physicians during AD discussions. When length of visit was controlled statistically, the expert physicians gave less information about treatment procedures and biomedical issues (P<.05) and asked fewer related questions (P<. 05) but tended toward more psychosocial and lifestyle discussion and questions. Experts engaged in more partnership building (P<.05) with their patients. Patients of the expert physicians engaged in more psychosocial and lifestyle discussion (P<.001), and more positive talk (P<.05) than patients of community physicians. Expert physicians scored higher on the 21 items reflecting AD-specific skills (P<.001).

CONCLUSIONS

Best practices as reflected in the performance of expert physicians reflect differences in measures of communication style and in specific AD-related proficiencies. Physician training in ADs must be broad enough to include both of these domains. Arch Intern Med. 2000;160:3477-3485.

The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.

Due to the increasing need for subject privacy, the ability to deidentify structural MR images so that they do not provide full facial detail is desirable. A program was developed that uses models of nonbrain structures for removing potentially identifying facial features. When a novel image is presented, the optimal linear transform is computed for the input volume (Fischl et al. [2002]: Neuron 33:341-355; Fischl et al. [2004]: Neuroimage 23 (Suppl 1):S69-S84). A brain mask is constructed by forming the union of all voxels with nonzero probability of being brain and then morphologically dilated. All voxels outside the mask with a nonzero probability of being a facial feature are set to 0. The algorithm was applied to 342 datasets that included two different T1-weighted pulse sequences and four different diagnoses (depressed, Alzheimer's, and elderly and young control groups). Visual inspection showed none had brain tissue removed. In a detailed analysis of the impact of defacing on skull-stripping, 16 datasets were bias corrected with N3 (Sled et al. [1998]: IEEE Trans Med Imaging 17:87-97), defaced, and then skull-stripped using either a hybrid watershed algorithm (Ségonne et al. [2004]: Neuroimage 22:1060-1075, in FreeSurfer) or Brain Surface Extractor (Sandor and Leahy [1997]: IEEE Trans Med Imaging 16:41-54; Shattuck et al. [2001]: Neuroimage 13:856-876); defacing did not appreciably influence the outcome of skull-stripping. Results suggested that the automatic defacing algorithm is robust, efficiently removes nonbrain tissue, and does not unduly influence the outcome of the processing methods utilized; in some cases, skull-stripping was improved. Analyses support this algorithm as a viable method to allow data sharing with minimal data alteration within large-scale multisite projects.

Cochlear implantation is an accepted treatment method for adults and children with severe to profound hearing loss. Confidence in technology has led to changes in individuals who can receive a cochlear implant and changes in expected benefit with a cochlear implant. This article describes the research and development activities at MED-EL, which make possible the implementation of new speech-coding strategies as well as the application of acoustic and electric stimulation via a combined speech processor in MED-EL devices. Research on benefits from bilateral cochlear implantation and electric-acoustic stimulation are also reviewed. Finally, the potential of drug delivery systems is considered as a way to improve cochlear implant outcomes, and results from preliminary evaluations of a hybrid cochlear implant system with drug delivery capabilities are reported.

Renal cell carcinoma is characterized by an accumulation of complex chromosomal alterations during tumor progression. Chromosome 3p deletions are known to occur early in the carcinogenesis, but the nature of subsequent events, their interrelationships, and their sequence is poorly understood, as one usually only obtains a single "view" of the dynamic process of tumor development in a particular cancer patient. To address this limitation, we used comparative genomic hybridization analysis in combination with a distance-based and a branching-tree method to search for tree models of the oncogenesis process of 116 conventional (clear cell) renal carcinomas. This provides a means to analyze and model cancer development processes based on a more dynamic model, including the presence of multiple pathways, as compared with the fixed linear model first proposed by Vogelstein et al. (N. Engl. J. Med., 319: 525-532, 1988) for colorectal cancer. The most common DNA losses involved 3p (61%), 4q (50%), 6q (40%), 9p (35%), 13q (37%), and Xq (21%). The most common gains were seen at chromosome 17p and 17q (20%). The tree model derived from the distance-based method is consistent with the established theory that -3p is an important early event in conventional (clear cell) renal cancer and supports the prediction made from the branching tree that -4q is another important early event. Both tree models suggest that there may be two groups of clear cell renal cancers: one characterized by -6q, +17q, and + 17p, and another by -9p, -13q, and -18q. Putative prognostic parameters were -9p and -13q. The distance-based tree clarifies that -8p (present in 12% of tumors) is a late event, largely independent of other events. In summary, tree modeling of comparative genomic hybridization data provided new information on the interrelationships of genetic changes in renal cancer and their possible order, as well as a clustering of these events. Using tree analysis, one can derive a more in-depth understanding of the renal cancer development process than is possible by simply focusing on the frequencies of genetic events in a given cancer type.

The influence of a short-term elevation of free fatty acids (FFAs) on intramyocellular lipids (IMCL) under hyperinsulinemic conditions was monitored in five healthy male subjects in the course of a 5-hr hyperinsulinemic glucose clamp. During the glucose clamp a lipid emulsion (Intralipid 20(R)) and heparin were administered intravenously. IMCL was quantified in the tibialis anterior (TA) and the soleus (SOL) muscle by (1)H-MRS. A rapid elevation of the IMCL pool was found in both muscles (61% in TA and 22% in SOL) in the 5-hr time period. A control hyperinsulinemic glucose clamp in the same study group, repeated without elevation of circulating FFAs, did not lead to significant changes in IMCL for both muscles. The present study shows for the first time that only the combination of high concentrations of FFAs and insulin lead to marked storage of lipids in skeletal muscle cells in humans. Magn Reson Med 45:179-183, 2001.

OBJECTIVE

An objective cochlear framework, for evaluation of the cochlear anatomy and description of the position of an implanted cochlear implant electrode, would allow the direct comparison of measures performed within the various subdisciplines involved in cochlear implant research.

BACKGROUND

Research on the human cochlear anatomy in relation to tonotopy and cochlear implantation is conducted by specialists from numerous disciplines such as histologists, surgeons, physicists, engineers, audiologists, and radiologists. To allow accurate comparisons between and combinations of previous and forthcoming scientific and clinical studies, cochlear structures and electrode positions must be specified in a consistent manner.

METHODS

Researchers with backgrounds in the various fields of inner ear research as well as representatives of the different manufacturers of cochlear implants (Advanced Bionics Corp., Med-El, Cochlear Corp.) were involved in consensus meetings held in Dallas, March 2005, and Asilomar, August 2005. Existing coordinate systems were evaluated, and requisites for an objective cochlear framework were discussed.

RESULTS

The consensus panel agreed upon a 3-dimensional, cylindrical coordinate system of the cochlea using the "Cochlear View" as a basis and choosing a z axis through the modiolus. The zero reference angle was chosen at the center of the round window, which has a close relationship to the basal end of the Organ of Corti.

CONCLUSIONS

Consensus was reached on an objective cochlear framework, allowing the outcomes of studies from different fields of research to be compared directly.

SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD). Several independent research groups have reported significant associations between OCD and single nucleotide polymorphisms (SNPs) in this gene. Previously, we evaluated 13 SNPs in, or near, SLC1A1 and reported a strong association signal with rs301443, a SNP 7.5 kb downstream of the gene [Shugart et al. (2009); Am J Med Genet Part B 150B:886–892]. The aims of the current study were first, to further investigate this finding by saturating the region around rs301443; and second, to explore the entire gene more thoroughly with a dense panel of SNP markers. We genotyped an additional 111 SNPs in or near SLC1A1, covering from 9 kb upstream to 84 kb downstream of the gene at average spacing of 1.7 kb per SNP, and conducted family-based association analyses in 1,576 participants in 377 families.We found that none of the surrounding markers were in linkage disequilibrium with rs301443, nor were any associated with OCD. We also found that SNP rs4740788, located about 8.8 kb upstream of the gene, was associated with OCD in all families (P = 0.003) and in families with male affecteds (P = 0.002). A three-SNP haplotype (rs4740788–rs10491734–rs10491733) was associated with OCD in the total sample (P = 0.00015) and in families with male affecteds (P = 0.0007). Although of nominal statistical significance considering the number of comparisons, these findings provide further support for the involvement of SLC1A1 in the pathogenesis of OCD.

UV irradiation induces a variety of cutaneous responses, including disruption of epidermal permeability barrier function, the basis for which is not known. Herein, we investigated the separate roles of hyperproliferation and inflammation in the pathogenesis of UVB-induced barrier disruption. Adult hairless mice were exposed to increasing doses of UVB (1.5-7.5 MED), and transepidermal water loss (TEWL) was monitored daily for up to 7 d. The extent of TEWL increase was dependent on the UVB dose, but with all doses, the increase began after>> or =48 h and peaked at 96 h, decreasing by 120 h. Epidermal [(3)H]thymidine incorporation increased at 24 h and peaked at 48 h (570%), preceding the maximal increase in TEWL. Cyclosporin A, methotrexate, 5-fluorouracil, or arabinosylcytosine significantly diminished the UVB-induced TEWL increase. Athymic nude mice also displayed a markedly diminished response to UVB, and DNA synthesis did not increased at 48 h. Transplantation of athymic mice with T-cell-enriched mixed immune cells significantly restored sensitivity to both the UVB-induced hyperproliferation and the barrier defect. Finally, although UVB exposure increased PGE2 levels in whole skin samples (2- to 3-fold within 1-3 h; p < 0.005), this increase was completely blocked by topical indomethacin, and neither topical indomethacin nor topical glucocorticoids blocked development of the barrier abnormality. These results show that (i) UVB produces delayed alteration in barrier function and (ii) both an epidermal proliferative response and thymocyte-mediated events (but not PGE2 production and nonspecific inflammation) appear to contribute to UVB-induced abrogation of the permeability barrier.

Inhibitors of brain glial water channel aquaporin-4 (AQP4) are of potential clinical utility, as they are predicted to modulate brain edema, neuroexcitation and glial scarring. Recently, Huber et al. (Bioorg. Med. Chem.2007, 17, 1270-1273; in press) reported that a series of arylsulfonamides, antiepileptics, and related small molecules strongly inhibited AQP4 water transport with IC(50)s down to 1 microM. We retested the compounds with greatest reported potencies, including acetylsulfanilamide, acetazolamide, 6-ethoxy-benzothiazole-2-sulfonamide, topiramate, zonisamide, phenytoin, lamotrigine, and sumatriptan, in AQP4-transfected mammalian cells and primary cultures of brain glial cells, using several sensitive assays of osmotic water permeability. Contrary to the findings of Huber et al., in our studies we found no significant inhibition of AQP4 water permeability by any of the compounds at concentrations up to 100 microM.

OBJECTIVE

Measurement of ankle blood pressure is a simple method of assessing lower limb arterial blood supply. However, its use in diabetes has been questioned due to the presence of medial artery calcification. Measurement of toe blood pressure has been advocated as an alternative but it is technically more difficult. The aim of this study was to obtain information to guide clinicians as to when pressure measurements should be taken at the toe.

METHODS

Ankle brachial index (ABI) and toe brachial index (TBI) were measured by Doppler ultrasound, or photoplethysmography on 174 subjects with diabetes and 53 control subjects. The Bland and Altman method, and the Cohen's method of measuring agreement between two tests were used to compare ABI with TBI.

RESULTS

The mean differences between ABI and TBI in control and diabetic subjects are 0.40 +/- 0.13 and 0.37 +/- 0.15, respectively. Nearly all diabetic patients with an ABI < 1.3 have an ABI-TBI gradient falling within the normal range established from the non-diabetic cohort. In contrast, the majority of diabetic subjects with an ABI>> or = 1.3 have ABI-TBI differences outside this range. When patients are categorized according to ABI and TBI, there is also good agreement between the tests when ABI is low or normal (84% and 78% agreement, respectively), but not when ABI is elevated.

CONCLUSIONS

In the majority of patients with diabetes, assessment of TBI conveys no advantage over ABI in determining perfusion pressure of the lower limbs. Only in those patients with overt calcification, which gives an ABI>> or = 1.3, are toe pressure measurements superior. This guideline should simplify assessment and treatment of diabetic patients with disease of the lower limbs. Diabet. Med. 18, 528-532 (2001)

In 2011, an Advanced Notice of Proposed Rulemaking proposed that de-identified human data and specimens be included in biobanks only if patients provide consent. The National Institutes of Health Genomic Data Sharing policy went into effect in 2015, requiring broad consent from almost all research participants.

We conducted a systematic literature review of attitudes toward biobanking, broad consent, and data sharing. Bibliographic databases included MEDLINE, Web of Science, EthxWeb, and GenETHX. Study screening was conducted using DistillerSR.

The final 48 studies included surveys (n = 23), focus groups (n = 8), mixed methods (n = 14), interviews (n = 1), and consent form analyses (n = 2). Study quality was characterized as good (n = 19), fair (n = 27), and poor (n = 2). Although many participants objected, broad consent was often preferred over tiered or study-specific consent, particularly when broad consent was the only option, samples were de-identified, logistics of biobanks were communicated, and privacy was addressed. Willingness for data to be shared was high, but it was lower among individuals from under-represented minorities, individuals with privacy and confidentiality concerns, and when pharmaceutical companies had access to data.

Additional research is needed to understand factors affecting willingness to give broad consent for biobank research and data sharing in order to address concerns to enhance acceptability.Genet Med 18 7, 663-671.

Mutations in cartilage oligomeric matrix protein (COMP) cause two skeletal dysplasias, pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED/EDM1). Because COMP exists as a homopentamer, only one mutant COMP subunit may result in an abnormal complex that is accumulated in expanded rough endoplasmic reticulum (rER) cisternae, a hallmark of PSACH. Type IX collagen and matrilin-3 (MATN3), also accumulate in the rER cisternae of PSACH chondrocytes, but it is unknown how mutant COMP interacts with these proteins. The studies herein focus on defining the organization of these intracellularly retained proteins using fluorescence deconvolution microscopy. A unique matrix organization was identified in which type II procollagen formed a central core surrounded by a protein network of mutant COMP, type IX collagen, and MATN3. This pattern of matrix organization was found in multiple cisternae from single chondrocytes and in chondrocytes with different COMP mutations, indicating a common pattern of interaction. This suggests that stalling of mutant COMP and an interaction between mutant COMP and type II procollagen are initiating events in the assembly of matrix in the rER, possibly explaining why the material is not readily cleared from the rER. Altogether, these data suggest that mutant COMP initiates and perhaps catalyzes premature intracellular matrix assembly.

As photon-counting imaging systems become more complex, there is a trend toward measuring more attributes of each individual event. In various imaging systems the attributes can include several position variables, time variables, and energies. If more than about four attributes are measured for each event, it is not practical to record the data in an image matrix. Instead it is more efficient to use a simple list where every attribute is stored for every event. It is the purpose of this paper to discuss the concept of likelihood for such list-mode data. We present expressions for list-mode likelihood with an arbitrary number of attributes per photon and for both preset counts and preset time. Maximization of this likelihood can lead to a practical reconstruction algorithm with list-mode data, but that aspect is covered in a separate paper [IEEE Trans. Med. Imaging (to be published)]. An expression for lesion detectability for list-mode data is also derived and compared with the corresponding expression for conventional binned data.

This article investigates the effect on the mouse frailty index (FI), of factors known to influence lifespan and healthspan in mice: strain (short-lived DBA/2J mice vs long-lived C57BL/6J mice), calorie restriction (CR), and resveratrol treatment. The mouse FI, based on deficit accumulation, was recently validated in C57BL/6J mice by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) and shares many characteristics of the human FI. FI scores were measured in male and female aged (18 months) ad-libitum fed and CR DBA/2J and C57BL/6J mice, as well as male aged (24 months) C57BL/6J mice ad-libitum fed with or without resveratrol (100 mg/kg/day) in the diet for 6 months. Mean scores of two raters were used, and the raters had excellent inter-rater reliability (ICC = 0.88, 95% CI [0.80, 0.92]). Furthermore, the interventions of CR and resveratrol were associated with a significant reduction in FI scores in C57BL/6J mice, compared to age-matched controls. The short-lived DBA/2J mice also had slightly higher FI scores than the C57BL/6J mice, for the male calorie-restricted groups (DBA/2J FI = 0.16±0.03, C57BL/6J FI = 0.11±0.03, p = .01). This study uses the mouse FI developed by Whitehead JC, Hildebrand BA, Sun M, et al. (A clinical frailty index in aging mice: comparisons with frailty index data in humans. J Gerontol A Biol Sci Med Sci. 2014;69:621-632) in a different mouse colony and shows that this tool can be applied to quantify the effect of dietary and pharmaceutical interventions on frailty.