A compressed sensing approach to immobilized nanoparticle localization for superparamagnetic relaxometry.

Superparamagnetic relaxometry (SPMR) exploits the unique magnetic properties of targeted superparamagnetic iron oxide nanoparticles (SPIOs) to detect small numbers of cancer cells. Reconstruction of the spatial distribution of cancer-bound nanoparticles requires solving an ill-posed inverse problem. The current method, multiple source analysis (MSA), uses a least-squares fit to determine the strength and location of a pre-determined number of magnetic dipoles. In this proof-of-concept study, we propose the application of a sparsity averaged reweighting algorithm (SARA) for volumetric reconstruction of immobilized nanoparticle distributions. We first calibrate the parameters that define the location of the sensors in the forward model of measurement physics. Using this optimized model, we evaluated the performance of the algorithms on various configurations of single and multiple point-source phantoms. We investigated the effect of the data fidelity parameter, voxel size, and iterative reweighting on the reconstruction produced by SARA. We found that the calibrated physics model can predict the detected field values within 5% of the measured data. When only a single source was present, both algorithms were able to detect as little as 0.5 µg of immobilized particles. However, when two sources were measured simultaneously, MSA failed to detect sources containing as much as 10 µg of particles, while SARA detected all of the sources containing at least 5 µg of particles. We show that a suitable data fidelity parameter can be selected objectively, and the total magnitude and location of a point source reconstructed by SARA is not sensitive to voxel size. Detection and localization of multiple small clusters of nanoparticles is a crucial step in SPMR-based diagnostic applications. Our algorithm overcomes the need to know the number of dipoles before reconstruction and improves the sensitivity of the reconstruction when multiple sources are present.

Prevention of type 1 diabetes.

INTRODUCTION/BACKGROUND: Type 1 diabetes is a chronic autoimmune condition characterized by destruction of insulin-producing ß cells within the pancreatic islets. It is associated with considerable morbidity and mortality. Incidence levels are rising worldwide. SOURCES OF DATA: Pubmed search (Nov 2010) using keywords: Type 1 diabetes, prevention, trials, immunotherapy. AREAS OF AGREEMENT: The causes of disease are multifactorial with genetic and environmental factors playing a part. There is a long pre-clinical period before the onset of overt symptoms, which may be amenable to therapeutic intervention to prevent disease. AREAS OF CONTROVERSY: The exact nature of causative environmental factors is unknown and much debated. Immunotherapeutic intervention may therefore represent the best option for disease prevention. GROWING POINTS: Enhancement of 'regulatory' immune mechanisms currently shows the most promise as an approach to disease prevention. AREAS TIMELY FOR DEVELOPING RESEARCH: Clinical trials of early immunotherapeutic intervention may be the answer to disease prevention.

Strategies to prevent type 1 diabetes.

Type 1 diabetes is a chronic autoimmune condition resulting from T cell-mediated destruction of the insulin-producing cells in the islets of Langerhans. Its primary cause remains unknown, but it has been established that the clinical presentation is preceded by a long prodrome. This enables individuals at high risk of disease to be identified and offers the possibility of intervention to prevent clinical disease. Many groups are working in this field, concentrating on manipulation of environmental exposures that are potential triggers of autoimmunity and on immunomodulation strategies that aim to prevent destruction of beta-cells. Some interventions have shown promising results in early trials, but effective disease prevention remains elusive. This article reviews current progress in the field.

Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety study.

Immunotherapeutic strategies under consideration for type 1 diabetes include modification of the autoimmune response through antigen-specific routes. Administration of short peptides representing T cell epitopes targeted by patients with the disease represents one approach. This study evaluated safety and mechanistic outcomes during first-in-man intradermal administration of a human leucocyte antigen-DR4 (HLA-DR4)-restricted peptide epitope of proinsulin (C19-A3). This randomized, open-label study assessed two major theoretical risks of peptide immunotherapy, namely induction of allergic hypersensitivity and exacerbation of the proinflammatory autoimmune response, using clinical assessment and mechanistic assays in vitro. Patients with long-standing type 1 diabetes and HLA-DRB1*0401 genotype received 30 microg (n = 18) or 300 microg (n = 18) of peptide in three equal doses at 0, 1 and 2 months or no intervention (n = 12). Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from risk of systemic hypersensitivity and induction/reactivation of proinsulin-specific, proinflammatory T cells. Peptide-specific T cells secreting the immune suppressive cytokine interleukin (IL)-10 were observed at month 3 in four of 18 patients in the low-dose group (versus one of 12 in the control group; P = not significant). Mean IL-10 response to peptide in the low-dose group increased between 0 and 3 months (P = 0.05 after stimulation with 5 microM peptide in vitro) and then declined to baseline levels between 3 and 6 months (P = 0.01 at 10 microM peptide in vitro). These studies pave the way for future investigations in new-onset patients designed to examine whether proinsulin peptide immunotherapy has beneficial effects on markers of T cell autoimmunity and preservation of beta cell mass.

Occupational allergies in the seafood industry--a comparative study of Australian and South African workplaces.

Although seafood allergy due to ingestion is commonly observed in clinical practice, the incidence of seafood allergies in general and more specifically in the occupational setting in Australia is largely unknown. The work practices, occupational health services and allergic health problems in 140 seafood processing workplaces in Australia were examined and compared to previous studies in South Africa. A cross-sectional employer-based survey design was used to conduct the study in both countries. In the South African study a response rate of 60% (n = 41) was obtained, compared to a response rate of 18% (n = 140) in Australia. The most common seafood processed by workplaces in South Africa was finfish (76%) and rock lobster (34%). Similarly in Australia, finfish (34%) was the most frequently handled seafood. However, processing of prawns (24%) and oysters (21%) was more common in Australia. Common work processes in South Africa involved freezing (71%), cutting/filleting (63%) and degutting (58%) procedures. Similar processes were followed in Australian industries with the exception of shucking of oysters, particularly common in the aquaculture industries. About half of the workplaces in both countries provided an occupational health service and medical surveillance of workers. However, none of the workplaces in South Africa and only 9% of the workplaces in Australia had industrial hygiene programs for seafood aerosols in place. In both countries positive trends were observed between the size of the workforce and the provision of occupational health services (p<0.005). Similarly, skin rash accounted for highest of all reported health problems (78-81%) followed by asthmatic symptoms (7-10%) and other non-specific allergic symptoms (9-15%) in both countries. Most workplaces reported the annual prevalence of work-related symptoms to be less than 5%. In Australia 7% of respondents in workplaces reported workers having left their workplace due to work-related allergic problems. Despite a low response rate of contacted companies in Australia, there were great similarities between the two countries suggesting that there is a significantly elevated prevalence of work related allergic symptoms in both countries. Unexpectedly, mollusc processing was more common in Australia although the occupational health related effects among exposed workers has previously not been investigated in detail and merits further study. It is recommended that further epidemiological studies focus on seafood exposure in Australia and identify specific risk factors for sensitisation.

Utility of Mini-Mental State Exam scores in predicting functional impairment among white and African American dementia patients.

BACKGROUND: The Mini-Mental State Exam (MMSE) is widely used to assess cognitive impairment. Although education and race have been shown to affect the validity of the MMSE in detecting dementia, whether race and education influence the validity of the MMSE in gauging severity of dementia is unknown. METHODS: Patients diagnosed with Alzheimer's and other dementias (59 African American, 112 White) were administered the MMSE, and information was gathered on patient functional impairment, including Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), and the Memory and Behavior Problems Checklist (MBPC). Demographic information, including patient and caregiver education, and patient age, was also assessed. RESULTS: African American and White patients did not differ significantly on the MMSE or functional impairment variables, but White patients had higher educational attainment. Hierarchical multiple regression analysis showed that race and education did not predict functional impairment, and MMSE scores were strong predictors of ADL and IADL levels for both African American and White patients. MMSE predicted variability in MBPC scores for White patients only, perhaps related to racial differences in subjective caregiver report of behavioral problems. CONCLUSIONS: While race and education may affect the validity of the MMSE in detecting the presence of cognitive impairment, the MMSE can be a useful predictor of degree of ADL and IADL impairment in patients diagnosed with dementia, regardless of race.

Further studies of lectin binding by villous and extravillous trophoblast in normal and pathological pregnancy.

Examination of human pregnancy tissues with a panel of lectins provides the opportunity to probe different aspects of carbohydrate structure. Nine biotinylated lectins [concanavalin A (con A), wheat germ agglutin (WGA), Lens culinaris A (LCH-A), Pisum sativum (PSA), Phaseolus vulgaris (PHA-E and PHA-L), Ulex europaeus 1 (UEA1), Griffonia simplicifolia (GSI and GSII)] were used to investigate the lectin binding of human trophoblast in normal, tubal, and molar pregnancy. All lectins except UEA1 bound to normal villous syncytiotrophoblast. Binding of lectins to extravillous trophoblast was more restricted than to villous trophoblast, occurring predominantly with con A, PHA-E, PHA-L, WGA, GSI, and GSII. LCH-A reacted with cyto-trophoblastic columns but not with interstitial or endovascular trophoblast. Con A and GSII were the only lectins that bound to trophoblastic giant cells. GSI and GSII bound preferentially to extravillous trophoblast, showing only focal reactivity with villous trophoblast. Lectin binding in ectopic pregnancy was similar to that in normal first-trimester intrauterine pregnancy. Reactivity in molar pregnancy also generally mirrored that observed in normal pregnancy; however, reactivity of GSII with villous trophoblast was more consistent than that observed in normal pregnancy, and GSI showed uniform binding to proliferating syncytial areas. Thus, lectin binding studies allow definition of surface carbohydrates, which may play a role in the controlled trophoblast proliferation and invasion that occurs in normal pregnancy.

Expression of epidermal growth factor receptor and transferrin receptor by human trophoblast populations.

Epidermal growth factor (EGF) has several roles, including stimulation of cell division and differentiation. EGF receptor (EGFR) has been localized to villous syncytiotrophoblast, but expression by other human trophoblast populations has not been reported. EGFR expression was examined in normal and pathological placental tissues using a streptavidin-biotin-peroxidase technique; results were compared with expression of transferrin receptor (Tf-R) in similar tissues. EGFR was detected on villous syncytiotrophoblast in early and term pregnancy with labelling of the apical membrane, focal cytoplasmic reactivity, and patchy labelling of the trophoblast basement membrane. In contrast with other reports, EGFR was also consistently localized to villous cytotrophoblast, chorion laeve, and extravillous trophoblast populations in maternal uterine tissues. Maternal decidua showed diffuse labelling of stromal cells, particularly in the superficial zones. The reaction pattern in ectopic tubal pregnancy was similar to that in early intrauterine pregnancy. In molar pregnancy, EGFR was detected on villous syncytiotrophoblast and cytotrophoblast. In contrast, in normal, ectopic, and molar pregnancies labelling for Tf-R was confined to syncytiotrophoblast and to the proximal portions of the cytotrophoblast columns. Expression of EGFR by all trophoblast cells may represent a mechanism of placental growth and proliferation control. EGFR may also be involved with establishment of differentiated trophoblast functions including hormone secretion.

Asymptomatic peptic disease in patients undergoing major elective operations: a prospective endoscopic study.

Postoperative bleeding is usually attributed to stress ulcers; however, occult preoperative lesions could also be responsible. To determine their frequency and nature, we prospectively examined 72 patients endoscopically prior to major elective operations. Entry criteria included a planned stay in the Surgical Intensive Care Unit, greater than 2 days, and a negative history, physical examination, and stool guaiac. Gastric and duodenal mucosae were scored separately, using a 0- to 7-point scale. Scores were graded negative (0), hyperemia (1), gastroduodenitis (2-5), mucosal erosions (6), and ulcers (7). Erosions or ulcers were found in 14% of patients and gastroduodenitis is an additional 10%. We found that none of the 27 risk factors or any combination of factors tested correlated with ulcers, erosions, or gastroduodenitis. Thus, patients with asymptomatic gastroduodenal erosions or ulcerations could not be identified preoperatively, except by endoscopy. Until the significance of these lesions as cause of postoperative bleeding is determined, we recommend routine postoperative gastric pH titration with antacids for patients undergoing major elective operations.

Single session treatment for bleeding hemorrhoids.

Fifty consecutive outpatients with bleeding internal hemorrhoids were prospectively treated with a single application of rubber band ligation or infrared coagulation. Complete follow-up observation was obtained in 48 patients (23 underwent rubber band ligation and 25 underwent infrared coagulation). At one month after treatment, 22 patients who underwent rubber band ligation and 16 who underwent infrared coagulation, were symptomatically improved (p less than 0.05). At six months, 15 patients who had undergone rubber band ligation and ten who had infrared coagulation treatment, remained improved (p less than 0.05). There was no statistical difference in the discomfort experienced by either group during or after the procedure as determined by a self-assessment scale. Two patients who underwent rubber band ligation experienced complications--a thrombosed external hemorrhoid developed in one patient and another had delayed rectal bleeding. Although associated with occasional complications after treatment, rubber band ligation is more effective than in infrared coagulation for single session treatment of bleeding internal hemorrhoids.

The family circle method for integrating family systems concepts in family medicine.

The family circle method is a process that allows individuals to draw a schematic diagram of their family system. It is closely allied with family systems theory and family medicine philosophy. The method is readily understandable with brief instructions. Individuals can create a family circle drawing in as little as two or three minutes. Once instructions are given, the presence of the physician is not required during the drawing. Family circle drawings will often illustrate, in graphic form, patterns of closeness and distance, of power and decision making, of family alliances and boundaries. The drawings provide at a glance an overview of the family system as seen by the person who does the drawing. The drawings are a rich source of information concerning family dynamics and are useful for setting goals for changes in the family system.

The nuclear oestrogen receptor in the female rat. Effects of oestradiol administration during the oestrous cycle on the uterus and contrasting effects of progesterone on the uterus and hypothalamus.

Oestradiol administration to immature or ovariectomized rats has been reported to increase the uterine content of long-term nuclear oestrogen receptors. However, in the intact adult female rat, oestradiol administration did not increase the concentration of long-term nuclear oestrogen receptors at all phases of the oestrous cycle. Progesterone administration to rats in late dioestrus did not affect the concentration of uterine nuclear oestrogen receptors 24 h later, although it did prevent the normal cyclic increase at pro-oestrus in the concentration of hypothalamic nuclear oestrogen receptors. Our results therefore show that in the intact adult rat, factors other than the concentration of progesterone or oestradiol determine the nuclear concentration of oestrogen receptors in the uterus. They also demonstrate differences between neural and non-neural tissues in the regulation of oestrogen-receptor interactions.

The unoccupied nuclear oestradiol receptor in the rat uterus and hypothalamus during the oestrous cycle.

The nuclear oestrogen receptor population in the rat uterus contained an unoccupied receptor component that bound oestradiol with the high affinity (Kd congruent to 0.5 nM) characteristic of oestrogen receptors. This unoccupied receptor was present at all phases of the oestrous cycle. Its content changed in parallel with that of the total nuclear receptor during the cycle. Oestradiol administration to the immature rat resulted in increases in the uterine content of long-term nuclear receptors (i.e., those still present 8 h after administration); these increases were due to occupied oestrogen receptors, since the content of unoccupied receptor was unchanged. Our previous experiments [White & Lim (1980) Biochem. J. 190, 833-837] have shown in contrast, that oestradiol administration results in an increase in the content of unoccupied nuclear receptor in the hypothalamus. However, as in the uterus, similar cyclic changes in the content of unoccupied nuclear receptor occurred in parallel with those of the total nuclear receptor population in the hypothalamus. Differences and similarities between the unoccupied nuclear receptor of the uterus and hypothalamus are briefly discussed.

A comparison of the relationships between progestin receptors and oestrogen receptors in neural and non-neural target tissues of the rat during the oestrous cycle.

Similar cyclic changes in the content of nuclear oestrogen receptor occurred in the hypothalamus, cerebral cortex, uterus and pituitary during the oestrous cycle. The relationship of the unoccupied to the total nuclear oestrogen receptor at each phase was similar in all these tissues. However, cyclic changes in the content of the cytosol progestin receptor occurred only in the uterus and pituitary (where they paralleled changes in the nuclear oestrogen receptor), but not in the hypothalamus or cerebral cortex.

Characterization of rat hypothalamic progestin binding by spheroidal hydroxylapatite chromatography.

The progestin-high-affinity-binding components in rat target tissues have been assayed by a simple and precise procedure by using spheroidal hydroxylapatite. The progestin 'receptors' in the uterus and hypothalamus of female rats are highly specific for progestins, which they bind with high affinity (Kd for [3H]progesterone in hypothalamus is 1.9 nM and in uterus is 3.7 nM). The dissociation of [3H]progesterone from receptor in vitro is rapid: t1/2 6 degrees C = 45 min in uterine cytosol; t1/2 6 degrees C = 160 min in hypothalamic cytosol. The binding is destroyed by proteinase. In the cytosol of hypothalamus and cortex of developing rats, progestin 'receptors' were present in both male and female rats by 2-3 days after birth; subsequent changes in concentration of these 'receptors' appeared to be independent of sex. Concentrations of progestin 'receptor' were close to adult values by 8-9 days, and thereafter changed relatively little.

Uterine oestrogen-receptor binding to oligo(dT)-cellulose. An inhibitor from hypothalamic cytosol.

The binding of rat uterine cytosol oestrogen receptor in vitro to oligo(dT)-cellulose is mediated by an activating factor in the cytosol [Thrower, Hall, Lim & Davison (1976) Biochem. J. 160, 271-280]. A potent inhibitor of this binding is present in hypothalamic cytosol. This inhibitor may have a role in vivo in regulating receptor translocation in the hypothalamus.

Intracellular relationships of the oestrogen receptor in the rat uterus and hypothalamus during the oestrous cycle.

Simultaneous measurements were made of the specific oestrogen receptor in the nuclear and cytosol fractions prepared from the uterus and hypothalamus of 50--81-day-old female rats undergoing a 4-day oestrous cycle. In the uterus, the content of nuclear receptor fluctuated in concert with known cyclic changes in the secretion of oestrogen, being maximal at pro-oestrus. Over the period of 50--81 days, the nuclear content at all phases increased with age, again corresponding to known age-related increases in ovarian secretion of oestrogen. This age-related increase in nuclear content, averaged from the values of the different phases in each age group, was related to equivalent increases in uterine wet weight, an increase of 1 pmol of receptor being accompanied by an increase of 80--90 mg. The concentration of cytosol receptor was maintained constant, with respect to wet weight, throughout the cycle and with age, irrespective of changes in nuclear content. In the uterus of normal mature females, translocation of receptor into the nucleus did not lead to depletion of cytosol receptor, suggesting a process of continuous replenishment/synthesis. In the hypothalamus, the nuclear content of oestrogen receptor was also maximal at pro-oestrus. In contrast with the uterus, the content of hypothalamic cytosol receptor was minimal at this phase and reflects depletion of the cytosol receptor, possibly as a result of translocation. The extent of translocation was low compared with that in the uterus and did not alter with age during the age-period studied. This low nuclear binding of the receptor in vivo is discussed in relation to the presence of a cytosol factor, present in limiting amounts, which in vitro mediates the binding of cytosol receptor to oligo(dT)-cellulose. The difference in the physiological response of the uterus and of the hypothalamus to oestrogens may be related to the extent of nuclear binding of receptor.