Child and adolescent foraging: New directions in evolutionary research.

Young children and adolescents in subsistence societies forage for a wide range of resources. They often target child-specific foods, they can be very successful foragers, and they share their produce widely within and outside of their nuclear family. At the same time, while foraging, they face risky situations and are exposed to diseases that can influence their immune development. However, children's foraging has largely been explained in light of their future (adult) behavior. Here, we reinterpret findings from human behavioral ecology, evolutionary medicine and cultural evolution to center foraging children's contributions to life history evolution, community resilience and immune development. We highlight the need to foreground immediate alongside delayed benefits and costs of foraging, including inclusive fitness benefits, when discussing children's food production from an evolutionary perspective. We conclude by recommending that researchers carefully consider children's social and ecological context, develop cross-cultural perspectives, and incorporate children's foraging into Indigenous sovereignty discourse.

Introduction of hospital quality measures may lead to a temporary decrease in patient outcomes.

OBJECTIVES: To analyse the impact of hospital quality indicators on hip fracture mortality in Israel. STUDY DESIGN: A retrospective observational study. METHODS: Data were collected on all patients aged ≥65 years with an isolated hip fracture in the years 2010-2016 from the Israel's National Trauma Registry. These data were then cross checked with information on co-morbidities and medication intake from the Clalit medical fund. All successfully matched patients constituted the study population. The main outcome measures were in-hospital and 1-year mortality. Trend analysis of surgery on hip fractures within 48 h of hospitalisation (referred to as early hip fracture surgeries) and mortality was performed. The introduction of the proportion of early hip fracture surgeries as an official quality parameter in 2013 was considered an intervention. RESULTS: The proportion of early hip fracture surgeries continuously increased during the study period and, after the introduction of the quality measure, a significant increase in the uniformity of practice among hospitals was observed. The mortality trend was not related to the early surgeries trend, with a sharp upward spike detected in 2014, followed by a gradual return to previous levels in the subsequent years. The analysis has shown that when adjusting for demographic factors and co-morbidity, both in 2010-2013 and in 2015-2016, a clear benefit in survival existed for patients who were operated on within the first 48 h. In 2014, which was the first year of open publication of achieved quality measures reported in the media, no such benefit was found. CONCLUSIONS: Even when an improvement in a promoted practice is achieved, its positive impact on clinical outcomes may be delayed, possibly indicating the need for a learning period.

Incidence and prevalence of psoriasis in Israel between 2011 and 2017.

BACKGROUND: Psoriasis is a common chronic inflammatory skin disease associated with a heavy burden of morbidity, disability and cost. The occurrence of the disease in Israel has not been previously investigated. OBJECTIVES: To provide standardized estimates of trends in psoriasis incidence, prevalence and mortality among patients in Israel between 2011 and 2017. METHODS: Using electronic health records from Clalit Health Services, the largest nationwide public health provider in Israel, we conducted a population-based study investigating trends in the annual incidence and prevalence of psoriasis between the years 2011 and 2017. We report age- and sex-adjusted rates, using the standard European population as a reference. RESULTS: We identified 71 094 incident psoriasis cases. The mean (SD) age of onset was 42.4 (21.0) years with a bimodal distribution, peaking in the early '30s and early '60s. Late-onset psoriasis, occurring after 40 years of age, accounted for 51.1% of incident cases. The annual psoriasis incidence rate was constant throughout the study period (280/100 000 person-years). Psoriasis prevalence rose from 2.5% in 2011 to 3.8% in 2017. CONCLUSIONS: Psoriasis prevalence is increasing in Israel, although its incidence is stable. Clinicians and policymakers should plan to address the growing demands in the clinical, economic and societal burden of psoriasis.

Beyond sarcopenia: Characterization and integration of skeletal muscle quantity and radiodensity in a curable breast cancer population.

Skeletal muscle loss, commonly known as sarcopenia, is highly prevalent and prognostic of adverse outcomes in oncology. However, there is limited information on adults with early breast cancer and examination of other skeletal muscle indices, despite the potential prognostic importance. This study characterizes and examines age-related changes in body composition of adults with early breast cancer and describes the creation of a novel integrated muscle measure. Female patients diagnosed with stage I-III breast cancer with abdominal computerized tomography (CT) scans within 12 weeks from diagnosis were identified from local tumor registry (N = 241). Skeletal muscle index (muscle area per height [cm2 /m2 ]), skeletal muscle density, and subcutaneous and visceral adipose tissue areas, were determined from CT L3 lumbar segments. We calculated a novel integrated skeletal measure, skeletal muscle gauge, which combines skeletal muscle index and density (SMI × SMD). 241 patients were identified with available CT imaging. Median age 52 years and range of 23-87. Skeletal muscle index and density significantly decreased with age. Using literature based cut-points, older adults (≥65 years) had significantly higher proportions of sarcopenia (63 vs 28%) and myosteatosis (90 vs 11%) compared to younger adults (<50 years). Body mass index was positively correlated with skeletal muscle index and negatively correlated with muscle density. Skeletal muscle gauge correlated better with increasing age (ρ = 0.52) than with either skeletal muscle index (ρ = 0.20) or density (ρ = 0.46). Wide variations and age-related changes in body composition metrics were found using routinely obtained abdominal CT imaging. Skeletal muscle index and density provide independent, complementary information, and the product of the two metrics, skeletal muscle gauge, requires further research to explore its impact on outcomes in women with curable breast cancer.

Geriatric assessment-identified deficits in older cancer patients with normal performance status.

BACKGROUND: We investigated whether a brief geriatric assessment (GA) would identify important patient deficits that could affect treatment tolerance and care outcomes within a sample of older cancer patients rated as functionally normal (80%-100%) on the Karnofsky performance status (KPS) scale. METHODS: Cancer patients aged ≥65 years were assessed using a brief GA that included both professionally and patient-scored KPS and measures of comorbidity, polypharmacy, cognition, function, nutrition, and psychosocial status. Data were analyzed using descriptive statistics and multivariable logistic regression. RESULTS: The sample included 984 patients: mean age was 73 years (range: 65-99 years), 74% were female, and 89% were white. GA was conducted before (23%), during (41%), or after (36%) treatment. Overall, 54% had a breast cancer diagnosis (n = 528), and 46% (n = 456) had cancers at other sites. Moreover, 81% of participants (n = 796) had both professionally and self-rated KPS ≥80, defined as functionally normal, and those patients are the focus of analysis. In this subsample, 550 (69%) had at least 1 GA-identified deficit, 222 (28%) had 1 deficit, 140 (18%) had 2 deficits, and 188 (24%) had ≥3 deficits. Specifically, 43% reported taking ≥9 medications daily, 28% had decreased social activity, 25% had ≥4 comorbidities, 23% had ≥1 impairment in instrumental activities of daily living, 18% had a Timed Up and Go time ≥14 seconds, 18% had ≥5% unintentional weight loss, and 12% had a Mental Health Index score ≤76. CONCLUSION: Within this sample of older cancer patients who were rated as functionally normal by KPS, GA identified important deficits that could affect treatment tolerance and outcomes.

Effects of dichlorvos and carbaryl on the activity of free and immobilized acetylcholinesterase.

Acetylcholinesterase (AChE) is responsible for the rapid hydrolytic degradation of the neurotransmitter acetylcholine into inactive products choline and acetic acid. The purpose of this study was to examine the effect of carbaryl and dichlorvos on the activity of AChE. In this experimental study, 60 samples of free and immobilized form of AChE were prepared. Determination of AChE activity followed the Ellman's method with modifications. Briefly, 200 µl of the enzyme solution was combined with 400 µl of 25 mM phosphate-buffered saline, 200 µl of DTNB [5,5'-dithio-bis(2-nitrobenzoic acid)], and 200 µl of 300 µM acetylthiocholine iodide. Triplicate (1000 µl) samples were transferred to clean 1.5-ml centrifuge tubes, mixed, and held on ice until analysed and the change in absorbance was measured. For inhibition studies, substrate solutions were pre-incubated with dichlorvos and/or carbaryl. Dichlorvos and carbaryl were used at the concentrations of 100 and 500 µM. The activity was evaluated at 412 nm using Ceceil, CE 1020 spectrophotometer. Phosphate buffer (pH 7.35) was used for blanks. AChE activity was quantified as mM/ml/min. AChE activity of free form is more affected by Dichlorvos (0.09 ± 0.03 mM/ml/min) than immobilized form (0.19 ± 0.02 mM/ml/min). AChE activity of free form is more affected by carbaryl (0.11 ± 0.01 mM/ml/min) than immobilized form (0.1 ± 0.04 mM/ml/min). Comparison of mean AChE activity showed that the activity of the enzyme in presence of dichlorvos and carbaryl was significantly lower compared to controls. To calculate the significance of the difference, the t-test for paired values was applied. The results of our study indicate that dichlorvos and carbaryl cause decrease in AChE activity for both free and immobilization form of enzyme. It is therefore concluded that measuring AChE activity is a way to evaluate poisoning with carbaryl and dichlorvos.

Opportunities and challenges in delivering remote primary care during the Coronavirus outbreak.

BACKGROUND: Social distancing and lockdowns were implemented during the first period of the COVID-19 pandemic. Primary care physicians needed to adapt quickly to deliver remote care/telemedicine. METHODS: A cross-sectional, 47-item online Google Survey was distributed through the Israel Association of Family Physicians (IAFP) mailing list between March 31-May 5, 2020. The questionnaire included demographics, physician characteristics, and information on usage and perceived telemedicine quality. Sampling weights by sex and age groups were applied. RESULTS: One hundred fifty-nine primary care physicians (10.6% of registered IAFP members; 63.5% women; mean age 53.4 ± 10.4 years and median professional experience 21.3 years) replied to the survey. The majority (59.7%) of the participants performed a mixture of in-person along with phone counseling. About 40% had no former telemedicine experience. The majority indicated that telephone and video formats were inferior to in-person consultation (68%, 57.1% online and phone, respectively). The overall counseling quality grade (on a 1-10 scale,)median (IQR)) was 6.2 (3) for telephone and 7(2) for video. While 66.9% reported experiencing no challenges, 10% had technical problems, 10% interpersonal problems, 5.6% scheduling difficulties, and 7.5% other difficulties. Majority of 56.6% physicians indicated they prescribed more antibiotics,16.4% sent more blood tests, 24.5% referred more to experts, and 49.7% referred more to imaging in comparison to usual counseling. Higher phone quality score was significantly associated with physicians who indicated not prescribing more antibiotics during the pandemic (OR = 0.30, 95%CI 0.134-0.688, p = 0.004). Higher online quality score was associated with physicians who indicated not sending more blood tests during the pandemic (OR = 0.06 95%CI 0.008-0.378, P = 0.003). CONCLUSIONS: Our findings suggest telehealth holds considerable promise for counseling in the primary care setting. However, interpersonal challenges raised by physicians should be understood in-depth to develop tailored training and further examine it in randomized trials while integrating patient-reported outcomes. Finally, further research on utility, cost, and cost-efficiency during remote counseling with follow-ups, medical prescribing, and additional referrals is needed.

Design and synthesis of bis-biotin-containing reagents for applications utilizing monoclonal antibody-based pretargeting systems with streptavidin mutants.

Previous studies have shown that pretargeting protocols, using cancer-targeting fusion proteins, composed of 4 anti-CD20 single chain Fv (scFv) fragments and streptavidin (scFv(4)-SAv), followed by a biotinylated dendrimeric N-acetyl-galactosamine blood clearing agent (CA), 1, then a radiolabeled DOTA-biotin derivative (a monobiotin), 3a, can provide effective therapy for lymphoma xenografts in mouse models. A shortcoming in this pretargeting system is that endogenous biotin may affect its efficacy in patients. To circumvent this potential problem, we investigated a pretargeting system that employs anti-CD20 scFv(4)-SAv mutant fusion proteins with radioiodinated bis-biotin derivatives. With that combination of reagents, good localization of the radiolabel to lymphoma tumor xenografts was obtained in the presence of endogenous biotin. However, the blood clearance reagents employed in the studies were ineffective, resulting in abnormally high levels of radioactivity in other tissues. Thus, in the present investigation a bis-biotin-trigalactose blood clearance reagent, 2, was designed, synthesized, and evaluated in vivo. Additionally, another DOTA-biotin derivative (a bis-biotin), 4a, was designed and synthesized, such that radiometals (e.g., (111)In, (90)Y, (177)Lu) could be used in the pretargeting protocols employing scFv(4)-SAv mutant fusion proteins. Studies in mice demonstrated that the CA 2 was more effective than CA 1 at removing [(125)I]scFv(4)-SAv-S45A mutant fusion proteins from blood. Another in vivo study compared tumor targeting and normal tissue concentrations of the new reagents (2 and [(111)In]4b) with standard reagents (1 and [(111)In]3b) used in pretargeting protocols. The study showed that lymphoma xenografts could be targeted in the presence of endogenous biotin when anti-CD20 fusion proteins containing SAv mutants (scFv(4)-SAv-S45A or scFv(4)-SAv-Y43A) were employed in combination with CA 2 and [(111)In]4b. Importantly, normal tissue concentrations of [(111)In]4b were similar to those obtained using the standard reagents (1 and [(111)In]3b), except that the blood and liver concentrations were slightly higher with the new reagents. While the reasons for the higher blood and liver concentrations are unknown, the differences in the galactose structures of the clearance agents 1 and 2 may play a role.

Rituximab blocks binding of radiolabeled anti-CD20 antibodies (Ab) but not radiolabeled anti-CD45 Ab.

Rituximab therapy is associated with a long in vivo persistence, yet little is known about the effect of circulating rituximab on B-cell non-Hodgkin lymphoma (B-NHL) targeting by the other available anti-CD20 monoclonal antibodies (MoAbs) (131)iodine-tositumomab and (90)yttrium-ibritumomab tiuxetan. Therefore we assessed the impact of preexisting rituximab on the binding and efficacy of second anti-CD20 MoAbs to B-NHL and determined whether targeting an alternative lymphoma-associated antigen, CD45, could circumvent this effect. We demonstrated that rituximab concentrations as low as 5 microg/mL nearly completely blocked the binding of a second anti-CD20 MoAbs (P < .001), but had no impact on CD45 targeting (P = .89). Serum from patients with distant exposures to rituximab also blocked binding of anti-CD20 MoAbs to patient-derived rituximab-naive B-NHL at concentrations at low as 7 microg/mL, but did not affect CD45 ligation. A mouse xenograft model (Granta, FL-18, Ramos cell lines) showed that rituximab pretreatment significantly reduced B-NHL targeting and tumor control by CD20-directed radioimmunotherapy (RIT), but had no impact on targeting CD45. These findings suggest that circulating rituximab impairs the clinical efficacy of CD20-directed RIT, imply that novel anti-CD20 MoAbs could also face this same limitation, and indicate that CD45 may represent an alternative target for RIT in B-NHL.

Regulatory elements that control the lineage-specific expression of myoD.

The molecular basis of skeletal muscle lineage determination was investigated by analyzing DNA control elements that regulate the myogenic determination gene myoD. A distal enhancer was identified that positively regulates expression of the human myoD gene. The myoD enhancer and promoter were active in myogenic and several nonmyogenic cell lines. In transgenic mouse embryos, however, the myoD enhancer and promoter together directed expression of a lacZ transgene specifically to the skeletal muscle lineage. These data suggest that during development myoD is regulated by mechanisms that restrict accessibility of myoD control elements to positive trans-acting factors.

Are animal models as good as we think?

Models have been a tool of science at least since the 18th century and serve a variety of purposes from focusing abstract thoughts to representing scaled down version of things for study. Generally, animal models are needed when it is impractical or unethical to study the target animal. Biologists have taken modeling by analogy beyond most other disciplines, deriving the relationship between model and target through evolution. The "unity in diversity" concept suggests that homology between model and target foretells functional similarities. Animal model studies have been invaluable for elucidating general strategies, pathways, processes and guiding the development of hypotheses to test in target animals. The vast majority of animals used as models are used in biomedical preclinical trials. The predictive value of those animal studies is carefully monitored, thus providing an ideal dataset for evaluating the efficacy of animal models. On average, the extrapolated results from studies using tens of millions of animals fail to accurately predict human responses. Inadequacies in experimental designs may account for some of the failure. However, recent discoveries of unexpected variation in genome organization and regulation may reveal a heretofore unknown lack of homology between model animals and target animals that could account for a significant proportion of the weakness in predictive ability. A better understanding of the mechanisms of gene regulation may provide needed insight to improve the predictability of animal models.

Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice.

BACKGROUND: Cognitive deterioration is a characteristic symptom of Alzheimer's disease. This deterioration is notably associated with structural changes and subsequent cell death which occur, primarily, in acetylcholine-producing neurons, progressively damaging cholinergic neurotransmission. We have reported previously that excess acetylcholinesterase (AChE) alters structural features of neuromuscular junctions in transgenic Xenopus tadpoles. However, the potential of cholinergic imbalance to induce progressive decline of memory and learning in mammals has not been explored. RESULTS: To approach the molecular mechanisms underlying the progressive memory deficiencies associated with impaired cholinergic neurotransmission, we created transgenic mice that express human AChE in brain neurons. With enzyme levels up to two-fold higher than in control mice, transgenic mice displayed an age-independent resistance to the hypothermic effects of the AChE inhibitor, paraoxon. In addition to this improved scavenging capacity for anti-AChEs, however, these transgenic mice also resisted muscarinic, nicotinic and serotonergic agonists, indicating that secondary pharmacological changes had occurred. The transgenic mice also developed progressive learning and memory impairments, although their locomotor activities and open-field behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to training in a spatial learning water maze test, whereas they performed normally in this test at the age of four weeks. This animal model is therefore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. CONCLUSION: We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease.

Tissue-specific and developmentally regulated expression of a chimeric actin-globin gene in transgenic mice.

A chimeric plasmid containing about 2/3 of the rat skeletal muscle actin gene plus 730 base pairs of its 5' flanking sequences fused to the 3' end of a human embryonic globin gene (D. Melloul, B. Aloni, J. Calvo, D. Yaffe, and U. Nudel, EMBO J. 3:983-990, 1984) was inserted into mice by microinjection into fertilized eggs. Eleven transgenic mice carrying the chimeric gene with or without plasmid pBR322 DNA sequences were identified. The majority of these mice transmitted the injected DNA to about 50% of their progeny. However, in transgenic mouse CV1, transmission to progeny was associated with amplification or deletion of the injected DNA sequences, while in transgenic mouse CV4 transmission was distorted, probably as a result of insertional mutagenesis. Tissue-specific expression was dependent on the removal of the vector DNA sequences from the chimeric gene sequences prior to microinjection. None of the transgenic mice carrying the chimeric gene together with plasmid pBR322 sequences expressed the introduced gene in striated muscles. In contrast, the six transgenic mice carrying the chimeric gene sequences alone expressed the inserted gene specifically in skeletal and cardiac muscles. Moreover, expression of the chimeric gene was not only tissue specific, but also developmentally regulated. Similar to the endogenous skeletal muscle actin gene, the chimeric gene was expressed at a relatively high level in cardiac muscle of neonatal mice and at a significantly lower level in adult cardiac muscle. These results indicate that the injected DNA included sufficient cis-acting control elements for its tissue-specific and developmentally regulated expression in transgenic mice.

Expression of the rat myosin light-chain 2 gene in transgenic mice: stage specificity, developmental regulation, and interrelation with the endogenous gene.

The expression of the rat skeletal myosin light-chain 2 gene in two transgenic strains was tissue specific and stage specific. However, the temporal regulation during development of the transgene was different from that of the endogenous gene. Surprisingly, in one strain, the expression of the transgene was associated with a significant down-regulation of the endogenous gene. The possible mechanisms to account for the suppression of the endogenous gene and the potential implications of this suppression are discussed.

Differential regulation of the rat phosphoenolpyruvate carboxykinase gene expression in several tissues of transgenic mice.

The selective expression of a unique copy gene in several mammalian tissues has been approached by studying the regulatory sequences needed to control expression of the rat phosphoenolpyruvate carboxykinase (PEPCK) gene in transgenic mice. A transgene containing the entire PEPCK gene, including 2.2 kb of the 5'-flanking region and 0.5 kb of the 3'-flanking region, exhibits tissue-specific expression in the liver, kidney, and adipose tissue, as well as the hormonal and developmental regulation inherent to endogenous gene expression. Deletions of the 5'-flanking region of the gene have shown the need for sequences downstream of position -540 of the PEPCK gene for expression in the liver and sequences downstream of position -362 for expression in the kidney. Additional sequences upstream of position -540 (up to -2200) are required for expression in adipose tissue. In addition, the region containing the glucocorticoid-responsive elements of the gene used by the kidney was identified. This same sequence was found to be needed specifically for developmental regulation of gene expression in the kidney and, together with upstream sequences, in the intestine. The apparently distinct sequence requirements in the various tissues indicate that the tissues use different mechanisms for expression of the same gene.

Endothelial survival factors and spatial completion, but not pericyte coverage of retinal capillaries determine vessel plasticity.

Pericyte loss and capillary regression are characteristic for incipient diabetic retinopathy. Pericyte recruitment is involved in vessel maturation, and ligand-receptor systems contributing to pericyte recruitment are survival factors for endothelial cells in pericyte-free in vitro systems. We studied pericyte recruitment in relation to the susceptibility toward hyperoxia-induced vascular remodeling using the pericyte reporter X-LacZ mouse and the mouse model of retinopathy of prematurity (ROP). Pericytes were found in close proximity to vessels, both during formation of the superficial and the deep capillary layers. When exposure of mice to the ROP was delayed by 24 h, i.e., after the deep retinal layer had formed [at postnatal (p) day 8], preretinal neovascularizations were substantially diminished at p18. Mice with a delayed ROP exposure had 50% reduced avascular zones. Formation of the deep capillary layers at p8 was associated with a combined up-regulation of angiopoietin-1 and PDGF-B, while VEGF was almost unchanged during the transition from a susceptible to a resistant capillary network. Inhibition of Tie-2 function either by soluble Tie-2 or by a sulindac analog, an inhibitor of Tie-2 phosphorylation, resensitized retinal vessels to neovascularizations due to a reduction of the deep capillary network. Inhibition of Tie-2 function had no effect on pericyte recruitment. Our data indicate that the final maturation of the retinal vasculature and its resistance to regressive signals such as hyperoxia depend on the completion of the multilayer structure, in particular the deep capillary layers, and are independent of the coverage by pericytes.

Rb+ occlusion in renal (Na+ + K+)-ATPase characterized with a simple manual assay.

This paper describes properties of a simple manual assay for Rb+ occlusion on renal (Na+ + K+)-ATPase. Rb+ occlusion is measured by applying the enzyme plus Rb+ (86Rb) mixture to a Dowex-50 cation exchange column at 0 degree C, and eluting the enzyme with occluded Rb+ using an ice-cold sucrose solution. The enzyme-Rb+ complex is quite stable at 0 degree C. This method is useful for measuring Rb+ occlusion under equilibrium binding conditions and slow rates of dissociation of the enzyme-Rb+ complex. The stoichiometry of Rb+ occluded per phosphorylation site is 2. Rb+ saturation curves are strictly hyperbolic, suggesting that the two Rb+ sites have very different affinities, one in the micromolar range and one in the tens of millimolar range. ATP shifts the Rb+ saturation curves to the right (control K0.5 100-200 microM; plus ATP, K0.5 0.8-1.4 mM, in a 100 mM Tris-HCl medium, pH 7.0) and reduces the maximal level occluded (control approx. 4 nmol/mg; plus ATP approx. 3 nmol/mg protein). Thus, as expected, ATP shifts the E(1)2Rb+-E2(2Rb+)occ equilibrium towards E1. Sodium ions at concentrations of up to 30 mM compete with the rubidium ions, KNa = 1.86 mM in the Tris-HCl medium. Na+ at higher concentrations (30-100 mM) has an added non-competitive antagonistic effect. At room temperature, Rb+ dissociates slowly from the enzyme, kobs = 0.08 s-1, in the presence of either Rb+ (20 mM) or Na, (100 mM). As expected, dissociation is greatly accelerated by ATP, the rate being to fast to be measured by this technique. (Na+ + K+)-ATPase proteolyzed selectively by chymotrypsin in a Na+ medium, occludes Rb+. For control and proteolyzed (Na+ + K+)-ATPase the Rb+ saturation curves are similar and the rates of dissociation of the enzyme-Rb+ complex are identical. The chymotryptic split appears to disrupt antagonistic interactions between cation and ATP binding domains, while the E1-E2 conformational transition of the unphosphorylated protein probably remains.

Early loss of arteriolar smooth muscle cells: more than just a pericyte loss in diabetic retinopathy.

Incipient diabetic retinopathy is characterized by increased capillary permeability and progressive capillary occlusion. The earliest structural change is the loss of pericytes (PC) from the retinal capillaries. With the availability of the XLacZ mouse, which expresses the LacZ reporter in a PC/vascular smooth muscle cell (vSMC) specific fashion, we quantitatively assessed the temporal dynamics of smooth muscle cells in arterioles under hyperglycemic conditions. We induced stable hyperglycemia in XLacZ mice. After 4, 8, and 12 weeks of diabetes retinae were isolated and beta-galactosidase/lectin stained. The numbers of smooth muscle cells were counted in retinal whole mounts, and diameters of retinal radial and branching arterioles and venules were analyzed at different distances apart from the center of the retina. After eight weeks of diabetes, the numbers of vSMCs were significantly reduced in radial arterioles 1000 microm distant from the optic disc. At proximal sites of branching arterioles (400 microm distant from the center), and at distal sites (1000 microm), vSMC were significantly reduced already after 4 weeks (to a maximum of 31 %). These changes were not associated with any measurable variation in vessel diameters. These data indicate quantitatively that hyperglycemia not only causes pericyte loss, but also loss of vSMCs in the retinal vasculature. Our data suggest that arteriolar vSMC in the eye underlie similar regulations which induce early pericyte loss in the diabetic retina.

Secondary pituitary insufficiency: report of three cases of ectopia or hemiagenesis of the thyroid gland.

Three patients with clinical and laboratory manifestations suggestive of pituitary insufficiency due to the presence of a pituitary tumor were found to have long-standing myxedema. The insidious appearance of the signs of hypothyroidism was explained by the cause of their disease--an ectopic thyroid gland in two patients and hemiagenesis of the thyroid in the third. Early recognition and treatment of such cases is important.

Prevalence of sarcopenia in older patients with colorectal cancer.

OBJECTIVE: Sarcopenia is the age-related loss of muscle mass, strength, and function. It is a common finding in older patients and is associated with decreased life expectancy and potentially higher susceptibility to chemotherapy toxicity. This study describes the prevalence of sarcopenia in older adults with early stage colorectal cancer. MATERIALS AND METHODS: Patients ≥70 years old who underwent surgical resection for stage I-III colorectal cancer between 2008 and 2013 were identified from the medical record. Sarcopenia was assessed by measuring the total muscle area on computerized tomography (CT) images obtained prior to surgery. Total muscle area was measured at the level of L3 and normalized using each patient's height to produce a skeletal muscle index (SMI). Sarcopenia was defined using sex- and body mass index (BMI)-specific threshold values of SMI. RESULTS: Eighty-seven patients were included, with a median age of 77 years (70-96). Twenty-five men (60% of 42) and 25 women (56% of 45) had sarcopenia. Sarcopenic patients had significantly lower BMI (p=0.03) compared to non-sarcopenic patients. There was a positive correlation between BMI and SMI for both men (r=0.44) and women (r=0.16). CONCLUSION: Sarcopenia is highly prevalent among older patients with early stage colorectal cancer. BMI alone is a poor indicator of lean body mass and improved methods of screening for sarcopenia are necessary. CT scans are a viable option for identifying sarcopenic patients in whom timely interventions may improve survival, quality of life, and functional outcomes.