Assessing head and neck cancer patient preferences and expectations: A systematic review

Publication date: November 2016
Source:Oral Oncology, Volume 62
Author(s): Pierre Blanchard, Robert J. Volk, Jolie Ringash, Susan K. Peterson, Katherine A. Hutcheson, Steven J. Frank
IntroductionTo enhance the value of care, interventions should aim at improving endpoints that matter to patients. The preferences of head and neck cancer patients regarding treatment outcomes are therefore a major topic for patient-centered research.MethodsA systematic review (PROSPERO number CRD42016035692) was conducted by searching electronic databases (Medline, Embase, Cochrane, CINAHL) for articles evaluating patient or surrogate preferences in head and neck cancer. A qualitative review was performed but no quantitative synthesis.ResultsOf 817 references retrieved, 20full-text articles were eventually included in the qualitative analysis Disease sites included mixed head and neck tumor sites, n=9; larynx, n=6; oropharynx/oral cavity, n=5. Overall, patients prioritized survival over functional endpoints. However, preferences and utility scores varied greatly between patients and healthy subjects, and differences were less pronounced with spouses or healthcare providers. Findings from studies of laryngeal preservation are consistent and conclude that a subset of patients would be willing to compromise a certain amount of survival to avoid laryngectomy. On the other hand, studies of patients with oropharyngeal cancer are too heterogeneous to draw conclusions about acceptable functional trade-offs or priorities, and should be the focus of future research.ConclusionFuture research surrounding head and neck cancer patients will most likely be clinically applicable if the questions are focused on well-defined patient groups and treatment options. Gathering reliable and valid quality-of-life data, designing patient preference studies that use reliable and generalizable methods, and using the results to develop decision aids for shared decision-making strategies are recommended going forward.



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Identification of a gene expression signature in peripheral blood of multiple sclerosis patients treated with disease-modifying therapies

Publication date: Available online 5 October 2016
Source:Clinical Immunology
Author(s): Chiara Cordiglieri, Fulvio Baggi, Pia Bernasconi, Dimos Kapetis, Elisa Faggiani, Alessandra Consonni, Francesca Andreetta, Rita Frangiamore, Paolo Confalonieri, Carlo Antozzi, Renato Mantegazza
Multiple Sclerosis (MS) is an inflammatory disease with neurodegenerative alterations, ultimately progressing to neurological handicap. Therapies are effective in counteracting inflammation but not neurodegeneration. Biomarkers predicting disease course or treatment response are lacking. We investigated whether altered gene and protein expression profiles were detectable in the peripheral blood of 78 relapsing remitting MS (RR-MS) patients treated by disease-modifying therapies. A discovery/validation study on RR-MS responsive to glatiramer acetate identified 8 differentially expressed genes: ITGA2B, ITGB3, CD177, IGJ, IL5RA, MMP8, P2RY12, and S100β. A longitudinal study on glatiramer acetate, Interferon-β, or Fingolimod treated RR-MS patients confirmed that 7 out of 8 genes were downregulated with reference to the different therapies, whereas S100β was always upregulated. Thus, we identified a peripheral gene signature associated with positive response in RR-MS which may also explain drug immunomodulatory effects. The usefulness of this signature as a biomarker needs confirmation on larger series of patients.



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Successful treatment of palmoplantar pustulosis with rheumatoid arthritis, with tofacitinib: Impact of this JAK inhibitor on T-cell differentiation

Publication date: Available online 5 October 2016
Source:Clinical Immunology
Author(s): Tomohiro Koga, Tomohito Sato, Masataka Umeda, Shoichi Fukui, Yoshiro Horai, Shin-ya Kawashiri, Naoki Iwamoto, Kunihiro Ichinose, Hideki Nakamura, Atsushi Kawakami




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HIC1 epigenetically represses CIITA transcription in B lymphocytes

Publication date: Available online 6 October 2016
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Sheng Zeng, Yuyu Yang, Xian Cheng, Bisheng Zhou, Ping Li, Yuhao Zhao, Xiaocen Kong, Yong Xu
Differentiation of B lymphocytes into isotope-specific plasma cells represents a hallmark event in adaptive immunity. During B cell maturation, expression of class II transactivator (CIITA) gene is down-regulated although the underlying epigenetic mechanism is not completely defined. Here we report that hypermethylated in cancer 1 (HIC1) was up-regulated in differentiating B lymphocytes paralleling CIITA repression. Over-expression of HIC1 directly repressed endogenous CIITA transcription in B cells. Reporter assay and chromatin immunoprecipitation (ChIP) assay confirmed that HIC1 bound to the proximal CIITA type III promoter (−545/−113); mutation of a conserved HIC1 site within this region abrogated CIITA trans-repression. More important, depletion of HIC1 with small interfering RNA (siRNA) restored CIITA expression in differentiating B cells. Mechanistically, HIC1 preferentially interacted with and recruited DNMT1 and DNMT3b to the CIITA promoter to synergistically repress CIITA transcription. On the contrary, silencing of DNMT1/DNMT3b or inhibition of DNMT activity with 5-aza-dC attenuated CIITA trans-repression. Therefore, our data identify HIC1 as a novel factor involved in B cell differentiation acting as an epigenetic repressor of CIITA transcription.



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New properties with old materials: Layered black phosphorous

Publication date: Available online 5 October 2016
Source:Nano Today
Author(s): Tianchao Niu
Layered black phosphorous (BP), its tunable direct bandgap, higher carrier mobility and unique in-plane anisotropy, enables it to a promising candidate in design and optimization of electronics and optoelectronic devices with excellent performance. Although recent studies and perspectives aim at bringing this material to a level of maturity, the lack of wafer scale production and the surface reactivity of BP hindered a fully industrial processes. Here, we addressed the probable solutions to overcome these challenges black phosphorous was facing.

Graphical abstract

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Interaction of O2 with monolayer MoS2: Effect of doping and hydrogenation

Publication date: 5 January 2017
Source:Materials & Design, Volume 113
Author(s): B. Zhao, L.L. Liu, G.D. Cheng, T. Li, N. Qi, Z.Q. Chen, Z. Tang
The interaction of O2 with doped monolayer MoS2 and the effect of hydrogenation are studied by first-principles calculations coupled with the CI-NEB method. Surface chemically inertness of the MoS2 (001) plane can be broken by doping with Co, Ni and Cu atoms. Impurity levels are induced around the Fermi level and lead to the decrease of band gap, which is beneficial to the adsorption of O2 molecule. The activated oxygen atoms are produced through a dissociation reaction. The introduction of hydrogen atoms into the surface of doped MoS2 system presents favorable effect for O2 adsorption and dissociation. More impurity levels appear in the hydrogenated MoS2-Co/Ni system, and more electrons are localized at 3d orbital of Co/Ni atom, these systems all present excellent adsorption capacity. Hydrogenation reaction occurs by a hydrogen adatom smoothly migrating to the adsorbed O2 with the formation of OOH radical. The elongated OO bond of OOH radical can be dissociated with a lower activation energy barrier, producing an OH radical and activated oxygen atom. Our theoretical studies suggest that the doped monolayer MoS2 system is effective for capturing O2 molecule, and the hydrogenation is found to facilitate adsorption and dissociation of O2 molecule.

Graphical abstract

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Histopathologic Validation of Grayscale Carotid Plaque Characteristics Related to Plaque Vulnerability

Publication date: Available online 5 October 2016
Source:Ultrasound in Medicine & Biology
Author(s): Carol C. Mitchell, James H. Stein, Thomas D. Cook, Shahriar Salamat, Xiao Wang, Tomy Varghese, Daren C. Jackson, Carolina Sandoval Garcia, Stephanie M. Wilbrand, Robert J. Dempsey
Inflammation and angiogenesis play major roles in carotid plaque vulnerability. The purpose of this study was to determine whether gray-scale features of carotid plaques are associated with histologic markers for inflammation. Thirty-eight individuals completed a dedicated research carotid ultrasound exam before carotid endarterectomy. Gray-scale analysis was performed on plaque images to measure plaque echogenicity (gray-scale median [GSM] pixel brightness), plaque area, presence of discrete white areas (DWAs) and the percent of black area near the lumen on any one component of the plaque. Plaques with higher ultrasound GSM had greater percent calcification (p = 0.013) on histopathology. Presence of an ultrasound DWA was associated with more plaque hemosiderin (p = 0.0005) and inflammation (p = 0.019) on histopathology examination. The percent of plaque black area in any one component was associated with a higher score for macroscopic ulceration (p = 0.028). Ultrasound plaque characteristics (GSM, DWAs and black areas) represent histopathologic markers associated with plaque vulnerability. ClinicalTrials.gov identifier: NCT02476396.



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Successful treatment of residual pituitary adenoma in persistent acromegaly following localisation by 11C-methionine PET co-registered with MRI

Objective

To determine if functional imaging using ¹¹C-methionine positron emission tomography co-registered with 3D gradient echo MRI (Met-PET/MRI), can identify sites of residual active tumour in treated acromegaly, and discriminate these from post-treatment change, to allow further targeted treatment.

Design/methods

Twenty-six patients with persistent acromegaly after previous treatment, in whom MRI appearances were considered indeterminate, were referred to our centre for further evaluation over a 4.5-year period. Met-PET/MRI was performed in each case, and findings were used to decide regarding adjunctive therapy. Four patients with clinical and biochemical remission after transsphenoidal surgery (TSS), but in whom residual tumour was suspected on post-operative MRI, were also studied.

Results

Met-PET/MRI demonstrated tracer uptake only within the normal gland in the four patients who had achieved complete remission after primary surgery. In contrast, in 26 patients with active acromegaly, Met-PET/MRI localised sites of abnormal tracer uptake in all but one case. Based on these findings, fourteen subjects underwent endoscopic TSS, leading to a marked improvement in (n = 7), or complete resolution of (n = 7), residual acromegaly. One patient received stereotactic radiosurgery and two patients with cavernous sinus invasion were treated with image-guided fractionated radiotherapy, with good disease control. Three subjects await further intervention. Five patients chose to receive adjunctive medical therapy. Only one patient developed additional pituitary deficits after Met-PET/MRI-guided TSS.

Conclusions

In patients with persistent acromegaly after primary therapy, Met-PET/MRI can help identify the site(s) of residual pituitary adenoma when MRI appearances are inconclusive and direct further targeted intervention (surgery or radiotherapy).

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Long-term outcomes of letrozole treatment for precocious puberty in girls with McCune-Albright syndrome

Objective

McCune–Albright syndrome (MAS) is a rare disorder with a broad spectrum including precocious puberty (PP) due to recurrent estrogen-secreting ovarian cysts. This study evaluates the long-term safety and efficacy of letrozole treatment in large cohort of girls with MAS-associated PP.

Design

Retrospective cohort analysis.

Methods

Clinical data, including history and physical examination, bone age, and pelvic ultrasounds, were reviewed on 28 letrozole-treated girls. Adult height was reviewed for 42 historical controls. Outcomes included rate of skeletal maturation, growth velocity, predicted adult height and adult height.

Results

Twenty-eight girls received letrozole treatment. Treatment duration was 4.1 ± 2.6 years (mean ± 1 s.d.) (range: 0.5–10.9) and mean follow-up was 6.0 ± 3.3 years (range: 0.5–15.0), for a total of 135.9 person-years of follow-up. Letrozole treatment was highly effective at decreasing the rate of skeletal maturation, with a decline in change in bone age over change in chronological age (BA/CA) from 1.7 (IQR: 2.3) to 0.5 (IQR: 0.4) (P < 0.0001), and growth velocity Z-scores, which declined from 2.2 ± 2.3 to –0.6 ± 1.6 (P = 0.0004). Predicted adult height Z-scores increased significantly from –2.9 ± 3.2 to –0.8 ± 1.5 for subjects on treatment (P = 0.004). Four subjects who completed treatment reached adult height Z-scores ranging from –1.5 to 1.7 (median: –0.6), which were increased in comparison with untreated historical controls (P = 0.02). There was no change in uterine size or ovarian volumes, and no adverse events over the treatment period.

Conclusions

In this study with the longest follow-up to date, letrozole treatment resulted in sustained beneficial effects on skeletal maturation, growth velocity and predicted adult height.

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ENDOCRINOLOGY IN PREGNANCY: Pregnancy and the incidence, diagnosing and therapy of Graves disease

Thyroid hormones are essential developmental factors, and Graves' disease (GD) may severely complicate a pregnancy. This review describes how pregnancy changes the risk of developing GD, how early pregnancy by several mechanisms leads to considerable changes in the results of the thyroid function tests used to diagnose hyperthyroidism, and how these changes may complicate the diagnosing of GD. Standard therapy of GD in pregnancy is anti-thyroid drugs. However, new studies have shown considerable risk of birth defects if these drugs are used in specific weeks of early pregnancy, and this should be taken into consideration when planning therapy and control of women who may in the future become pregnant. Early pregnancy is a period of major focus in GD, where pregnancy should be diagnosed as soon as possible, and where important and instant change in therapy may be warranted. Such change may be an immediate stop of anti-thyroid drug therapy in patients with a low risk of rapid relapse of hyperthyroidism, or it may be an immediate shift from methimazole/carbimazole (with risk of severe birth defects) to propylthiouracil (with less risk), or maybe to other types of therapy where no risk of birth defects have been observed. In the second half of pregnancy, an important concern is that not only the mother with GD but also her foetus should have normal thyroid function.

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MECHANISMS IN ENDOCRINOLOGY: Parity and risk of type 2 diabetes: a systematic review and dose-response meta-analysis

Objective

Epidemiologic studies regarding the association between parity and risk of type 2 diabetes have yielded inconsistent results. Therefore, we performed a systematic review and dose-response meta-analysis to determine the relation between parity and type 2 diabetes risk.

Methods

We searched PubMed and Embase for published epidemiologic studies that assessed the relation between parity and risk of type 2 diabetes up to 31 March 2016. A dose-response random-effects model was used to combine study-specific relative risks (RRs) and 95% confidence intervals (CIs). Potential sources of heterogeneity were explored by meta-regression and subgroup analyses.

Results

Seven cohort studies, 1 case-control study and 9 cross-sectional studies including 296 923 participants were eligible for inclusion. The combined RR for the highest versus lowest category of parity indicated a 54% increment in type 2 diabetes risk (95% CI: 29–83%). In the cubic spline model, a nonlinear association was found between parity and risk of type 2 diabetes (P = 0.02 for nonlinearity). Compared with nulliparous women, the estimated RR (95% CI) of type 2 diabetes for women with one to seven children was 1.01 (0.96–1.07), 1.08 (1.00–1.16), 1.20 (1.12–1.30), 1.32 (1.22–1.42), 1.37 (1.27–1.48), 1.39 (1.26–1.52) and 1.39 (1.23–1.57) respectively.

Conclusions

Higher parity is significantly associated with an increased risk of type 2 diabetes. Further studies are warranted to fully adjust for the potential confounders and explore the causality between parity and type 2 diabetes risk.

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The link between metabolic features and TSH levels in polycystic ovary syndrome is modulated by the body weight: an euglycaemic-hyperinsulinaemic clamp study

Objective

To evaluate the link among thyroid function, glucose/insulin metabolism and steroid hormones in women with polycystic ovary syndrome (PCOS), and to verify if the body mass index (BMI) might influence the interplay between PCOS features and subclinical hypothyroidism (SCH).

Study design

Case–control study conducted from January to December 2014.

Methods

One-hundred fifty-four young women with PCOS, according to Rotterdam criteria, and 88 controls were enrolled in an academic research environment. Anthropometric evaluation, hormonal and lipid assays, oral glucose tolerance test (OGTT) and euglycaemic–hyperinsulinaemic clamp were performed. Hirsutism was assessed with the Ferriman–Gallwey (FG) score.

Main results

SCH was found in 14% of PCOS subjects and in 1% of controls (P < 0.01). In PCOS women, TSH levels were directly correlated with fasting glycaemia, but not with other hormonal and metabolic parameters. When PCOS patients were classified on the basis of BMI, TSH levels significantly correlated with insulin secretion, insulin resistance, DHEAS and cortisol levels in obese PCOS women. Inverse correlations were found between TSH and both oestradiol and SHBG in the same group. In nonobese PCOS patients, only waist-to-hip ratio values were correlated with TSH. The prevalence of SCH was not different between nonobese and obese PCOS groups (14 and 15% respectively). However, SCH was associated with higher levels of insulin, DHEAS, cortisol and FG score only in the obese subgroup.

Conclusions

Our data confirm that the prevalence of SCH is increased in PCOS women. The presence of SCH is associated with endocrine and metabolic imbalances of PCOS, and the excessive body weight seems to promote this interplay.

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Epidemiological characteristics and methodological quality of meta-analyses on diabetes mellitus treatment: a systematic review

Objective

Well-conducted meta-analyses (MAs) are considered as one of the best sources of clinical evidence for treatment decision. MA with methodological flaws may introduce bias and mislead evidence users. The aim of this study is to investigate the characteristics and methodological quality of MAs on diabetes mellitus (DM) treatments.

Design

Systematic review.

Methods

Cochrane Database of Systematic Review and Database of Abstract of Reviews of Effects were searched for relevant MAs. Assessing methodological quality of systematic reviews (AMSTAR) tool was used to evaluate the methodological quality of included MAs. Logistic regression analysis was used to identify association between characteristics of MA and AMSTAR results.

Results

A total of 252 MAs including 4999 primary studies and 13,577,025 patients were included. Over half of the MAs (65.1%) only included type 2 DM patients and 160 MAs (63.5%) focused on pharmacological treatments. About 89.7% MAs performed comprehensive literature search and 89.3% provided characteristics of included studies. Included MAs generally had poor performance on the remaining AMSTAR items, especially in assessing publication bias (39.3%), providing lists of studies (19.0%) and declaring source of support comprehensively (7.5%). Only 62.7% MAs mentioned about harm of interventions. MAs with corresponding author from Asia performed less well in providing MA protocol than those from Europe.

Conclusions

Methodological quality of MA on DM treatments was unsatisfactory. There is considerable room for improvement, especially in assessing publication bias, providing lists of studies and declaring source of support comprehensively. Also, there is an urgent need for MA authors to report treatment harm comprehensively.

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Impact of sleep behavior on glycemic control in type 1 diabetes: the role of social jetlag

Background

Sleep behavior is changing toward shorter sleep duration and a later chronotype. It results in a sleep debt that is acquitted on work-free days, inducing a small but recurrent sleep misalignment each week, referred to as "social jetlag". These sleep habits could affect health through misalignment with circadian rhythms.

Objectives

The primary objective is to address the impact of sleep behavior on glycemic control, assessed by HbA1c, in patients with type 1 diabetes, independently of other lifestyle or sleep-related factors. The secondary objective is to address whether circadian phase affects glycemic control.

Design

In total, 80 adult patients with type 1 diabetes (46% female) were included in a clinical cohort study.

Methods

Sleep behavior was addressed objectively by a 7-day actimetry, lifestyle by questionnaires, sleep breathing disorders by nocturnal oximetry and circadian phase by dim light melatonin onset (DLMO).

Results

Univariate analyses showed that chronotype (r = 0.23, P = 0.042) and social jetlag (r = 0.30, P = 0.008) were significantly associated with HbA1c. In multivariable analysis, social jetlag was the only sleep habit independently associated with HbA1c (β = 0.012 (0.006; 0.017), P < 0.001). HbA1c was lower in patients with a social jetlag below versus above the median (7.7% (7.1–8.7) and 8.7% (7.6–9.8), P = 0.011). DLMO was not associated with HbA1c. However, the later the DLMO, the worse the sleep efficiency (r = –0.41, P < 0.001) and fragmentation index (r = 0.35, P = 0.005).

Conclusions

Social jetlag, a small but recurrent circadian misalignment, is associated with worse glycemic control in type 1 diabetes, whereas circadian phase is not. Further intervention studies should address the potential improvement of glycemic control by correcting social jetlag.

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Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours

Objective

To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers.

Design and methods

Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2x upper limit of normal (ULN), 2–10x ULN, or >10x ULN. For neuron-specific enolase (NSE), this was the reference range or >1x ULN. OS was compared using Kaplan–Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses.

Results

A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10x ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10x ULN was a negative predictor (HR 1.62, 95% CI: 1.09–2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01–1.08), grade 3 disease (HR 5.09, 95% CI: 2.20–11.79), NSE >1x ULN (HR 2.36, 95% CI: 1.34–4.14) and CgA >10x ULN (HR 3.61, 95% CI: 1.56–8.34) remained as the predictors.

Conclusion

Urinary 5-HIAA excretion >10x ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.

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Stress hormone release is a key component of the metabolic response to lipopolysaccharide: studies in hypopituitary and healthy subjects

Objective

Acute and chronic inflammatory and metabolic responses are generated by lipopolysaccharide (LPS) during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but whether these responses depend on intact pituitary release of hormones are not clearly identified. We compared the metabolic effects of LPS in hypopituitary patients (HPs) (in the absence of growth hormone (GH) and ACTH responses) and healthy control subjects (CTR) (with normal pituitary hormone responses).

Design

Single-blind randomized.

Methods

We compared the effects of LPS on glucose, protein and lipid metabolism in eight HP and eight matched CTR twice during 4-h basal and 2-h hyperinsulinemic–euglycemic clamp conditions with muscle and fat biopsies in each period during infusion with saline or LPS.

Results

LPS increased cortisol and GH levels in CTR but not in HP. Also, it increased whole-body palmitate fluxes (3-fold) and decreased palmitate-specific activity (SA) 40–50% in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 – an inhibitor of lipolysis) adipose tissue (AT) mRNA was decreased in CTR. Although LPS increased phenylalanine fluxes significantly more in CTR, there was no difference in glucose metabolism between groups and intramyocellular insulin signaling was unaltered in both groups.

Conclusions

LPS increased indices of lipolysis and amino acid/protein fluxes significantly more in CTR compared with HP and decreased adipocyte G0S2 mRNA only in CTR. Thus, in humans intact pituitary function and appropriate cortisol and GH release are crucial components of the metabolic response to LPS.

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Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

Objective

Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional.

Design and methods

We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers.

Results

Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin.

Conclusions

Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

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Cord blood leptin and gains in body weight and fat mass during infancy

Objectives

Low early-life leptin concentrations may promote faster weight gain in infancy. We aimed to examine the associations between cord blood leptin concentrations and changes in weight and body composition during infancy.

Design and methods

Serum leptin was measured at 15 weeks gestation, in umbilical cord blood collected at delivery and at 2 years in 334 children from the Cork Baseline Birth Cohort Study. Body composition was measured at 2 days and 2 months using air displacement plethysmography. Conditional change in weight standard deviation scores over a number of age intervals in the first 2 years and conditional change in fat mass index (FMI) and fat-free mass index (FFMI) (kg/(length)m²) between birth and 2 months were calculated and associations with cord blood leptin were examined using linear regression.

Results

At birth, cord blood leptin was positively correlated with FMI (r = 0.48, P < 0.001) and showed a weaker correlation with FFMI (r = 0.12, P = 0.05). After adjustment for confounders, higher cord blood leptin (per ng/mL) was associated with slower conditional weight gain between birth and 2 months (β (95% CI): –0.024 (–0.035, –0.013), P < 0.001) but not over subsequent age intervals. Cord blood leptin was also inversely associated with conditional change in FMI (–0.021 (–0.034, –0.007, P = 0.003) but not FFMI between birth and 2 months.

Conclusions

These are the first data to show that associations between higher cord blood leptin and slower weight gain during infancy are driven by lower increases in adiposity, at least in early infancy.

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The role of FDG-PET in localization of recurrent lesions of differentiated thyroid cancer (DTC) in patients with asymptomatic hyperthyroglobulinemia in a real clinical practice

Introduction

Available methods, including serum thyroglobulin (Tg) measurement and whole-body scan (WBS) performed after radioiodine administration, allow for a precise diagnostics in differentiated thyroid cancer (DTC). However, some asymptomatic patients demonstrate negative WBS despite a high Tg serum concentration. In these subjects, fluorodeoxyglucose-positron emission tomography (FDG-PET) should be considered. The primary aim of our study was to evaluate a diagnostic value of FDG-PET in asymptomatic hyperthyroglobulinemia. The secondary one was to determine a prognostic value of a negative FDG-PET result in DTC patients with elevated Tg level.

Material

One hundred and ten FDG-PET/CT scans were retrospectively analyzed, 85 scans were done under TSH stimulation and 25 on LT₄ suppressive therapy. Follow-up ranged between 4 and 9 years.

Results

The first FDG-PET/CT detected cancer foci in 49 subjects with a global sensitivity of 45%. When the sensitivity was evaluated with reference to TSH stimulation and suppression, its values were 50 and 28% respectively. In 42 patients, FDG-PET failed to diagnose the reason for elevated Tg level. During further follow-up, in 17 of them, DTC recurrence was detected by other methods (CT, MRI, US). Fourteen subjects with asymptomatic hyperthyroglobulinemia were free of DTC progression for at least 4 years.

Conclusions

FDG-PET in DTC patients with asymptomatic hyperthyroglobulinemia constitutes a valuable diagnostic tool. Negative FDG-PET demonstrated a limited prognostic significance, as only every third patient did not show DTC progression. Moreover, negative FDG-PET does not justify less strict DTC monitoring, because it is related to 40% risk of relapse during the 5-year follow-up.

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Heterozygous inactivating CaSR mutations causing neonatal hyperparathyroidism: function, inheritance and phenotype

Background

Homozygous inactivating mutations of the calcium-sensing receptor (CaSR) lead to neonatal severe hyperparathyroidism (NSHPT), whereas heterozygous inactivating mutations result in familial hypocalciuric hypercalcemia (FHH). It is unknown why in some cases heterozygous CaSR mutations cause neonatal hyperparathyroidism (NHPT) clinically similar to NSHPT but with only moderately elevated serum calcium.

Methods

A literature survey was conducted to identify patients with heterozygous CaSR mutations and NHPT. The common NHPT CaSR mutants R185Q and R227L were compared with 15 mutants causing only FHH in the heterozygous state. We studied in vitro calcium signaling including the functional consequences of co-expression of mutant and wild-type (wt) CaSR, patients' phenotype, age of disease manifestation and mode of inheritance.

Results

All inactivating CaSR mutants impaired calcium signaling of wt-CaSR regardless of the patients' clinical phenotype. The absolute intracellular calcium signaling response to physiologic extracellular calcium concentrations in vitro showed a high correlation with patients' serum calcium concentrations in vivo, which is similar in NHPT and FHH patients with the same genotype. Pedigrees of FHH families revealed that paternal inheritance per se does not necessarily lead to NHPT but may only cause FHH.

Conclusions

There is a significant correlation between in vitro functional impairment of the CaSR at physiologic calcium concentrations and the severity of alterations in calcium homeostasis in patients. Whether a particular genotype leads to NHPT or FHH appears to depend on additional predisposing genetic or environmental factors. An individual therapeutic approach appears to be warranted for NHPT patients.

http://ift.tt/2dB4KZU