Prospective evaluation of intra-observer variability of the hydronephrosis index in sonographic examination of 44 patients with acute renal colic

Purpose

The aim of our prospective designed study was to confirm the intra-observer agreement of assessments of the hydronephrosis index (HI) with a sonographic technique that potentially provides additional information in patients with acute renal colic (ARC).

Methods

Sonographic measurement of HI and valuation of common clinical criteria were performed in 44 consecutive patients presenting with unilateral stone-related ARC. HI of colic side was recorded twice in predefined time intervals. Intra-observer agreement was evaluated with the Spearman’s rank correlation/rho (ρ) for attributive-metric characteristics. Data of HI-measurement on the colic side were compared with data of the unaffected side using t test.

Results

Intra-observer agreement was significant for HI in the colic side (ρ = 0.918, p < 0.001) and in the unaffected side (ρ = 0.826, p < 0.001). The mean HI between colic and unaffected side differed significantly on the first evaluation (85.2 vs. 93.7, respectively; p < 0.001) and on the second evaluation (85.1 vs. 93.6, respectively; p < 0.001) as well.

Conclusions

The HI method is a slightly feasible examination method in patients presenting with stone-related renal colic. Moreover, it offers a solid discrimination between obstruction and non-obstruction. Our prospective trial illustrates HI as a reproducible method with a high-grade intra-observer agreement. However, potential change of values under medical expulsive therapy and coherency with the functionality of the obstructed kidney may lead to bias and therefore remain to be analyzed. Further studies to specify exact thresholds for this method and to state our findings are required.     

Age-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans

The dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States. Bromocriptine inhibits prolactin secretion, and patients with hyperprolactinaemia display impaired insulin sensitivity. We therefore hypothesized that low prolactin levels are associated with lower glycaemia and higher insulin sensitivity in healthy subjects. Prolactin levels were determined from fasting serum in participants without diabetes from the cross-sectional Tübingen family study for type 2 diabetes (m/f = 562/1,121, age = 40 ± 13 years, BMI = 30 ± 9 kg/m²). A 75 g oral glucose tolerance test was performed, and the area under the glucose curve (AUC_0–120Glucose) and insulin sensitivity index were calculated. A subgroup (n = 494) underwent hyperinsulinaemic–euglycaemic clamp tests. Prolactin associated positively with insulin sensitivity (p = 0.001, adjusted for gender, age, and BMI). Age strongly interacted (p < 0.0001) with the effect of prolactin on insulin sensitivity, inverting the positive relationship to a negative one in younger participants. Glycated haemoglobin (HbA1c) and AUC_0–120Glucose correlated negatively with prolactin, and an interaction with age was found as well. Higher prolactin levels are associated with improved insulin sensitivity and lower glucose in individuals without diabetes. This relationship turns to its opposite in younger persons. As prolactin is a proxy for the dopaminergic tone in the central nervous system, these associations may indicate an age-dependent influence of the brain on peripheral insulin sensitivity.     

Differential effect of glucose ingestion on the neural processing of food stimuli in lean and overweight adults

Eating behavior is crucial in the development of obesity and Type 2 diabetes. To further investigate its regulation, we studied the effects of glucose versus water ingestion on the neural processing of visual high and low caloric food cues in 12 lean and 12 overweight subjects by functional magnetic resonance imaging. We found body weight to substantially impact the brain's response to visual food cues after glucose versus water ingestion. Specifically, there was a significant interaction between body weight, condition (water versus glucose), and caloric content of food cues. Although overweight subjects showed a generalized reduced response to food objects in the fusiform gyrus and precuneus, the lean group showed a differential pattern to high versus low caloric foods depending on glucose versus water ingestion. Furthermore, we observed plasma insulin and glucose associated effects. The hypothalamic response to high caloric food cues negatively correlated with changes in blood glucose 30 min after glucose ingestion, while especially brain regions in the prefrontal cortex showed a significant negative relationship with increases in plasma insulin 120 min after glucose ingestion. We conclude that the postprandial neural processing of food cues is highly influenced by body weight especially in visual areas, potentially altering visual attention to food. Furthermore, our results underline that insulin markedly influences prefrontal activity to high caloric food cues after a meal, indicating that postprandial hormones may be potential players in modulating executive control. Hum Brain Mapp 35:918–928, 2014. © 2013 Wiley Periodicals, Inc.     

Resting‐state functional connectivity of the human hypothalamus

The hypothalamus is of enormous importance for multiple bodily functions such as energy homeostasis. Especially, rodent studies have greatly contributed to our understanding how specific hypothalamic subregions integrate peripheral and central signals into the brain to control food intake. In humans, however, the neural circuitry of the hypothalamus, with its different subregions, has not been delineated. Hence, the aim of this study was to map the hypothalamus network using resting‐state functional connectivity (FC) analyses from the medial hypothalamus (MH) and lateral hypothalamus (LH) in healthy normal‐weight adults (n = 49). Furthermore, in a separate sample, we examined differences within the LH and MH networks between healthy normal‐weight (n = 25) versus overweight/obese adults (n = 23). FC patterns from the LH and MH revealed significant connections to the striatum, thalamus, brainstem, orbitofrontal cortex, middle and posterior cingulum and temporal brain regions. However, our analysis revealed subtler distinctions within hypothalamic subregions. The LH was functionally stronger connected to the dorsal striatum, anterior cingulum, and frontal operculum, while the MH showed stronger functional connections to the nucleus accumbens and medial orbitofrontal cortex. Furthermore, overweight/obese participants revealed heightened FC in the orbitofrontal cortex and nucleus accumbens within the MH network. Our results indicate that the MH and LH network are tapped into different parts of the dopaminergic circuitry of the brain, potentially modulating food reward based on the functional connections to the ventral and dorsal striatum, respectively. In obese adults, FC changes were observed in the MH network. Hum Brain Mapp 35:6088–6096, 2014. © 2014 Wiley Periodicals, Inc.     

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.     

International validation of the prognostic value of lymphovascular invasion in patients treated with radical cystectomy

Study Type – Prognosis (retrospective cohort)
Level of Evidence 2b

OBJECTIVE

To externally validate the prognostic value of lymphovascular invasion (LVI) in a large international cohort of patients treated with radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB).

PATIENTS AND METHODS

We collected data from 4257 patients treated with RC and pelvic lymphadenectomy for UCB, without neoadjuvant chemotherapy, at 12 centres. LVI was defined as presence of nests of tumour cells within an endothelium‐lined space.

RESULTS

LVI was detected in 1407 patients (33.1%); the proportion of LVI increased with advancing stage, higher grade, soft‐tissue surgical margin involvement, and lymph node metastasis (P < 0.001 for all). In standard multivariate models, LVI was associated with both disease recurrence (hazard ratio 1.43, P < 0.001) and cancer‐specific mortality (1.45, P < 0.001). In the entire cohort, adding LVI to a base model that included standard features improved only minimally its predictive accuracy for both recurrence and cancer‐specific mortality (by 1.1% and 1.2%, respectively). In 3122 patients with negative lymph nodes, LVI remained independently associated with and improved the predictive accuracy of the standard predictors for recurrence (hazard ratio 1.68, P < 0.001; +2.3%) and cancer‐specific mortality (1.70, P < 0.001; +2.4%). By contrast, in 1071 node‐positive patients, LVI only marginally improved the prediction of cancer‐specific recurrence (hazard ratio 1.20, P < 0.001; +0.2%) and survival (1.23, P < 0.001; +0.5%).

CONCLUSIONS

LVI is strongly associated with clinical outcome in node‐negative patients treated with RC. The assessment of LVI might help to identify patients who could benefit from adjuvant therapy after RC. After confirmation in different populations, LVI should be included in the staging of UCB.     

Empagliflozin Improves Insulin Sensitivity of the Hypothalamus in Humans With Prediabetes: A Randomized,Double-Blind,Placebo-Controlled,Phase 2 Trial

OBJECTIVEInsulin action in the human brain reduces food intake, improves whole-body insulin sensitivity, and modulates body fat mass and its distribution. Obesity and type 2 diabetes are often associated with brain insulin resistance, resulting in impaired brain-derived modulation of peripheral metabolism. So far, no pharmacological treatment for brain insulin resistance has been established. Since sodium–glucose cotransporter 2 (SGLT2) inhibitors lower glucose levels and modulate energy metabolism, we hypothesized that SGLT2 inhibition may be a pharmacological approach to reverse brain insulin resistance.RESEARCH DESIGN AND METHODSIn this randomized, double-blind, placebo-controlled clinical trial, 40 patients (mean ± SD; age 60 ± 9 years; BMI 31.5 ± 3.8 kg/m²) with prediabetes were randomized to receive 25 mg empagliflozin every day or placebo. Before and after 8 weeks of treatment, brain insulin sensitivity was assessed by functional MRI combined with intranasal administration of insulin to the brain.RESULTSWe identified a significant interaction between time and treatment in the hypothalamic response to insulin. Post hoc analyses revealed that only empagliflozin-treated patients experienced increased hypothalamic insulin responsiveness. Hypothalamic insulin action significantly mediated the empagliflozin-induced decrease in fasting glucose and liver fat.CONCLUSIONSOur results corroborate insulin resistance of the hypothalamus in humans with prediabetes. Treatment with empagliflozin for 8 weeks was able to restore hypothalamic insulin sensitivity, a favorable response that could contribute to the beneficial effects of SGLT2 inhibitors. Our findings position SGLT2 inhibition as the first pharmacological approach to reverse brain insulin resistance, with potential benefits for adiposity and whole-body metabolism.