According to Alix-Panabières, this discrepancy could be the result of higher PD-L1 expression by CTCs than by primary tumours, and potential differences in methods.
Oxalate nephropathy with renal failure is caused by multiple disorders leading to hyperoxaluria due to either overproduction of oxalate (primary hyperoxaluria) or excessive absorption of dietary ...oxalate (enteric hyperoxaluria). To study the etiology of renal failure in crystal-induced kidney disease, we created a model of progressive oxalate nephropathy by feeding mice a diet high in soluble oxalate (high oxalate in the absence of dietary calcium). Renal histology was characterized by intratubular calcium-oxalate crystal deposition with an inflammatory response in the surrounding interstitium. Oxalate nephropathy was not found in mice fed a high oxalate diet that also contained calcium. NALP3, also known as cryopyrin, has been implicated in crystal-associated diseases such as gout and silicosis. Mice fed the diet high in soluble oxalate demonstrated increased NALP3 expression in the kidney. Nalp3-null mice were completely protected from the progressive renal failure and death that occurred in wild-type mice fed the diet high in soluble oxalate. NALP3 deficiency did not affect oxalate homeostasis, thereby excluding differences in intestinal oxalate handling to explain the observed phenotype. Thus, progressive renal failure in oxalate nephropathy results primarily from NALP3-mediated inflammation.
Gait disturbance is an early feature in Parkinson's disease. Its pathophysiology is poorly understood; however, cholinergic dysfunction may be a non-dopaminergic contributor to gait. Short-latency ...afferent inhibition is a surrogate measure of cholinergic activity, allowing the contribution of cholinergic dysfunction to gait to be evaluated. We hypothesized that short-latency afferent inhibition would be an independent predictor of gait dysfunction in early Parkinson's disease. Twenty-two participants with Parkinson's disease and 22 age-matched control subjects took part in the study. Gait was measured objectively using an instrumented walkway (GAITRite), and subjects were asked to walk at their preferred speed for 2 min around a 25-m circuit. Spatiotemporal characteristics (speed, stride length, stride time and step width) and gait dynamics (variability described as the within subject standard deviation of: speed, stride time, stride length and step width) were determined. Short-latency afferent inhibition was measured by conditioning motor evoked potentials, elicited by transcranial magnetic stimulation of the motor cortex, with electrical stimuli delivered to the contralateral median nerve at intervals ranging from N20 (predetermined) to N20 + 4 ms. Short-latency afferent inhibition was determined as the percentage difference between test and conditioned response for all intervals and was described as the group mean. Participants were optimally medicated at the time of testing. Participants with Parkinson's disease had significantly reduced gait speed (P = 0.002), stride length (P = 0.008) and stride time standard deviation (P = 0.001). Short-latency afferent inhibition was also significantly reduced in participants with Parkinson's disease (P = 0.004). In participants with Parkinson's disease, but not control subjects, significant associations were found between gait speed, short-latency afferent inhibition, age and postural instability and gait disorder score (Movement Disorders Society Unified Parkinson's Disease Rating Scale) and attention, whereas global cognition and depression were marginally significant. No other gait variables were associated with short-latency afferent inhibition. A multiple hierarchical regression model explored the contribution of short-latency afferent inhibition to gait speed, controlling for age, posture and gait symptoms (Postural Instability and Gait Disorder score-Movement Disorders Society Unified Parkinson's Disease Rating Scale), attention and depression. Regression analysis in participants with Parkinson's disease showed that reduced short-latency afferent inhibition was an independent predictor of slower gait speed, explaining 37% of variability. The final model explained 72% of variability in gait speed with only short-latency afferent inhibition and attention emerging as independent determinants. The results suggest that cholinergic dysfunction may be an important and early contributor to gait dysfunction in Parkinson's disease. The findings also point to the contribution of non-motor mechanisms to gait dysfunction. Our study provides new insights into underlying mechanisms of non-dopaminergic gait dysfunction, and may help to direct future therapeutic approaches.
Context: Because clinical manifestations of thyroid disorders are variable and subtle in children and adolescents, thyroid function tests are often repeated in patients with nonspecific symptoms.
...Objectives: The objective of the study was to determine the natural history of initial abnormal TSH and define populations at greater risk for developing a subsequent thyroid dysfunction.
Methods: A total of 121,052 of 1.043 million outpatients aged 0.5–16 yr insured by the Clalit Health Medical Organization had a TSH determination in 2002 and follow-up to 2007. Extracted from the Clalit Health Medical Organization database were their demographic data, referral diagnoses, and laboratory results (TSH, free T4, thyroid antibodies). Excluded were patients with overt hypothyroidism or hyperthyroidism on initial testing.
Results: Results of 96.5% of initial serum TSH concentrations were normal (0.35–5.5 mIU/liter), 0.2% were low (<0.35 mIU/liter), 2.9% elevated (>5.5 to ≤10 mIU/liter), and 0.4% highly elevated (>10 mIU/liter). The frequency of TSH testing increased with age and female gender. During follow-up, repeated (two to more than four) TSH tests were performed in 45.7% of the patients. In the second TSH determination, normal TSH was documented in 40, 73.6, and 78.9% of those whose initial serum TSH was highly elevated, elevated, and low, respectively, and in 97% of those with normal initial TSH. Predictive factors for a sustained highly elevated TSH were initial TSH greater than 7.5 mIU/liter (P = 0.014) and female gender (P = 0.047).
Conclusions: In the pediatric population, initial normal or slightly elevated TSH levels are likely to remain normal or spontaneously normalize without treatment. Patients with initial levels greater than 7.5 mIU/liter, particularly girls, are at a greater risk for sustained abnormal TSH levels.
Most children with mild subclinical thyroid dysfunctions revert to normal TSH levels; those with TSH > 7.5 mU/liter are at greater risk for sustained abnormal levels.
Data regarding glycemic control in children and adolescents with a dual diagnosis of type 1 diabetes mellitus (T1DM) and attention-deficit/hyperactivity disorder (ADHD) are limited.
To compare ...various aspects of diabetes control among youth with T1DM, between those with and without ADHD.
In this cross-sectional study of youth with T1DM, 39 had ADHD (mean age 14.1 ± 2.8 years) and 82 did not (control group, mean age 12.6 ± 3.3 years). Health-related quality of life was assessed by a Diabetes Quality of Life (DQOL) questionnaire submitted to their parents. Glycemic data were downloaded from glucometers, pumps, and continuous glucose monitoring systems. HbA1c levels, hospitalizations, and severe hypoglycemic and diabetes ketoacidosis events were retrieved from the medical files.
Compared to the control group mean HbA1c level of the ADHD group was higher: 8.3 ± 1.1% versus 7.7 ± 1.0% (p = 0.005) and the percent of time that glucose level was in the target range (70-180 mg/dl) was lower: 48 ± 17% versus 59 ± 14% (p = 0.006). Mean glucose and glucose variability were higher in the ADHD group. Youth with ADHD who were not pharmacologically treated had worse HbA1c and more hospitalizations than those who were treated. DQOL did not differ between the control group, the treated ADHD group, and the untreated ADHD-Group.
Dual diagnosis of T1DM and ADHD during childhood leads to worse diabetes control, which is more pronounced in the context of untreated ADHD. Healthcare providers should be aware of the difficulties facing youth with T1DM and ADHD in coping with the current intensive treatment of diabetes.
Aim
To examine the effectiveness and safety over a 12-month period of a telemedicine intervention in adults with type 1 diabetes (T1D) treated with insulin pumps.
Methods
74 T1D patients on insulin ...pumps for at least 1 year (mean 19.5 11.5 years) and HbA1
c
≥ 6.5% (≥ 48 mmol/mol) were randomized to the telemedicine (
n
= 37) or the standard care group (
n
= 37). The intervention group was instructed to download data from insulin pumps and glucometers monthly. They received immediate phone feedback and recommendations for insulin dose adjustment; and face-to-face visits once in 6 months, compared to once every 3 months for the standard care group. Satisfaction with treatment, quality of life and frequency of hypoglycemic events was evaluated.
Results
The mean changes in HbA1c adjusted to baseline were − 0.08% (0.25 mmol/mol) vs. − 0.01% (0.03 mmol/mol), in the intervention and control groups, respectively (
p
= 0.18) at 12 months, without an increased frequency of hypoglycemia. Patients in the intervention group felt satisfied and interested in continuing with the treatment (
p
= 0.04). The quality of life scores were similar in both groups. Direct total costs were 24% less in the intervention group, and indirect total costs decreased by 22% compared to the year preceding the study.
Conclusions
Internet-based insulin dose adjustment is as effective and safe as routine care in adults with type 1 diabetes treated by insulin pumps. For suitable patients, some of the time-consuming routine visits may be replaced by user-friendly digital medicine.
Clinical trial registration
Clinical Trial.gov Identifier NCT01887431.
Millions of Australians use the private health system every year. They should receive safe, high-quality, value-based care. However, poor policy and inadequate regulation of medical technology is ...driving low-value care at great expense to consumers and the broader health system. Key drivers include the Prescribed List of Medical Devices and Human Tissue, gaps in quality and safety controls for devices being used, and marketing and conflicts of interest. All of these should be addressed to reduce low-value care in Australia's private health system, so consumers are protected from harm and limited health budgets are used effectively.
ABSTRACT
Biliary atresia is a fibroinflammatory neonatal disease with no effective therapies. A subset of cases (10-20%) is associated with laterality defects – labeled biliary atresia splenic ...malformation (BASM) syndrome. Recently, whole-exome sequencing of patients with BASM identified deleterious variants in PKD1L1. PKD1L1 is involved in left-right axis determination; however, its role in cholangiocytes is unknown. We generated the pkd1l1hsc117 allele using CRISPR/Cas9 mutagenesis in zebrafish to determine the role of Pkd1l1 in biliary development and function. Wild-type and mutant larvae were assessed for laterality defects, biliary function and biliary tree architecture at 5 days post fertilization. pkd1l1hsc117 mutant larvae exhibited early left-right patterning defects. The gallbladder was positioned on the left in 47% of mutants compared to 4% of wild-type larvae. Accumulation of PED6 in the gallbladder, an indicator of hepatobiliary function, was significantly reduced in pkd1l1hsc117 mutants (46%) compared to wild-type larvae (4%). pkd1l1hsc117 larvae exhibited fewer biliary epithelial cells and reduced density of the intrahepatic biliary network compared to those in wild-type larvae. These data highlight the essential role of pkd1l1 in normal development and function of the zebrafish biliary system, supporting a role for this gene as a cause of BASM.
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