Individuals with type 1 diabetes have mild performance deficits on a range of neuropsychological tests compared with nondiabetic control subjects. The mechanisms underlying this cognitive ...deterioration are still poorly understood, but chronic hyperglycemia is now emerging as a potential determinant, possibly through microvascular changes in the brain. In 24 type 1 diabetic patients, we tested at euglycemia and at acute hypoglycemia whether the presence of proliferative diabetic retinopathy, as a marker of microvascular disease, adversely affects the ability of the brain to respond to standardized hypoglycemia, using functional magnetic resonance imaging with a cognitive task. Patients with retinopathy, compared with patients without, showed less deactivation (hence, an increased response) in the anterior cingulate and the orbital frontal gyrus during hypoglycemia compared with euglycemia (P < 0.05). Task performance and reaction time were not significantly different for either group. We conclude that microvascular damage in the brain of patients with retinopathy caused this increased brain response to compensate for functional loss.
Background. Our institution has experienced excellent success using hepatic artery embolization for treating symptoms and slowing tumor progression for patients with unresectable hepatic metastases ...for carcinoid tumors. Our previous treatment strategies used hepatic artery embolization alone, examining control of symptoms and dependence on octreotide therapy. However, some patients exhibit hepatic metastases that are unresponsive to embolization. This report describes the use of radiofrequency ablation (RFA) as salvage treatment for these refractory metastases.
Methods. Thirteen patients with unresectable bilobar hepatic metastases from biochemically confirmed carcinoid tumors were treated with selective hepatic artery embolization using Lipiodol/Gelfoam between 1994 and 2000. Three patients developed symptoms resistant to embolization treatment resulting from progression of existing metastases or development of new metastases. These patients underwent surgical exploration and intraoperative ultrasound of their refractory lesions, followed by treatment with RFA. Tumor size, symptoms of carcinoid syndrome, and octreotide requirements were monitored postoperatively.
Results. Median follow-up for the three patients treated with RFA was 6 months. During the first 3-month interval following RFA, all three patients demonstrated decrease in the size of treated lesions. Using our previously developed symptom scoring system, all three patients demonstrated decreased symptoms following treatment. One patient was able to discontinue octreotide treatment, and the other two patients required decrease octreotide dosages.
Conclusions. This study demonstrates that utilization of RFA treatment for carcinoid metastases refractory to hepatic artery embolization may represent a useful adjunct for symptomatic control, decreased octreotide dependence, and slowing of disease progression.
Life-history plasticity is widespread among organisms. However, an important question is whether it is adaptive. Most models for plasticity in life-history timing predict that animals, once they have ...reached the minimal nutritional threshold under poor conditions, will accelerate development or time to reproduction. Adaptive delays in reproduction are not common, especially in short-lived species. Examples of adaptive reproductive delays exist in mammalian populations experiencing strong interspecific (e.g., predation) and intraspecific (e.g., infanticide) competition. But are there other environmental factors that may trigger an adaptive delay in reproductive timing? We show that the short-lived flesh fly Sarcophaga crassipalpis will delay reproduction under nutrient-poor conditions, even though it has already met the minimal nutritional threshold for reproduction. We test whether this delay strategy is an adaptive response allowing the scavenger time to locate more resources by experimentally providing supplemental protein pulses (early, mid and late) throughout the reproductive delay period. Flies receiving additional protein produced more and larger eggs, demonstrating a benefit of the delay. In addition, by tracking the allocation of carbon from the pulses using stable isotopes, we show that flies receiving earlier pulses incorporated more carbon into eggs and somatic tissue than those given a later pulse. These results indicate that the reproductive delay in S. crassipalpis is consistent with adaptive post-threshold plasticity, a nutritionally linked reproductive strategy that has not been reported previously in an invertebrate species.
Type 1 diabetes mellitus (T1DM) is associated with cerebral compromise, typically found in patients with microangiopathy. Associations between subclinical macroangiopathy and the brain, whether or ...not in the presence of microangiopathy, have not been fully explored in T1DM. We hypothesized that subclinical macroangiopathy in adult T1DM may affect the brain and interacts with microangiopathy.
In 51 asymptomatic T1DM patients with, 53 without proliferative retinopathy and 51 controls, right common carotid artery ultrasound was used to assess intima media thickness (cIMT) and distensibility (cD). Neuropsychological tests for cognitive functions, and magnetic resonance imagining for white matter integrity and functional connectivity, i.e. neuronal communication, were used.
After correction for confounders, cIMT was borderline significantly increased in all T1DM patients (P = 0.071), whereas cD was not statistically significantly altered (P = 0.45). Patients with proliferative retinopathy showed the largest increase in cIMT and decrease in cD. In all participants, after adjustment for confounders, increased cIMT was related to decreased white matter integrity (β = -0.198 P = 0.041) and decreased functional connectivity in visual areas (β = -0.195 P = 0.046). For cognition, there was a significant interaction between cIMT and the presence of proliferative retinopathy after adjustment for confounding factors (all P < 0.05). Increased cIMT was associated with lower general cognitive ability (β = -0.334; P = 0.018), information processing speed (β = -0.361; P = 0.010) and attention (β = -0.394; P = 0.005) scores in patients without, but not in patients with proliferative retinopathy.
These findings suggest that subclinical macroangiopathy may be a factor in the development of diabetes-related cognitive changes in uncomplicated T1DM, whereas in patients with advanced T1DM, proliferative retinopathy may rather be the driving force of cerebral compromise.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The 2B protein of enterovirus is responsible for the alterations in the permeability of secretory membranes and the plasma membrane in infected cells. The structural requirements for the membrane ...association and the subcellular localization of this essential virus protein, however, have not been defined. Here, we provide evidence that the 2B protein is an integral membrane protein in vivo that is predominantly localized at the Golgi complex upon individual expression. Addition of organelle-specific targeting signals to the 2B protein revealed that the Golgi localization is an absolute prerequisite for the ability of the protein to modify plasma membrane permeability. Expression of deletion mutants and heterologous proteins containing specific domains of the 2B protein demonstrated that each of the two hydrophobic regions could mediate membrane binding individually. However, the presence of both hydrophobic regions was required for the correct membrane association, efficient Golgi targeting, and the membrane-permeabilizing activity of the 2B protein, suggesting that the two hydrophobic regions are cooperatively involved in the formation of a membrane-integral complex. The formation of membrane-integral pores by the 2B protein in the Golgi complex and the possible mechanism by which a Golgi-localized virus protein modifies plasma membrane permeability are discussed.
IMPORTANCE: Implementation of new cancer treatment strategies as recommended by evidence-based guidelines is often slow and suboptimal. OBJECTIVE: To improve the implementation of guideline-based ...best practices in the Netherlands in pancreatic cancer care and assess the impact on survival. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, stepped-wedge cluster randomized trial compared enhanced implementation of best practices with usual care in consecutive patients with all stages of pancreatic cancer. It took place from May 22, 2018 through July 9, 2020. Data were analyzed from April 1, 2022, through February 1, 2023. It included all patients in the Netherlands with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma. This study reports 1-year follow-up (or shorter in case of deceased patients). INTERVENTION: The 5 best practices included optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy (PERT), referral to a dietician, and use of metal stents in patients with biliary obstruction. A 6-week implementation period was completed, in a randomized order, in all 17 Dutch networks for pancreatic cancer care. MAIN OUTCOMES AND MEASURES: The primary outcome was 1-year survival. Secondary outcomes included adherence to best practices and quality of life (European Organisation for Research and Treatment of Cancer EORTC global health score). RESULTS: Overall, 5887 patients with pancreatic cancer (median age, 72.0 IQR, 64.0-79.0 years; 50% female) were enrolled, 2641 before and 2939 after implementation of best practices (307 during wash-in period). One-year survival was 24% vs 23% (hazard ratio, 0.98, 95% CI, 0.88-1.08). There was no difference in the use of neoadjuvant chemotherapy (11% vs 11%), adjuvant chemotherapy (48% vs 51%), and referral to a dietician (59% vs 63%), while the use of palliative chemotherapy (24% vs 30%; odds ratio OR, 1.38; 95% CI, 1.10-1.74), PERT (34% vs 45%; OR, 1.64; 95% CI, 1.28-2.11), and metal biliary stents increased (74% vs 83%; OR, 1.78; 95% CI, 1.13-2.80). The EORTC global health score did not improve (area under the curve, 43.9 vs 42.8; median difference, −1.09, 95% CI, −3.05 to 0.94). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, implementation of 5 best practices in pancreatic cancer care did not improve 1-year survival and quality of life. The finding that most patients received no tumor-directed treatment paired with the poor survival highlights the need for more personalized treatment options. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03513705
Background
Unnecessary D2-gastrectomy and associated costs can be prevented after detecting non-curable gastric cancer, but impact of staging on treatment costs is unclear. This study determined the ...cost impact of
18
F-fluorodeoxyglucose positron emission tomography/computed tomography (
18F
FDG-PET/CT) and staging laparoscopy (SL) in gastric cancer staging.
Materials and Methods
In this cost analysis, four staging strategies were modeled in a decision tree: (1)
18F
FDG-PET/CT first, then SL, (2) SL only, (3)
18F
FDG-PET/CT only, and (4) neither SL nor
18F
FDG-PET/CT. Costs were assessed on the basis of the prospective PLASTIC-study, which evaluated adding
18F
FDG-PET/CT and SL to staging advanced gastric cancer (cT3–4 and/or cN+) in 18 Dutch hospitals. The Dutch Healthcare Authority provided
18F
FDG-PET/CT unit costs. SL unit costs were calculated bottom-up. Gastrectomy-associated costs were collected with hospital claim data until 30 days postoperatively. Uncertainty was assessed in a probabilistic sensitivity analysis (1000 iterations).
Results
18F
FDG-PET/CT costs were €1104 including biopsy/cytology. Bottom-up calculations totaled €1537 per SL. D2-gastrectomy costs were €19,308. Total costs per patient were €18,137 for strategy 1, €17,079 for strategy 2, and €19,805 for strategy 3. If all patients undergo gastrectomy, total costs were €18,959 per patient (strategy 4). Performing SL only reduced costs by €1880 per patient. Adding
18F
FDG-PET/CT to SL increased costs by €1058 per patient; IQR €870–1253 in the sensitivity analysis.
Conclusions
For advanced gastric cancer, performing SL resulted in substantial cost savings by reducing unnecessary gastrectomies. In contrast, routine
18F
FDG-PET/CT increased costs without substantially reducing unnecessary gastrectomies, and is not recommended due to limited impact with major costs.
Trial registration
: NCT03208621. This trial was registered prospectively on 30-06-2017.
The disposable soma hypothesis predicts that when reproduction is reduced, life span is increased because more nutrients are invested in the soma, increasing somatic repair. Rigorously testing the ...hypothesis requires tracking nutrients from ingestion to allocation to the soma or to reproduction. Fruit flies on life-extending dietary restriction increase allocation to the soma “relative” to reproduction, suggesting that allocation of nutrients can be associated with extension of life span. Here, we use stable isotopes to track ingested nutrients in ovariectomized grasshoppers during the first oviposition cycle. Previous work has shown that ovariectomy extends life span, but investment of protein in reproduction is not reduced until after the first clutch of eggs is laid. Because ovariectomy does not affect investment in reproduction at this age, the disposable soma hypothesis would predict that ovariectomy should also not affect investment in somatic tissues. We developed grasshopper diets with distinct signatures of 13C and 15N, but that produced equivalent reproductive outputs. These diets are, therefore, appropriate for the reciprocal switches in diet needed for tracking ingested nutrients. Incorporation of stable isotopes into eggs showed that grasshoppers are income breeders, especially for carbon. Allocation to the fat body of nitrogen ingested as adults was slightly increased by ovariectomy; this was our only result that was not consistent with the disposable soma hypothesis. In contrast, ovariectomy did not affect allocation of nitrogen to femoral muscles. Further, allocation of carbon to the fat body or femoral muscles did not appear to be affected by ovariectomy. Total anti-oxidant activities in the hemolymph and femoral muscles were not affected by ovariectomy. These experiments showed that allocation of nutrients was altered little by ovariectomy in young grasshoppers. Additional studies on older individuals are needed to further test the disposable soma hypothesis.
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