Pericytes and the pathogenesis of diabetic retinopathy

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.     

The reliability of cardiogenic impedance and correlation with echocardiographic and plethysmographic parameters for predicting CRT time intervals post implantation

Aims

Encouraging data have been reported on the use of cardiogenic impedance (CI) in cardiac resynchronization therapy (CRT) optimization. The purposes of this study were to: evaluate the stability of certain CI vectors 24 h postimplantation, study the correlation between these CI signals and selected echocardiographic parameters, and examine the possibility of non-invasive calibration of the patient-specific impedance-based prediction model.

Methods and results

Thirteen patients received a CRT–defibrillator device with monitor capability of the dynamic impedance between several electrodes. At implantation, a patient-specific impedance-based prediction model was created for identification of optimal atrioventricular and interventricular (VV) delays and calibrated on invasive measurements of left ventricular contractility (LV dP/dt_max). Simultaneously, non-invasive measurements of LV dP/dt_max and stroke volume (SV) were obtained using a finger plethysmograph. Patients were re-evaluated with echocardiography and new CI measurements the day after implantation. The hemodynamic benefit achieved by optimal VV setting according to the patient-specific impedance-based prediction model at follow-up was not as large as the one obtained at implantation. In a multivariate partial least square regression analysis, a correlation was found between aortic velocity time integral (VTI) and a generic linear combination of CI features (P?<?0,005). No correlation was found between the patient-specific impedance-based prediction models and the non-invasive measurements of LV dP/dt_max and SV.

Conclusion

Cardiogenic impedance signals can be used to optimize CRT settings but seem less feasible as an ambulatory tool since calibration is required. The positive correlation between aortic VTI and CI measurements seems promising, although a larger cohort is required to create an echocardiography-based patient-specific model.     

On the unconscious subcortical origin of human fear

Consistent with the hypothesis that the amygdala is central to fear activation, brain imaging studies show that fear stimuli activate the amygdala, even when conscious recognition is prevented by backward masking. The bulk of the data suggest that the amygdala can be activated from potentially accessible but unattended fear stimuli. Activation of the amygdala facilitates low level visual processing. Several lines of evidence suggest that activation of the amygdala is mediated by a subcortical pathway. Thus, according to data from patients with lesions in the primary visual cortex, the amygdala can be activated in the absence of cortical processing. There is considerable support for the hypothesis that visual stimuli can access the amygdala via a pathway that includes the superior colliculus and the pulvinar nucleus of the thalamus. These data are consistent with an evolutionary argument, focusing of the role of snakes as a predator on primates.     

Experiencing neonatal death: an ambivalent transition into motherhood

OBJECTIVE: To illuminate the lived experience of women facing the threat of lossing their newborn child and then experiencing the reality of their infant's death. STUDY DESIGN: Sixteen women were interviewed approximately 2 years after the death of their infant using a hermeneutic phenomenological approach. FINDINGS: The main theme was ambivalent transition into motherhood. The women went through the whole life-span of their infant during a very short time. The women's narratives were interpreted as broken expectations, total confusion, reality awareness, consciously leave-taking, and elusive grief. CONCLUSIONS: Women need the opportunity to evolve their own patterns and rhythms in the ambivalent transition from expected motherhood to experiencing neonatal dying and death. Knowledge about the individuality of this process may assist nurses in improving the quality of care.     

Allogeneic hematopoietic cell transplantation as immunotherapy for solid tumors: current status and future directions

Although myeloablative conditioning can cytoreduce or debulk malignancies, the curative antitumor effects of allogeneic hematopoietic stem cell transplantation (HCT) are mostly mediated by transplanted donor immune cells. A heightened awareness and appreciation of the immune-mediated anticancer effects that occur after allogeneic transplantation has led to the increasing use of reduced-intensity stem cell transplantation (RIST) approaches to treat advanced malignancies. The graft-versus-leukemia effects that occur against hematologic cancers after RIST have recently attracted oncologists to explore the therapeutic potential of allogeneic HCT for treatment-refractory solid tumors. Delayed tumor regression after RIST in a subset of patients with metastatic renal cell, breast, ovarian, pancreatic, and colon carcinoma has recently been reported, confirming the existence of a graft-versus-tumor effect in solid tumors. Advanced disease states, rapidly growing tumors, and accrual of patients with extremely short survival are factors that have been identified to limit the efficacy of allogeneic immunotherapy. This review discusses results of allogeneic HCT for solid tumors and the development of newer transplant strategies to optimize the potential of the graft-versus-tumor effect.     

Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine.

Deficient hydroxylation of debrisoquine is an autosomal recessive trait that affects approximately 7% of the Caucasian population. These individuals (poor metabolizers) carry deficient CYP2D6 gene variants and have an impaired metabolism of severely commonly used drugs. The opposite phenomenon also exists, and certain individuals metabolize the drugs very rapidly, resulting in subtherapeutic plasma concentrations at normal doses. In the present study, we have investigated the molecular genetic basis for ultrarapid metabolism of debrisoquine. Restriction fragment length polymorphism analysis of the CYP2D locus in two families with very rapid metabolism of debrisoquine [metabolic ratio (MR) for debrisoquine = 0.01-0.1] revealed the variant CYP2D6 gene CYP2D6L. Eco RI RFLP and Xba I pulsed-field gel electrophoresis analyses showed that this gene had been amplified 12-fold in three members (father and his two children) of one of the families, and two copies were present among members of the other family. The CYP2D6L gene had an open reading frame and carried two mutations causing amino acid substitutions: one in exon 6, yielding an Arg-296-->Cys exchange and one in exon 9 causing Ser-486-->Thr. The MR of subjects carrying one copy of the CYP2D6L gene did not significantly differ from that of those with the wild-type gene, indicating that the structural alterations were not of importance of the catalytic properties of the gene product. Examination of the MR among subjects carrying wild-type CYP2D6, CYP2D6L, or deficient alleles revealed a relationship between the number of active genes and MR. The data show the principle of inherited amplification of an active gene. Furthermore, the finding of a specific haplotype with two or more active CYP2D6 genes allows genotyping for ultrarapid drug metabolizers. This genotyping could be of predictive value for individualized and more efficient drug therapy.     

A clinical comparison of alternative alloys

For the purpose of evaluating the clinical performance of 2 alternative dental casting alloys, 17 crowns made from the low-gold alloy Midas and 14 crowns made from the silver-palladium alloy Albacast were inserted at random into 23 patients. In each patient a high-gold type-3 alloy, JS C, served as a reference alloy. The patients were examined after 1 year with regard to tarnishing and certain factors such as plaque index, gingival index, and margin index. In addition, the California Dental Association's quality evaluation of dental care was used by two independent calibrated examiners. The results of the present study showed that the crowns made of the silver-palladium alloy were tarnished and had rough occlusal surfaces more often than crowns made of the low-gold and high-gold alloys.     

Quality of life related to tooth loss and prosthetic replacements among persons with dependency and functional limitations

Abstract

Objectives: To examine if tooth loss or treatment with different prosthetic replacements are associated with oral health-related or health-related quality of life (OHRQoL or HRQoL) among persons with dependency and functional limitations.

Material and Methods: Comparisons between results of questionnaires and clinical data (number of teeth, Eichner index, presence, type, and condition of prosthetic replacements) from a population of 180 individuals with dependency and functional limitations sampled from the register of increased financial support in Norrbotten County, Sweden.

Results: The associations between clinical variables and the questionnaire responses were weak overall, e.g. Spearman’s rho was 0.162 (p?=?.033) for correlation between number of teeth and GOHAI, 0.094 (p?=?.249) for number of teeth and OHIP, ?0.070 (p?=?.356) for complete dentures and GOHAI, and ?0.108 (p?=?.185) for complete dentures and OHIP.

Conclusions: The weak associations between clinical variables and questionnaire results in the present study suggest that good results on measured QoL do not necessarily indicate good oral health. As we cannot expect this specific population to report oral disorders by themselves, regular check-ups are necessary.     

Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake,Blood Flow,Neural Activity,and Cognitive Function During Normo- and Hypoglycemia

While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.