Design of a composite drug delivery system to prolong functionality of cell-based scaffolds

Cell encapsulation technology raises hopes in medicine and biotechnology. However, despite important advances in the field in the past three decades, several challenges associated with the biocompatibility are still remaining. In the present study, the effect of a temporary release of an anti-inflammatory agent on co-administered encapsulated allogeneic cells was investigated. The aim was to determine the biocompatibility and efficacy of the approach to prevent the inflammatory response. A composite delivery system comprised of alginate-poly-l-lysine-alginate (APA)-microencapsulated Epo-secreting myoblasts and dexamethasone (DXM)-releasing poly(lactic-co-glycolic acid) (PLGA) microspheres was implanted in the subcutaneous space of Balb/c mice for 45 days. The use of independently co-implanted DXM-loaded PLGA microspheres resulted in an improved functionality of the cell-based graft, evidenced by significantly higher hematocrit levels found in the cell-implanted groups by day 45, which was found to be more pronounced when higher cell-doses (100 μL) were employed. Moreover, no major host reaction was observed upon implantation of the systems, showing good biocompatibility and capability to partially avoid the inflammatory response, probably due to the immunosuppressive effects related to DXM. The findings of this study imply that DXM-loaded PLGA microspheres show promise as release systems to enhance biocompatibility and offer advantage in the development of long-lasting and effective implantable microencapsulated cells by generating a potential immunopriviledged local environment and an effective method to limit the structural ensheathing layer caused by inflammation.     

Illness Perception and Cardiovascular Risk Factors in Patients with Type 2 Diabetes: Cross-sectional Questionnaire Study

Aim

To investigate illness perception in patients with type 2 diabetes mellitus and its association with the degree of control over relevant cardiovascular risk factors.

Methods

A cross-sectional questionnaire-based study was performed from June 2007 to March 2008. A stratified random sample of 46 Croatian general practitioners was asked to select, using systematic sampling, the first 6 patients with type 2 diabetes mellitus aged ≥18 years who visited them for consultation during the study period. Data on 250 patients included patient illness perception assessment (Brief Illness Perception Questionnaire, IPQ), cardiovascular risk factors, and socio-demographic data.

Results

The patients’ mean age was 63.0 ± 10.9 years and mean duration of diabetes was 9.3 ± 7.8 years. The patients’ illness perception assessment on an 11-point (0 to 10) scale showed the highest median scores (interquartile range): 10 (8 to 10) for “timeline” and 8 (7 to 9) for “treatment control,” followed by 7 (5 to 8) for “personal control,” 7 (5 to 9) for “understanding,” 5 (3 to 7) for “consequences,” 6 (4 to 7) for “concern,” and 5 (2 to 7) for “emotional response.” The lowest score was 3 (1 to 5) for “identity.” Multivariate logistic regression showed that the Brief IPQ item “concern” (P < 0.001) was a significant predictor of body mass index; “personal control” (P < 0.001) and “concern” (P = 0.048) were significant predictors of fasting blood glucose; “treatment control” (P = 0.009) was a significant predictor of total cholesterol; and “understanding” (P = 0.010) was a significant predictor of blood pressure.

Conclusion

As patients'' beliefs seem to be associated with the degree of control over cardiovascular risk factors, they should be included in routine clinical assessments.Although the quality of guidelines to diabetes care appears to be improved, a poor metabolic control over the illness has been found in as many as 30%-60% of patients with type 2 diabetes treated in routine general practice (GP) settings (1). Despite of the vital role of health care providers, the responsibility for diabetes management largely rests on the patient. Ninety-five percent of health-related decisions are to be made by patients on a daily basis, without even consulting with health care professionals (2,3). These decisions are related to diet, tobacco smoking, foot care, and exercising, adherence to daily urine or blood glucose monitoring, and drug regulation, which should all be harmonized and embedded into working, domestic, and leisure routines. Research has shown the enhancement of active participation and self-care to be the key factor responsible for the improvement of outcomes in diabetic patients (4). Furthermore, there is a growing body of evidence corroborating that the perception of the disease plays an important role in the degree of compliance (5-7).The study on individual perceptions of illness stemmed from the research on health-threat communication (7). Different health behavior theories have been developed to describe individual response to a perceived health threat and the manner of coping with it. One of the widely adopted models is the self-regulation model introduced by Leventhal et al (8,9). The self-regulation model assumes that health-related behavioral patterns are a result of complex multi-faceted representations of illness. Cognitive representation of illness embraces 5 core dimensions (8): identity (ie, label and symptoms that a person ascribes to his or her illness); consequences (ie, expected effects and outcomes of the illness); cause (ie, causal attribution that a patient assigns to his or her illness); timeline (ie, the expected duration of illness viewed from the patient’s perspective); and cure or control modalities (ie, the extent to which a patient believes he/she can recover from the illness or place it under control). Emotional representation also includes negative reactions to the illness, such as fear, anger, and distress. Other studies have provided a quantitative support as to the existence of structural relations between the 5 illness representation components described by Leventhal (8), and to the existence of links between illness perceptions and a number of psychological outcomes, such as coping, mood, functional adaptation, and compliance (9-21).While researchers have often examined the relation of illness perception with psychological outcomes, its relation with cardiovascular risk factors has been studied only on rare occasions (4,22,23). We find this area important, since diabetes and cardiovascular disease often appear as “the two sides of the same coin” (24). Furthermore, in type 2 diabetes, the presence of cardiovascular risk factors at least doubles the risk of cardiovascular death (1). As with most European transitional countries, in Croatia cardiovascular disease is the leading cause of death and accounts for more than half of the overall mortality (25).The aim of this study was to investigate the illness perception in patients with type 2 diabetes and its association with the degree of control over cardiovascular risk factors.     

Stem cells in alginate bioscaffolds

The immobilization of cells into polymeric scaffolds releasing therapeutic factors, such as alginate microcapsules, has been widely employed as a drug-delivery system for numerous diseases for many years. As a result of the potential benefits stem cells offer, during recent decades, this type of cell has gained the attention of the scientific community in the field of cell microencapsulation technology and has opened many perspectives. Stem cells represent an ideal tool for cell immobilization and so does alginate as a biomaterial of choice in the elaboration of these biomimetic scaffolds, offering us the possibility of benefiting from both disciplines in a synergistic way. This review intends to give an overview of the many possibilities and the current situation of immobilized stem cells in alginate bioscaffolds, showing the diverse therapeutic applications they can already be employed in; not only drug-delivery systems, but also tissue engineering platforms.     

Intravaginal 1-week high-dose-rate brachytherapy alone for Stages I-II endometrial cancer

OBJECTIVE: To evaluate the feasibility and intermediate-term results of a short course of high-dose-rate (HDR) intravaginal brachytherapy only after hysterectomy. METHODS AND MATERIALS: From December 1999 to February 2005, 50 patients with International federation of gynecology and obstetrics Stages IA-IIB endometrioid endometrial adenocarcinoma were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by postoperative HDR brachytherapy alone. The mean age of the patients was 62.6 years (range 42-86). International federation of gynecology and obstetrics patient grouping included IaG3N(x) (n=1), IbG1N(0) (n=1), IbG1N(x) (n=2), IbG2N(0) (n=10), IbG2N(x) (n=20), IbG3N(0) (n=3), IbG3N(x) (n=1), IcG1N(x) (n=2), IcG2N(0) (n=3), IcG3N(0) (n=3), IIaG1N(x) (n=2), IIaG2N(x) (n=1), and IIbG1N(0) (n=1). Twenty-one patients (42.0%) had been surgically staged. Four to 16 weeks after surgery (median 42d, range 28-112), all patients received HDR intravaginal brachytherapy to 25Gy in five consecutive 5-Gy daily fractions prescribed at 0.5-cm depth. Median HDR brachytherapy treatment duration was 5 days (range 5-12). RESULTS: After a median followup of 37 months (range 12-80), the overall survival and disease-free survival were 96%. No vaginal or pelvic recurrences have been observed. One patient (2%) developed distant metastases. No late toxicities of Grade 3 or greater have been reported. CONCLUSIONS: The results reported in this study are in agreement with previous reports of postoperative HDR brachytherapy alone in early-stage endometrial cancer. HDR brachytherapy alone seems to provide adequate tumor control. The fractionation schedule proposed (25Gy in five consecutive daily treatments) was well tolerated and is convenient for patients living far from the radiation center.     

Doppler sonographic diagnosis of severe portal vein pulsatility in constrictive pericarditis: Flow normalization after pericardiectomy

This case report describes the noninvasive assessment of hepatic and portal vein hemodynamics in a patient with constrictive pericarditis before and after pericardiectomy. Doppler sonography of the hepatic veins demonstrated a typical W‐shaped pattern with pronounced late diastolic flow reversal that disappeared after surgery. Preoperatively, we observed severe pulsatility of the portal vein with flow reversal in systole; after pericardiectomy, portal venous flow was normal. We concluded that the high right atrial pressure in this patient might have led to increased hepatic venous outflow resistance, with subsequent trans‐sinusoidal shunting between the hepatic artery and portal vein causing severe portal vein pulsatility. After pericardiectomy and a decrease in right atrial pressure, portal vein flow normalized. © 1999 John Wiley & Sons, Inc. J Clin Ultrasound 27:84–88, 1999.     

Association between respiratory sinus arrhythmia and reductions in startle responding in three independent samples

Evidence suggests that respiratory sinus arrhythmia (RSA) may be an important indicator of physiological flexibility. However, few studies have examined the relation between RSA and defensive habituation, a process contingent on physiological flexibility. In three independent samples, habituation was defined as the time course of 9 startle responses. In Sample one and two, startle was recorded (1) while shock electrodes were attached to participants’ and (2) before a threat-of-shock task. In Sample three, startle was recorded without these two components. In the first two samples, startle magnitude significantly decreased over time but in Sample three, startle only decreased at a trend level. Further, low RSA was associated with less of a reduction in startle magnitude over time within the first two samples, but was unrelated to startle reduction in the third. This suggests that low RSA is associated with less habituation to contextual anxiety, which may reflect difficulties regulating anxiety.     

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features,genetic analyses,and sorbitol dosages

Background and purpose

Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot–Marie–Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants.

Methods

Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol.

Results

Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants.

Conclusions

This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.