Histochemical and biochemical studies on the effect of the prostacyclin derivative iloprost on CCl4-induced lipid peroxidation in rat liver and its significance for hepatoprotection

In the present study, it was investigated whether the prostacyclin derivative Iloprost would protect hepatocytes against CCl4-induced liver injury and which mechanism(s) of hepatocellular pathogenesis might be affected by it. Rats were treated with a single oral dose of CCl4 (2 ml per kg); Iloprost was infused continuously from 2 to 4 hr before intoxication until killing. The following results were obtained. The CCl4-induced release of AST, lactate dehydrogenase and alkaline phosphatase into the serum was reduced by 50 to 70% in rats treated with doses of 0.1 and 0.5 micrograms Iloprost per kg per min. Infusion of 0.02 and 0.004 micrograms Iloprost per kg per min did not affect the CCl4-induced enzyme release into the blood. CCl4 induced the occurrence of aldehydes (products of lipid peroxidation), which were detected by histochemical and biochemical means. At 12, 48 and 72 hr after CCl4, the aldehyde-positive liver section area was about 58, 69 and 16% in rats treated with CCl4 alone, but only about 18, 13 and less than 1% in rats treated additionally with Iloprost. The aldehyde-positive hepatocytes were located predominantly in the centrilobular zone of the liver. At 24 hr the extent of the aldehyde-positive section area was the same in rats with or without Iloprost treatment (about 90%). Biochemical determination, however, revealed that at this time point the malondialdehyde content after Iloprost in rats was about 70% lower than without Iloprost treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer

Gain-of-function of the androgen receptor (AR) and activation of PI3K/AKT/mTOR pathway have been demonstrated to correlate with progression to castration-resistant prostate cancer (CRPC). However, inhibition of AR or PI3K/mTOR alone results in a reciprocal feedback activation. Therefore, we hypothesized that dual inhibition of the AR and PI3K/mTOR pathway might lead to a synergistic inhibition of cell growth and overcome drug resistance in CRPC. Here, we reported that androgen-depletion increased AR protein level and Akt phosphorylation at Ser473 and Thr308 in LNCaP cells. Moreover, we developed resistance cell lines of LNCaP to Enzalutamide (or MDV3100), an AR inhibitor (named as LNCaP ‘MDV-R’) and PF-04691502, a PI3K/mTOR inhibitor (named as LNCaP ‘PF-R’). MTS analysis showed that LNCaP ‘PF-R’ was strongly resistant to Enzalutamide treatment, and on the other hand, LNCaP ‘MDV-R’ was 6-fold resistant to PF-04691502 treatment. Mechanistically, LNCaP ‘MDV-R’ cells had significantly reduced AR, loss of PSA and increase Akt activity in contrast with LNCaP ‘PF-R’ cells. Combined inhibition of PI3K/mTOR and AR pathways with a variety of small molecular inhibitors led to a synergistic suppression of cell proliferation and a profound increase of apoptosis and cell cycle arrest in both androgen-dependent LNCaP and independent CRPC 22Rv1 cell lines. In conclusion, this study provides preclinical proof-of-concept that the combination of a PI3K/mTOR inhibitor with an AR inhibitor results in a synergistic anti-tumor response in non-CRPC and CRPC models.     

Late psychiatric morbidity in survivors of cancer at a young age: A nationwide registry‐based study

Childhood cancer survivors have been shown to be prone to psychosocial adverse outcomes. Data on young adults and their psychiatric late effects are still scarce. In a nationwide, registry‐based study, we explored the risk (HR) of new psychiatric diagnoses in 5‐year survivors of childhood and young adulthood (YA) cancer (n = 13,860) compared with a sibling cohort (n = 43,392). Hazard ratios (HRs) were calculated using Cox regression models. Patients and siblings were identified from the Finnish Cancer Registry and Central Population Registry, respectively. Outcome diagnoses were retrieved from the national hospital discharge register. The risk of organic memory/brain disorders was significantly increased in both childhood (HR 4.9; 95%CI 2.7–8.9) and YA (HR 2.1; 95%CI 1.4–3.1) cancer survivors compared with siblings. Mood disorders were also more common in childhood (HR 1.3; 95%CI 1.1–1.7) and YA survivors (1.3; 95%CI 1.1–1.5) than in siblings. Radiotherapy did not explain the differences. Female childhood cancer survivors had significantly increased HRs for mood disorders, psychotic disorders, neurotic/anxiety disorders, somatization/eating disorders and personality disorders. In survivors of YA cancers, females had significantly increased HR for neurotic/anxiety disorders, and the difference between female survivors and siblings was significantly (p < 0.05) higher than that between male survivors and male siblings. The effect of treatment era was also analyzed, and the risk of organic memory and brain disorders in childhood cancer survivors did not diminish over time. Despite the trend of decreased use of cranial irradiation in children, the risk of organic memory/brain disorders was elevated, even during the most recent era. Thus, additional research on chemotherapy‐only protocols and their impact on mental health, is warranted.     

Tensile strength testing for resorbable mesh fixation systems in laparoscopic ventral hernia repair

Background

In an attempt to improve patient outcome and quality of life after laparoscopic ventral hernia repair, resorbable fixation devices have been developed to allow adequate mesh fixation while minimizing accompanying side-effects as tack erosion and adhesion formation.

Materials and methods

In experimental set-up, 24 pigs were treated by laparoscopic mesh placement. Two different meshes (PP/ORC and PP/ePTFE) and four fixation devices were evaluated: a 6.4?mm poly(D,L)-lactide pushpin (tack I), a 6.8?mm poly(D,L)-lactide with blunt tip (tack II), a 4.1?mm poly(glycolide-co-L-lactide) (tack III) and one titanium tack (control tack). A first group of animals (n?=?12) was euthanized after 2?weeks survival and a second group (n?=?12) after 6?months. At euthanasia, a relaparoscopy was performed to assess adhesion formation followed by laparotomy with excision of the entire abdominal wall. Tensile strength of the individual fixation systems was tested with the use of a tensiometer by measuring the force to pull the tack out of the mesh. Additionally, the foreign body reaction to the fixation systems was evaluated histologically as was their potential degradation.

Results

At 2?weeks the tensile strength was significantly higher for the control tack (31.98?N/cm2) compared to the resorbable devices. Except for tack II, the tensile strength was higher when the devices were fixed in a PP/ePTFE mesh compared to the PP/ORC mesh. After 6?months only tack III was completely resorbed, while tack I (9.292?N/cm2) had the lowest tensile strength. At this time-point similar tensile strength was observed for both tack II (29.56?N/cm2) and the control tack (27.77?N/cm2). Adhesions seem to be more depending on the type of mesh, in favor of PP/ePTFE.

Conclusion

At long term, the 4.1?mm poly(glycolide-co-L-lactide) tack was the only tack completely resorbed while the 6.8?mm poly(D,L)-lactide tack with blunt tip reached equal strengths to the permanent tack.     

Respiratory sinus arrhythmia as a predictor of sudden cardiac death after myocardial infarction

Background. Measurement of high-frequency (HF) spectral power of heart rate (HR) variability has not been able to identify the patients at risk of sudden cardiac death (SCD) despite the experimental evidence of protective role of vagal activity for fatal arrhythmias.

Aim. We developed a novel respiratory sinus arrhythmia (RSA) analysis method and tested its ability to predict SCD after an acute myocardial infarction.

Method. The RSA analysis method was developed in 13 subjects from simultaneous recordings of respiration and R-R intervals. An adaptive threshold was computed based on the zero-phase forward and reverse digital filtering in the analysis of RSA. With this method, only respiration-related R-R interval fluctuations are included. The prognostic power of RSA, analyzed from 24-hour electrocardiographic recordings, was subsequently assessed in a large postinfarction population including 1631 patients with mean follow-up of 40±17 months.

Results. Depressed RSA was a strong predictor of SCD (hazard ratio 7.4; 95% CI 3.6–15.1; P <0.0001) but only a weak predictor of non-SCD. The RSA index remained an independent predictor of SCD after adjustments for ejection fraction and other clinical risk variables (RR 4.7; 95% CI 2.28–9.85).

Conclusions. Reduced respiratory-related HR dynamics, detected by RSA index, are a specific marker of an increased risk of SCD among postinfarction patients.     

Hypodense white matter lesions in computed tomography of neurosarcoidosis

Cerebral CT was performed on 32 patients with neurosarcoidosis and found to be abnormal in 13 (41%). One of the most common abnormalities (five patients) was represented by low density white matter lesions, which have not, to the best of our knowledge, been previously reported in association with neurosarcoidosis. Other types of abnormalities were ventricular enlargement (five patients) and mass lesions (four patients). Nineteen of the 32 patients had normal CT findings; thus normal CT does not exclude neurosarcoidosis. Nine magnetic resonance examinations carried out in seven patients failed to reveal more lesions than CT.     

Low immunoglobulin G3 levels in wheezy children

This study aimed to investigate the prevalence of IgG subclass deficiency in wheezy children aged <3y. Serum levels of IgA, IgE and IgG subclasses were measured in 310 children with recurrent wheezing and in 100 healthy controls. IgG3 levels were below the normal lower limit in 123 (39.6%) patients. This finding may reflect delayed maturation of the immune system, predisposing young children <3 y of age to wheezing.