Biochemical assessment of the neurotoxicity of gold nanoparticles functionalized with colorectal cancer-targeting peptides in a rat model.

The application of gold nanoparticle-peptide conjugates as theranostic agents for colorectal cancer shows much promise. This study aimed at determining the neurotoxic impact of 14 nm gold nanoparticles (AuNPs) functionalized with colorectal cancer-targeting peptides (namely p.C, p.L or p.14) in a rat model. Brain tissue samples, obtained from Wistar rats that received a single injection of citrate-capped AuNPs, polyethylene glycol-coated (PEG) AuNPs, p.C-PEG-AuNPs, p.L-PEG-AuNPs or p.14-PEG-AuNPs, and sacrificed after 2- and 12-weeks, respectively, were analysed. Inflammation marker (tumour necrosis factor-α, interleukin-6, interleukin-1ß), oxidative stress (superoxide dismutase, catalase, glutathione peroxidase) and apoptotic biomarker (cytochrome c, caspase-3) levels were measured. Gold nanoparticle-treated groups sacrificed after 2-weeks did not exhibit any significant inflammatory, oxidative stress or apoptotic effects in brain tissue compared to the untreated control group. In brain tissue from rats that were exposed to citrate-capped AuNPs for 12-weeks, tumour necrosis factor-α and interleukin-6 levels were significantly increased compared to the untreated control. Exposure to PEG-AuNP, p.C-PEG-AuNP, p.L-PEG-AuNP and p.14-PEG-AuNP did not elicit significant toxic effects compared to the control after 12-weeks, as evidenced by the absence of inflammatory, oxidative stress and apoptotic effects in brain tissue. We thus report on the safety of PEG-coated AuNP-peptide conjugates for potential application in the diagnosis of colorectal cancer; however, exposure to citrate-capped AuNPs could induce delayed neuro-inflammation, and as such, warrants further investigation.

Anticancer activity of the liposome-encapsulated cyclic dipeptides, cyclo(His-Gly) and cyclo(His-Ala).

Cyclic dipeptides have been well characterized for their biological activity, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently demonstrated significant anticancer activity against a range of cell lines, however, as a result of their physicochemistry, namely high solubility and low lipophilicity, it can be predicted that cellular permeability would be low, making them ideal candidates for liposome drug delivery. Liposomes were composed of phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), stearylamine, alpha-tocopherol and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (PEG-DSPE) or folate-polyethylene glycol-cholesteryl hemisuccinate (F-PEG-CHEMS) using the thin-film hydration method and characterized for size and encapsulation. The cytotoxic activity of the encapsulated cyclic dipeptides was tested against HeLa, low folate HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol with folic acid to target folate receptors significantly decreased the IC50 values recorded in all cells lines tested, particularly HeLa cells cultured in media containing physiological concentrations of folic acid with the lowest IC50 being recorded as 0.0962 mM for folate-targeted cyclo(His-Ala). Therefore, hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes.

[Rheopheresis for recurrent sudden hearing loss : therapeutic options for patients refractory to infusion therapy]. / Rheopherese bei rezidivierendem Hörsturz : Therapieoption für Patienten nach erfolgloser Infusionstherapie.

BACKGROUND AND OBJECTIVE: For patients suffering from recurrent sudden hearing loss (SHL) that is refractory to infusion therapy, new therapeutic options must be established. PATIENTS AND METHODS: Patients suffering from recurrent and progressive SHL refractory to infusion therapy according to German guidelines were analysed retrospectively. After unsuccessful infusion therapy following the last onset of SHL, patients were treated with Rheopheresis twice. Hearing gain and recovery of speech discrimination were analysed. RESULTS: Twenty-five patients with a mean of 2.1+/-0.4 events of SHL within 30.0+/-21.6 months were examined. The patients' mean hearing loss before the first onset of SHL was 34 dB and was reduced by infusion therapy to 20 dB. With the second onset of SHL, hearing loss remained almost unchanged after infusion therapy. Patients showed a mean improvement of 20 dB after two consecutive Rheopheresis treatments. Forty percent showed complete remission of SHL, and a further 28% showed partial remission. CONCLUSION: Rheopheresis can efficiently improve the hearing of patients with recurrent SHL refractory to infusion therapy.

The in vitro biological activity of selected South African Commiphora species.

Ten South African Commiphora (Burseraceae) species were investigated to validate their use in traditional healing rites. The leaf and stem extracts of each species were analysed for the anti-oxidant (ABTS and DPPH assays), antimicrobial (MIC and death kinetic assays), anti-inflammatory (5-LOX assay), anticancer (SRB assay) properties, as well as the cytotoxic effects (tetrazolium-based assay). The best anti-oxidant activity (ABTS assay) was observed for the stem extracts of Commiphora tenuipetiolata IC(50)=5.10 microg/ml), Commiphora neglecta (IC(50)=7.28 microg/ml) and Commiphora mollis (IC(50)=8.82 microg/ml). Extracts generally exhibited poor anti-oxidant activity in the DPPH assay, with the exception of Commiphora schimperi (stem), Commiphora neglecta (stem), Commiphora tenuipetiolata (stem and leaf), and Commiphora edulis (stem), with IC(50) values ranging between 7.31 and 10.81 microg/ml. The stem extracts exhibited moderate to good 5-LOX inhibitory activity with Commiphora pyracanthoides (stem) displaying the greatest inhibitory effect (IC(50)=27.86+/-4.45 microg/ml). For the antimicrobial (MIC) assay, a greater selectivity was exhibited by the extracts against the Gram-positive bacteria (0.01-8.00 mg/ml) and the yeasts (0.25-8.00 mg/ml) than against the Gram-negative bacteria (1.00-8.00 mg/ml). Using death kinetic studies (time-kill studies), the rate at which Commiphora marlothii (stem) kills Staphylococcus aureus over a 24h period was determined. Mostly, a concentration-dependent antibacterial activity was observed beginning after ca. 30 min. All concentrations exhibited antibacterial activity, with complete bactericidal effect achieved by the 24(th) hour. The most active Commiphora species against the HT-29 cells (SRB anticancer assay) were Commiphora glandulosa (leaf and stem) and Commiphora marlothii (leaf). The MCF-7 cells (SRB anticancer assay) exhibited the highest sensitivity to indigenous Commiphora species, with Commiphora edulis (leaf and stem), Commiphora glandulosa (leaf and stem), Commiphora marlothii (leaf), Commiphora pyracanthoides (leaf and stem), Commiphora schimperi (stem), and Commiphora viminea (stem) all possessing a percentage inhibition greater than 80% at 100 microg/ml. Commiphora glandulosa (leaf and stem) and Commiphora pyracanthoides (leaf and stem) were the two most active species against the SF-268 cells (SRB anticancer assay), with IC(50) values ranging between 68.55+/-2.01 and 71.45+/-1.24 microg/ml. The majority of the Commiphora extracts were largely non-cytotoxic against Graham human kidney epithelial cells when investigated in the MTT assay.

Psychosocial intervention for lesbians with primary breast cancer.

This study examined the effects of a Supportive-Expressive group therapy intervention offered to lesbians with early stage breast cancer. Twenty lesbians diagnosed with breast cancer in the previous 12-months were recruited and assessed at baseline, and at 3, 6, and 12 months after the group intervention. During the 12-week intervention, group members focused on the problems of a new diagnosis, coping with the illness and treatment, mood changes, coping responses and self-efficacy, improving relationships with family, friends and physicians, the impact of the illness on life, pain and sleep, and changes in body image and sexuality. A within-subject slopes analysis was conducted on data collected for each woman over the first year. As predicted, women reported reduced emotional distress, intrusiveness, and avoidance, and improved coping. There were significant changes in their social support, but in the unexpected direction. Instrumental support and informational support declined. However, conflict in family relations also declined, while trends were found towards more cohesiveness and expressiveness. Participants reported less pain and better sleep. There were no changes in body image, sexuality, or attitudes toward health-care providers. These results suggest that Supportive/Expressive group intervention appears to be helpful for lesbians with breast cancer.

Comparison of lesbian and heterosexual women's response to newly diagnosed breast cancer.

In a study comparing lesbian and heterosexual women's response to newly diagnosed breast cancer, we compared data from 29 lesbians with 246 heterosexual women with breast cancer. Our hypotheses were that lesbian breast cancer patients would report higher scores of mood disturbance; suffer fewer problems with body image and sexual activity; show more expressiveness and cohesiveness and less conflict with their partners; would find social support from their partners and friends; and would have a poorer perception of the medical care system than heterosexual women. Our predictions regarding sexual orientation differences were supported for results regarding body image, social support, and medical care. There were no differences in mood, sexual activity or relational issues. Not predicted were differences in coping, indicating areas of emotional strength and vulnerability among the lesbian sample.

Endocrine function after hetero- and ortho-topic segmental pancreatic transplantation in primates.

This study assessed the early postoperative pancreatic endocrine function after intraperitoneal segmental hetero- and ortho-topic pancreatic allotransplantation in hemipancreatectomized, nonimmunesuppressed chacma baboons. Hemipancreatectomized animals remained normoglycaemic but rendered significantly reduced K values and insulin release during IVGTT, findings consistent with major pancreatic resection. Segmental hetero- or ortho-topic pancreatic transplantation did not improve reduced K values and hypoinsulinaemia following hemipancreatectomy although orthotopically sited grafts rendered the best glucose tolerance test curves. Glucagon output during IVGTT remained the same in both transplant models. It is concluded that the postoperative hormonal response was similar in both orthotopic and heterotopic transplant recipients, which indicates that drainage of graft venous effluent into the portal circulation has no advantage over systemic insulin drainage as reflected in this "diabetic" model.

Prolongation of segmental and pancreaticoduodenal allografts in the primate with total-lymphoid irradiation and cyclosporine.

The prolongation of segmental and pancreaticoduodenal allografts (PDA) by total lymphoid irradiation (TLI) and in combination with cyclosporine (CsA) was assessed in a well established total pancreatectomy, diabetic, primate transplantation model. Pancreatic transplantation was performed in 119 pancreatectomized baboons (Papio ursinus). Of a total of 109 allografts performed, 71 were segmental allografts (open duct drainage) and 38 PDA. Of 119 graft recipients, 10 received segmental pancreatic autografts. TLI and CsA administered separately to segmental allograft recipients resulted in modest allograft survival and indefinite graft survival was not observed. 8 of 17 (47%) segmental allograft recipients that received TLI and CsA had graft survival beyond 100 days, indicating highly significant pancreatic allograft survival. All long-term segmental allograft recipients were rendered normoglycemic (plasma glucose less than 8 mmol/L) by this immunosuppressive regimen. In contrast, poor results were observed in PDA recipients treated with TLI and CsA. Mean survival in 18 treated PDA recipients was 23.8 days, 8 survived longer than 20 days (44.4%), and 1 greater than 100 days (5.5%). Despite treatment, early rejection of the duodenum in PDA recipients frequently resulted in necrosis and perforation and contributed to a high morbidity and mortality. This study indicates that, in contrast to the significant prolongation of segmental allografts by TLI and CsA, poor immunosuppression was achieved by this regimen in PDA recipients and was associated with a high morbidity and mortality caused by early rejection of the duodenum.

Diabetes in pancreatectomized baboons: a model for pancreatic transplantation studies.

This study was designed to assess plasma glucose levels (PLG) and insulin release in totally pancreatectomized baboons when challenged with intravenous glucose administration (IVGTT). Ten animals (Papio ursinus) were used and duodenectomy was intentionally avoided. The PLG at death was 18.0 +/- mmol/L, and the mean K-value within 3 days after pancreatectomy was 0.4% +/- 0.2%, indicating a significant impairment of glucose disappearance from the blood when compared to the control animals (P less than 0.01). Plasma insulin levels before and after stimulation with glucose were below the lowest level of insulin assay sensitivity. We conclude that in the primate, as in the dog, surgical pancreatectomy produced a reliable diabetic model, which is uniformly lethal if left untreated.

Enzymatic assessment of myocardial injury after infarction or cardiac surgery. Is isoenzyme analysis required?

Estimation of enzyme release in plasma requires knowledge of the fractional catabolic rate constant (FCR) for the elimination enzyme activity from plasma. However, the total plasma content of such enzymes usually consists of several isoenzymes with different values of FCR. Thus, the use of a single overall value for FCR may cause error. This problem was studied by determination of the plasma isoenzyme activities of creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alpha-hydroxybutyrate dehydrogenase in patients after cardiac surgery and after acute myocardial infarction. Values of FCR and the cumulative release of activity in plasma are estimated for separate isoenzymes and for total enzyme activity. Results are compared with the enzyme content of myocardium, skeletal muscle and blood cells. It is concluded that isoenzyme separation is not required for the quantitative use of such data. The implications for the validation of enzymatic estimation of cardiac injury are discussed. The results indicate that local inactivation of enzymes after cardiac injury must be limited.

[Perirenal extravasation of contrast media during urography]. / Perirenale Kontrastmittelextravasate bei Urogrammen.

The authors report on 28 cases of contrast medium extravasates during urography. Own results and those obtained by other authors in respect of clinical findings, diagnosis and therapy are discussed. Our experiences have shown that an aggressive diagnostic or therapeutic approach is not indicated, since the sequels of these extravasates have no special clinical importance. As a rule, treatment is unnecessary, especially inpatient observation. Hence, our experiences confirm the trend to proceed as conservatively as possible.

Prolongation of intraperitoneal segmental pancreatic allografts in primates receiving cyclosporin A.

In this study the efficacy of the new immunosuppressive agent, cyclosporin A (CYA), was examined in a model of segmental, intraperitoneal pancreatic allotransplantation with free duct drainage in totally pancreatectomized, outbred Chacma baboons. CYA, in doses of 25 to 50 mg/kg/day administered to recipients of heterotopic segmental (tail) allografts, produced a slight but significant prolongation of graft survival. CYA (25 to 85 mg/kg/day), administered orally after pancreatic transplantation gave daily serum trough levels of CYA that ranged from 300 to 600 ng/ml. Mean serum trough levels on the first postoperative day in recipients of 50 mg/kg/day were 121.1 +/- 61.6 ng/ml. There was a wide variation in daily serum trough levels exhibited between primates on the same daily oral dose, and there was no correlation between absolute serum trough levels of CYA and rejection. It is postulated that adequate serum CYA levels were not achieved by the oral administration of the drug to ensure allograft survival beyond 60 days in pancreatectomized recipients. Adverse effects occurred frequently and included anorexia, diarrhea, and tremors and were in direct proportion to the quantity of CYA required to prolong graft survival. Free duct drainage into the abdominal cavity frequently resulted in pancreatic ascites, which necessitated paracentesis, indicating that this method of duct drainage has limited clinical application. Although heterotopic autotransplantation or allotransplantation of the tail of the pancreas in the baboon was capable of maintaining normoglycemia in pancreatectomized baboons, glucose intolerance, reduced K values, and hypoinsulinemia were consistent findings during glucose tolerance tests, suggesting that an insufficient islet cell mass had been transplanted.

Extent of myocardial damage after open-heart surgery assessed from serial plasma enzyme levels in either of two periods (1975 and 1980).

Perioperative myocardial damage caused by cardiac surgery in 32 patients operated upon in 1980 is quantified in terms of total quantity of alpha-hydroxybutyrate dehydrogenase released from the heart into the circulation, and compared with perioperative myocardial damage in 32 patients operated upon in 1975. In the five year period between 1975 and 1980, various aspects concerning anaesthesia, pharmacological treatment, and myocardial preservation techniques have been subjected to considerable changes. Comparison of calculated myocardial damage in 1980 with that in 1975 shows a general reduction of about 40% in patients having coronary artery bypass grafting, 75% in patients with aortic valve replacement, and 10% in patients with mitral valve replacement.

Recognition and quantification of myocardial injury by means of plasma enzyme and isoenzyme activities after cardiac surgery.

Serial plasma enzyme determinations were carried out in 32 patients who underwent cardiac surgery with the aid of extracorporeal circulation. Plasma creatine kinase (CK), the cardiospecific isoenzyme of CK (CKMB), and alpha-hydroxybutyrate dehydrogenase (HBDH) were determined from the onset of surgery up to 100 to 120 hours after operation. From the plasma enzyme activities, the total amount of enzyme released by the injured heart into the circulation could be calculated using mathematical equations solved numerically by means of a computer. The calculated amount of CK, CKMB, and HBDH released by the heart correlated well with (1) postoperative mortality, and (2) peak activities of the respective enzymes. The calculated amount of any of the 3 enzymes released showed poor or no correlation with (1) electrocardiographic criteria of myocardial infarction, (2) duration of cardiopulmonary bypass, and (3) duration of total aortic cross-clamping. This study shows that the extent of myocardial injury after surgery can be assessed quantitatively using the calculated amounts of enzyme released, as well as using peak plasma activities of CKMB and HBDH.