What happens after graft loss? A large,long-term,single-center observation

The number of patients returning to dialysis after graft failure increases. Surprisingly, little is known about the clinical and immunological outcomes of this cohort. We retrospectively analyzed 254 patients after kidney allograft loss between 1997 and 2017 and report clinical outcomes such as mortality, relisting, retransplantations, transplant nephrectomies, and immunization status. Of the 254 patients, 49% had died 5 years after graft loss, while 27% were relisted, 14% were on dialysis and not relisted, and only 11% were retransplanted 5 years after graft loss. In the complete observational period, 111/254 (43.7%) patients were relisted. Of these, 72.1% of patients were under 55 years of age at time of graft loss and only 13.5% of patients were ≥65 years. Age at graft loss was associated with relisting in a logistic regression analysis. In the complete observational period, 42 patients (16.5%) were retransplanted. Only 4 of those (9.5%) were ≥65 years at time of graft loss. Nephrectomy had no impact on survival, relisting, or development of dnDSA. Patients after allograft loss have a high overall mortality. Immunization contributes to long waiting times. Only a very limited number of patients are retransplanted especially when ≥65 years at time of graft loss.     

High affinity of sigma1-binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C₈–C₇ isomerase (ERG2 protein). Pharmacologically - but not structurally - the sigma₁-site is also related to the emopamil binding protein, the mammalian sterol C₈–C₇ isomerase. We therefore investigated if sterol C₈–C₇ isomerase inhibitors are high affinity ligands for the (+)-[³H]-pentazocine labelled sigma₁-binding site.
2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma₁-binding sites were the agricultural fungicide fenpropimorph (K_i 0.005 nM), the antihypocholesterinaemic drugs triparanol (K_i 7.0 nM), AY-9944 (K_i 0.46 nM) and MDL28,815 (K_i 0.16 nM), the enantiomers of the ovulation inducer clomiphene (K_i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K_i 26 nM).
3. Except for tamoxifen these affinities are essentially identical with those for the [³H]-ifenprodil labelled sterol C₈–C₇ isomerase of S. cerevisiae. This demonstrates that sigma₁-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma₁-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.

     

DHEA and DHEA-S: a review

Dehydroepiandrosterone (DHEA) and its sulfated metabolite DHEA-S are endogenous hormones secreted by the adrenal cortex in response to adrenocorticotrophin (ACTH). Much has been published regarding potential effects on various systems. Despite the identification of DHEA and DHEA-S more than 50 years ago, there is still considerable controversy as to their biological significance. This article reviews the metabolism and physiology of DHEA and DHEA-S, the influence of age and gender on concentrations, and changes in endogenous concentrations associated with disease states and other factors, including diet and exercise. This article is unique in that it also summarizes the influence of drugs on DHEA and DHEA-S concentrations, as well as concentrations of DHEA and DHEA-S observed after the administration of DHEA by various routes. Sections of the article specifically address DHEA and DHEA-S concentrations as they relate to stress, central nervous system function and psychiatric disorders, insulin sensitivity, immunological function, and cardiovascular disorders.     

Serious adverse effects of amifostine during radiotherapy in head and neck cancer patients

Background and purpose: Amifostine has been shown to protect against xerostomia induced by radiotherapy for head and neck cancer, but its impact on the therapeutic index is unknown. This is the first report focusing on amifostine related adverse effects leading to discontinuation of amifostine treatment.

Patients and methods: Thirty-nine patients from two centers irradiated for head and neck cancer received i.v.-infusions of amifostine prior to each radiation fraction. In a phase III study, two daily amifostine doses, 200 mg/m² (n=21) and 340 mg/m² (n=18), were compared for protection against radiation induced toxicity. Total radiation dose was 60–70 Gy (2 Gy per fraction), nine patients received concurrent chemotherapy with cisplatin/5-FU. amifostine was usually discontinued after >1 episode of serious toxicity during subsequent treatment sessions.

Results: In 16/39 patients (41%) amifostine was discontinued due to severe adverse effects, which led to discontinuation of the phase III study. In four of 16 patients radiotherapy was delayed due to amifostine related adverse effects for 1–3 days. Discontinuation occurred more often in patients receiving chemotherapy. The results led to a literature review for amifostine treatment during radiotherapy in head and neck cancer patients. Regarding our series and published series using an amifostine schedule comparable to ours, total discontinuation rate was 27% (57/214). Discontinuation was significantly influenced by chemotherapy (P=0.007), but not by amifostine dose (P=0.156).

Conclusion: Daily i.v. administration of amifostine during radiotherapy in head and neck cancer is associated with a high rate of serious adverse effects leading to discontinuation of amifostine treatment and sometimes delay of radiotherapy.     

Are single fractions of radiotherapy suitable for plantar fasciitis?

The use of radiotherapy for plantar fasciitis has never been reported in Australasia and is scarcely found in the English language medical literature, but it is commonly used in Europe, especially in Germany. In Europe, treatment courses consisting of multiple small fractions have been associated with high levels of pain relief. In the present report, the use of single fractions or radiotherapy was evaluated by reviewing seven consecutive patients referred for treatment and by applying objective and subjective criteria for pain relief. One patient died of unrelated causes soon after treatment and one declined to receive radiotherapy. Four patients each received a single dose of 8 Gy resulting in complete pain relief. One patient was treated with 8 Gy and 12 weeks later was retreated achieving partial pain relief. A follow‐up interview was conducted after a mean of 15.6 months, ranging from 1.5 to 30 months. No acute or late effects occurred; however, the possibility that delayed effects may yet occur, particularly carcinogenesis, cannot be excluded. Radiotherapy for this common condition should be investigated further as it might be safer and more effective than other methods currently in use.     

Resuscitation of severe chest trauma with four different hemoglobin-based oxygen-carrying solutions

BACKGROUND: The purpose of this study was to test whether polynitroxylation (PN) improved the therapeutic profile of hemoglobin-based oxygen-carrying compounds (HBOCs) that were unpolymerized (alphaalphaHb) or 70% polymerized (polyHb) in a clinically relevant model that combines pulmonary injury and reperfusion. To our knowledge, four different HBOC formulations have never been compared in the same trauma model. METHODS: Anesthetized, ventilated swine (n = 45) received a unilateral lung contusion + 25% hemorrhage. After 60 minutes, 250 mL of either PNalphaalphaHb (n = 5), alphaalphaHb (n = 10), PNpolyHb (n = 6), polyHb (n = 5), or normal saline (NaCl, n = 10) was administered for 20 minutes, followed by standard crystalloid resuscitation for 30 minutes, and supplemental crystalloid as required for 6 hours to maintain heart rate <100 beats/min and mean arterial pressure >70 mm Hg. RESULTS: Nine of 45 deaths occurred before resuscitation. Survival time was 395 minutes with NaCl versus 303 minutes with alphaalphaHb (p = 0.03) or 238 minutes with PNalphaalphaHb (p = 0.04). With both polymerized HBOCs, survival was 480 minutes (polyHb vs. alphaalphaHb, p = 0.005; PNpolyHb vs. PNalphaalphaHb, p = 0.006). All HBOCs were pressors (all p < 0.05) and all reduced the supplemental fluid required to maintain systemic hemodynamics during resuscitation (all p < 0.05). By 90 minutes postresuscitation, cardiac index was 112% of baseline with NaCl (p < 0.02), but was 78% with alphaalphaHb (p = not significant), 63% with PNalphaalphaHb (p < 0.01), 79% with PNpolyHb (p < 0.01), and 67% with polyHb p < 0.02). Relative to NaCI, no HBOC altered trauma-induced neutrophilia, thrombocytopenia, or the trauma-induced increases in bronchoalveolar lavage protein or bronchoalveolar lavage neutrophils. CONCLUSION: After resuscitation from chest trauma, we observed the following: (1) all HBOCs reduced fluid requirements and increased right and left ventricular afterload versus NaCl, which further compromised an already marginal cardiac performance; (2) mortality was less with polyHbs relative to alphaalphaHb, but the pressor action was unchanged; (3) the pressor action was less with polynitroxylated compounds relative to the unmodified HBOC, but this chemical modification had no effect on mortality; and (4) the pressor action of HBOCs must be attenuated by strategies other than polymerization or polynitroxylation for these compounds to be safe, effective resuscitants in humans.