With Respect to Elderly Patients: Finding Kidneys in the Context of New Allocation Concepts

The elderly have benefited from increased access to renal transplantation in recent years. New allocation concepts would shift distribution of kidneys to younger recipients, making expanded criteria and living donor kidneys more relevant for seniors. Current issues impacting expanded criteria donor kidney availability and living donor transplant opportunities for the elderly are explored. It is hoped that the kidney donor profile index will improve risk assessment and utilization of marginal kidneys. The usefulness of procurement biopsy remains controversial. Dual kidney transplantation and machine perfusion appear to be effective mechanisms to increase organ availability. “Old‐for‐old” allocation systems, donation service area variation and regulatory and reimbursement issues highlight disparities and disincentives affecting expanded criteria donor organ utilization, and considerations for the way forward are discussed. Living donor transplantation, even with older donors, may provide the best option for elderly recipients, and careful expansion of the living donor pool appears appropriate. In light of new allocation concepts, it will be important to understand issues pertinent to seniors and develop effective strategies to maintain or improve their access to the benefits of transplantation.     

Drastic neofunctionalization associated with evolution of the timezyme AANAT 500 Mya

Melatonin (N-acetyl-5-methoxytrypamine) is the vertebrate hormone of the night: circulating levels at night are markedly higher than day levels. This increase is driven by precisely regulated increases in acetylation of serotonin in the pineal gland by arylalkylamine N-acetyltransferase (AANAT), the penultimate enzyme in the synthesis of melatonin. This unique essential role of AANAT in vertebrate timekeeping is recognized by the moniker the timezyme. AANAT is also found in the retina, where melatonin is thought to play a paracrine role. Here, we focused on the evolution of AANAT in early vertebrates. AANATs from Agnathans (lamprey) and Chondrichthyes (catshark and elephant shark) were cloned, and it was found that pineal glands and retinas from these groups express a form of AANAT that is compositionally, biochemically, and kinetically similar to AANATs found in bony vertebrates (VT-AANAT). Examination of the available genomes indicates that VT-AANAT is absent from other forms of life, including the Cephalochordate amphioxus. Phylogenetic analysis and evolutionary rate estimation indicate that VT-AANAT evolved from the nonvertebrate form of AANAT after the Cephalochordate–Vertebrate split over one-half billion years ago. The emergence of VT-AANAT apparently involved a dramatic acceleration of evolution that accompanied neofunctionalization after a duplication of the nonvertebrate AANAT gene. This scenario is consistent with the hypotheses that the advent of VT-AANAT contributed to the evolution of the pineal gland and lateral eyes from a common ancestral photodetector and that it was not a posthoc recruitment.Eyes have evolved in all animals to facilitate interactions with the photic environment (1, 2). However, among animals, vertebrates are unique in that they also possess a photoneuroendocrine structure, the pineal gland (3). It converts the 24-h rhythm in environmental lighting into a 24-h rhythm in circulating melatonin, thereby providing a unique and valuable signal of the photic environment. The details of pineal evolution are not clear (4, 5). However, it has been posited that an essential element was arylalkylamine N-acetyltransferase (AANAT; E.C. 2.3.1.87), the penultimate enzyme in the melatonin biosynthesis pathway (6–8); this scenario is referred to as the AANAT hypothesis of pineal evolution (7, 8).AANAT catalyzes the N-acetylation of arylalkylamines using acetyl CoA (AcCoA) as the acetyl group donor. The AANAT family, which belongs to the GCN5 superfamily (9, 10), is composed of two subfamilies termed vertebrate (VT) AANAT and nonvertebrate (NV) AANAT.^† This nomenclature reflects the phylogenetic distribution of the family members (13–17). The most striking differences between VT- and NV-AANAT are found in regulatory and catalytic regions of the encoded proteins (Fig. 1), consistent with different metabolic roles (7, 8).Open in a separate windowFig. 1.Schematic organization of VT- and NV-AANATs. Major structural differences between NV- and VT-AANAT include the addition of PKA/14-3-3 binding sites flanking the core of the enzyme, which mediate regulation, the addition of histidines to facilitate catalysis by promoting removal of protons generated during the transfer of the acetyl group, and the addition of a short peptide sequence (Cys-Pro-Leu), which creates a floppy loop that facilitates arylalkylamine binding and product release in the active site. The highly conserved lysine found in the N-terminal flanking regions of VT-AANAT is thought to facilitate regulation of proteasomal proteolysis by serving as a ubiquitination site (10, 13, 14, 25, 26, 28, 29). Modified from ref. 51.The NV-AANAT is thought to perform a detoxification function through acetylation of a broad range of endogenous and exogenous arylalkylamines and polyamines (13–16). It has been found in Gram-positive bacteria, protists, fungi, some lower plants, algae, and cephalochordates. The broad detoxification role of NV-AANAT contrasts with the dedicated role that VT-AANAT plays in melatonin synthesis, which was seen in teleosts and tetrapods (6, 18).Melatonin is recognized as the vertebrate hormone of the night, because circulating levels are markedly elevated at night. In bony fish and tetrapods, VT-AANAT is highly expressed in the pineal gland, the primary source of circulating melatonin (6, 18). The unique and essential role that VT-AANAT plays in vertebrate timekeeping is recognized by the moniker the timezyme (10). VT-AANAT is also found in the retina, where N-acetylserotonin and/or melatonin may play paracrine roles (19).The AANAT hypothesis of pineal evolution holds that AANAT originally served a detoxification function in an ancestral photodetector and that its function evolved from broad acetylation of potentially toxic amines into selective acetylation of serotonin and the production of melatonin (7, 8). According to this hypothesis, as melatonin became recognized as a hormonal signal of darkness, the conflict of selective pressures to optimize both photodetection and melatonin signaling was resolved by the cellular separation of these functions and resulted in the independent evolution of the pinealocyte and retina.There is, however, no evidence available to determine whether VT-AANAT coevolved with the eyes and pineal gland or whether it was recruited after these structures evolved. The VT-AANAT is absent from the genomes of the urochordate Ciona intestinalis (sea squirt) and the cephalochordate Branchiostoma floridae (amphioxus), suggesting that VT-AANAT appeared after the split of these lineages from vertebrates. In the current report, we sought to determine whether VT-AANAT is present in representatives of early divergent vertebrate classes of Agnathans (jawless vertebrates: lampreys) and Chondrichthyes (cartilaginous fish: chimaeras and sharks), which share a common ancestor dating from nearly 500 Mya in the early Cambrian period (20, 21). The results provide clues to how and when VT-AANAT evolved and address the validity of the AANAT hypothesis of pineal evolution.     

Clinical outcome of parapneumonic empyema in children treated according to a standardized medical treatment

Treatment of parapneumonic empyema (PE) consists of intravenous antibiotics and, in case of large effusions and persisting fever, pleural chest drain (±intrapleural fibrinolytics) or video-assisted surgical intervention. We standardized the treatment for PE in our tertiary care center choosing a first-step nonsurgical approach. The aim was to evaluate the need for surgery and to collect data on disease course, outcome, and microbiology. For all children treated for PE between 2006 and 2013, data were prospectively collected concerning treatment, length of stay, duration of fever, complications, and causative agent. Of 132 children treated for PE, 20 % needed surgical intervention. Analyzed per year, the need for surgery decreased from almost 40 % in 2007 to 0 % in 2010 again increasing to 40 % although this did not reach statistical significance (p?=?0.115). Median duration of “in-hospital fever” was 5 days (IQR, 3–8). The duration of fever correlated with pleural LDH (r?=?0.324; p?=?0.002) and pleural glucose (r?=??0.248; p?=?0.021) and was inversely correlated with pleural pH (r?=??0.249; p?=?0.046). Based on pleural PCR data, 85 % of PE were caused by Streptococcus pneumoniae (40 % serotype 1). Conclusion: After introduction of a standardized primary medical approach (chest drain?±?fibrinolysis) for PE in our institution, the need for surgical rescue interventions overall remained at 20 %, which is higher than in some other reports. Difference in microbiology or disease severity could not be proven.     

Preperation of (99m)Tc labeled 5-fluorouracil as a potential diagnostic agent in advanced breast cancer: first clinical trial

The chemotherapeutic drug 5-fluorouracil (5FU) is used for treatment of various types of cancers. The present study was conducted to evaluate the potential of this drug as a diagnostic radiopharmaceutical in advanced breast cancer. We have labeled 5FU by using the stannous chloride reduction method with 555MBq of technetium-99m ((99m)Tc). The (99m)Tc-5FU was injected intravenously in 4 patients having advanced breast cancer. Dynamic and static images were taken at various time intervals till 2h. Whole body images were used to calculate the percentage of the injected dose, in each organ. Target to non target ratio was calculated to find out the optimum time for imaging. In conclusion, our study showed that (99m)Tc-5FU was a promising agent for diagnosing advanced breast cancer with optimum visualization at 1h.