Thursday, April 15, 2021

Exosomes and Exosome-like Nanoparticles: Applications for Biomedicine - Juniper Publishers

Organic & Medicinal Chemistry - Juniper Publishers

Abstract

With the rise of the average life expectancy in the last century, the prevalence of life-threatening diseases has greatly increased. Thus, the need for effective, cost efficient and easy to produce therapeutic systems, combined with recent technological advances, boosted nanotechnology research. Since their discovery more than 30 years ago, naturally occurring exosomes are an increasingly interesting vehicle for drug delivery, with the disadvantage that they are difficult and expensive to extract, characterize and their encapsulation efficiency is poor. Liposomes, known since the mid-60’s, can be used for various types of therapies for their capacity to encapsulate almost any molecule, with efficient production and encapsulation processes, but are less biocompatible. A new type of systems, exosome-like nanoparticles, that combine the advantages of these two systems, mitigating their limitations, show potential to be excellent therapeutic options with almost no side-effects.

Keywords: Nanotechnology; Liposomes; Exosome-like; Exosomes; Nanoparticles

Introduction

In recent decades, in the nanotechnology field, many new approaches have been developed, in basic and clinical research, to obtain a better diagnosis and an early effective therapy for the most debilitating diseases such as cancer or neurodegenerative disorders [1]. Extracellular vesicles are naturally occurring molecular vehicles, having an important role in the transport of molecules-being misfolded proteins to be degraded in the lysosome, or nucleic acids - and in intercellular communication [2,3]. Extracellular vesicles can be divided into three subpopulations according to their size and origin: exosomes, Microvesicles and apoptotic bodies [1]. These vesicles naturally do what some of the industrially manufactured nanoparticles aim to do: the encapsulation of molecules and their controlled release into a target cell [4]. Exosomes are becoming an increasingly interesting vehicle for the delivery of drugs due to their biocompatibility, capacity to cross biological barriers and to encapsulate hydrophilic and lipophilic molecules [3,5-7]. However, exosomes can also be difficult to extract and to characterize, and the costs of extraction and encapsulation of bioactive molecules can be high. Moreover, the encapsulation process can be difficult, very time-consuming, and can lead to poor encapsulation efficiencies [4.8].

Similarly, to exosomes, liposomes have a bilayer of lipid molecules, that can be synthetic or natural occurring ones, on the membrane of cells or vesicles [9,10]. This type of intensively studied synthetic vesicles have been used for various types of therapies, from imaging to the treatment of a wide range of diseases, since they can encapsulate almost every molecule [4,11]. These nanocarriers, while similar to exosomes to a certain degree, have a simple and efficient production process, and can encapsulate bioactive drugs more efficiently than exosomes, with the drawback that they can be far less biocompatible than these natural occurring nanovesicles [9]. Mitigating the drawbacks of these two systems, while retaining their excellent properties, exosome-like liposomes have been recently considered for therapy, with some very interesting systems-that can encapsulate biomolecules efficiently and deliver them safely in the targeted area - have been developed through various types of approaches. These can be considered as some of the most promising drug delivery nanoparticles, and more research in the area may lead to a more efficient and safe delivery of biomolecules.

Advantages and drawbacks of exosomes in drug delivery

Exosomes are the smallest in the extracellular vesicle class [12], with a diameter of 30 to 150 nm, which is why they are considered nanovesicles, are highly heterogeneous and with different molecular and charge compositions, depending on the type of producing cell [2], its structure is formed by a lipid bilayer with associated proteins on its membrane [13]. Exosomes can be produced by almost all human cells [14], wherein the mechanism is maintained for several classes of organisms. Exosomes can also be considered a waste disposal mechanism [1]. For drug delivery, exosomes have some advantages, one of which is to encapsulate lipids, proteins, DNA, mRNA, non-coding RNA or other bioactive substances [1,12], they can also circulate in biofluids and thus transport messages from one cell to another; when the exosome reaches the recipient cell, it can modify its behavior depending on the message received. Exosomes are an efficient platform for drug delivery, due to their biodistribution, biocompatibility and low immunogenicity. Moreover, they can also cross most biological barriers, allowing the delivery of biomolecules in all organs of the human body [12].

Advantages and drawbacks of liposomes in drug delivery

Liposomes have a spherical structure with one or more phospholipid bilayer [9,10], which can be classified according to size (small, large, and giant); number of bilayer (unilamellar, oligolamellar and multilamellar) and charge (neutral; anionic and cationic) [10,11]. While liposomes’ size can range from 50 to 200nm, they are more efficient when they have 100 to 140nm since they have a longer half-life in the blood stream. Moreover, these particles are not so easily detected by the immune system and are relatively more difficult to be recycled or eliminated from the body [10,15]. Liposomes can encapsulate antimicrobial drugs, nucleic acids, and antioxidants, within their bilayer or their aqueous area. This delivery is directed and controlled [16]. Since liposomes can be made by various types of naturally occurring or synthetic lipids, the toxicity of the system must be extensively studied, often limiting the use of these systems for various types of therapies [9,11].

Exosomes-like liposomes: fusing the advantages of liposomes with exosomes.

Exosome-like nanoparticles often have a similar size to liposomes (60nm–150nm) [17,18], joining the advantages such as the ease of production, tuning of the formulation, and encapsulation efficiencies of liposomes with the biocompatibility, longer circulation time, stability, and ability to cross biological barriers better than exosomes. Moreover, the cytotoxicity of this type of nanocarrier is often negligible since their composition is like naturally occurring exosomes. This type of nanoparticles can be obtained from various processes, such as the fusion of liposomes with exosomes [19], their extraction from plants [20,21], or serial extrusion of animal cells [17,22,23]. Exosomelike vesicles from plants are some of the most like exosomes, as they have a composition very similar to exosomes from human cells. More than that, their encapsulated molecules are like the ones found in animal exosomes, but differ in number, containing a lesser quantity of both nucleic acids and proteins than the animal ones [24], being non cytotoxic and being able to deliver biomolecules for the treatment of various diseases such as brain tumors [25].

Conclusion

Exosome-like nanoparticles, while newly discovered, have already been the target of multiple studies, with some interesting results [1,2]. In fact, their biocompatibility is excellent, and they can effectively encapsulate a fair number of biomolecules, being an interesting therapeutic option on their own, when they are extracted from plants. Studies in animals prove that they can effectively bioaccumulate in the desired therapeutic area and attenuate some of the most debilitating diseases as brain tumors or cancer [2,11,15]. While liposomes and exosomes remain more commonly studied and used systems for therapy, the advantages of exosome-like nanoparticles cannot be ignored as they continue to rise in interest among the scientific community.

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Friday, April 9, 2021

Ugwuele Prehistoric Site in Nigeria: Controversies and Directions - Juniper Publishers

Archaeology & Anthropology - Juniper Publishers



Abstract

Acheulean culture has been identified as one of the oldest industrial sites (for archaeological studies) with large quantities of Acheulean cultural tools like handaxes, cleavers, picks, side scrapers etc. A cross-cultural dating had earlier revealed that a similar culture may have existed in Ugwuelle, Southeastern Nigeria. The archaeological research was conducted by F.N. Anozie and his team in 1977. This has further raised some critical thoughts on the true position of this Ugwuelle site as having existed as an Acheulean site. For instance, there are currently divided opinions amongst scholars as to whether Ugwuelle artifacts are truly Acheulean or pre-forms of Achulean bifaces. Some authors like Philip Allsworth-Jones see the site as an axe factory with possible Holocene date. This paper advocates a systematic and detailed revisit of archaeological finds of this particular site in Nigeria to sought ways of aligning it with other known Acheulean sites in the world. This study was carried out using archaeological reconnaissance and a review of related literatures to make its positions. The implication of this paper is to further make clarifications on the true position of the Ugwuelle archaeological site in Nigeria.

Keywords: Acheulean; Stone tools; Ugwuele; Sites; Archaeology; Reconnaissance; Excavation

Introduction

Archaeological discoveries overtime have aided in tracing the origin and generational root of man from inception [1]. This is one of the reasons why the discipline of archaeology had commanded much respect and regard from some other disciplines. The archaeological study of earliest human settlement in the world is made possible through the understanding of various archaeological remains especially that from different regions of Africa. The archaeological record has been identified as a cultural period when the Homos (habilis and erectus) lived and made useful implements for a sustainable living. Braq & Trump [2] noted that; In Europe the term Acheulian is used for the later (i.e. post –ABBEVILLIAN) stages of the lower PALAEOLITHIC HANDAXE tradition. The conventional borderline between Abbevillian and Acheulian is marked by a technological innovation in the working of stone implements, the use of a flaking tool of soft material (wood, bone, antler) in place of a hammer stone... the type site is in France at Saint Acheul, Amiens, where the implements were found in deposits of the early part of the RISS glaciations. Study of evidences and other archaeological excavations are still revealing the spread of archaeological remains to some other continents of the world as Acheulean and other similar cultures of Abbrevillian, Chellean, etc which were said to have existed during the lower Paleolithic have been noticed to have existed in Africa and Europe. 

For instance the Chellean term was said to have been used to represent archaeological cultures during the lower Palaeolithic Hand axe tradition in Europe. Also the Chellean was said to have evolved to what is referred to today as the Acheulean hence the term Chelleo-Acheulean was formerly used for the succession of hand axe industries in Africa but has been replaced today by what is popularly known as Acheulean culture [2]. This later degenerated from the Acheulean to some other cultures, as man was rapidly developing both in thoughts and innovations through the exploration of various resources in the environment. There was equally increase in human population and tool traditions [3-5]. However, observations, excavations, inferences and other lab analysis are still in progress towards perfecting the true knowledge of existence of the early man in some parts of the world through cultural resemblances and linkages of notable archaeological cultures. As noted earlier, the understanding of activities of the early man in place is a function of availability and analysis of tools made and used like wood, stone, clay, metal, fossil remains and other available evidences.

Previous archaeological research in Africa had revealed that man originated from Africa throughout the whole world and his traces from the early Australopithecines to the Homo species. Evidence on this occur not only on the remains of man himself, but also on the tools he produced and used. These early human developments in Africa occurred in stages and were marked by different cultures. Thus, we have the Oldowan culture noted with tools like the choppers, spheroids and polyhedrals. Then the Achulean culture marked with tools like handaxes, cleavers, side scrapers and flakes. In some cases, picks are found in the assemblage. There is also the Sangoan culture marked by the picks. This claim on the origin from and spread out of Africa moved Alagoa & Derefaka [6] to write “Man began to move out of Africa, the first evidence of appearance of Homo sapiens about 200,000 years ago occurred again in Africa. Africa can, therefore, be said to be not only the cradle of mankind, but also the re- engineering homeland for humans”. The Acheulean culture marked by the above-mentioned tools which are the hall mark of this work has been found in many parts of Africa. Generally, it is associated with the genus Homo erectus (the erect moving hominid). Amongst the areas/sites where the Acheulean had been found in Africa are; West Africa - in Mali, Mauritania, Senegal and Nigeria. Within Nigeria, we have Jos Plateau in the sites of Mai Idon Toro, Pingell, Iying and the Nok valley. Allsworth-Jones [7] refers to Jos plateau area as the best for Acheulean in tropical West Africa. Ugwuele is another likely destination of Acheulean as was informed by Anozie [8]. Anozie [9] described his perception on the discovery of the site in 1977, in the following lines “We are not aware of any other site in the world with such an enormous amount of stone axes and other tools. An explanation is possible. Since suitable stone flaking materials were not available in the area, it is understandable if the Acheulean camped at the site for a very long time in order to use the dolerite in the manufacture of tools which were very essential to them. It is also likely that tools made at Ugwuele were used at places far away from the site”.

The Ugwuele Archaeological Site (1977).

The Nigerian site of Ugwuele-Uturu has attracted widespread interest since its discovery in part because of F. N. Anozie’s original description of it as Acheulean [10]. This site is about 7kms North of Hope – Ville Rehabilitation centre which is found immediately one enters Uturu Okigwe which is about 10kms east of Okigwe on the Okigwe Afikpo road [11]. It has 50 53’N, 70 26’E as its coordinates (Figure 1). While the vegetation of the site is savanna, “…dominant grasses are Pennisteum purpuram and Andapogon sp., with a sprinkling of others such as Imperata cylindrical. The few trees present include oil palm and Phyllanthus descoideus” [12]. Also, the vegetation of the area is also made up of shrubs and stunted trees like Acioa batari and Velvet tamarind (Figures 2 & 3). Allsworth-Jones [10] is of the opinion that the event that really exposed the site to the attraction of academic interests and subsequent researches was the activities of the quarrying company in the area. It has been described as the largest Stone Age factory in the world. Materials found here occur in stratigraphically sealed context and made from dolerite, an intrusive, fine-grained igneous rock [11,14]. The site was originally discovered in October 1977 and first investigated by a team of archaeologists from the University of Nigeria Nsukka [10].

The inconclusive nature of the Ugwuele archaeological investigation raised conflicting opinions amongst the actors who worked on the site. For instance, Allsworth-Jones has vehemently disagreed with Anozie who the Principal Investigator on the true nature of the lithic materials was discovered from the Test Pits conducted in the site. For instance, Allsworth-Jones was of the opinion that “the artifacts presented (by Anozie) ... as a ‘Point’, but the lower surface is worked and it appears to have been abandoned before completion. Of course, if the process described above is regarded as no more than roughouts, then the rather fancy morphological names given to them are illusory” [10]. Also, in his (Allsworth-Jones) current publication, he informed that Anozie could not date his samples hence he inquired from the dating company who denied any record of such sample from Anozie as was claimed. But Anozie [8] never claimed to have dated the samples as was claimed. He maintained that he wanted to date those samples but had a challenge which made the process inconclusive. This all-important archaeological site has been denied of extensive and detailed excavation to ascertain the true nature of the site and as well silence the long-existed arguments that have emanated from the site since its first preliminary investigation in 1977. Hence while Anozie was projecting the site as an Acheulean site, Allsworth-Jones insisted that the site could have been an axe factory site and that the only Acheulean site to have existed in Nigeria is within the vicinity of Jos Plateau where him (Allsworth-Jones) and Anozie were part of the archaeological investigators in the site. Also, Allsworth-Jones agreed with Marliac [14] who maintained that sites can equally be found at various localities within the vicinity apart from their original sources. To this regard Allsworth-Jones [10] expressed that “one could expect that the same might be true for Ugwuele-Uturu”. 

J. D. Clark had a different view of the site from that of Anozie when the result of the preliminary investigation was presented by Anozie, Andah and Derefaka during the 9th Pan-African Congress in Jos in December, 1983. This he made known in his report in ‘Nyame Akuma’ 1983 [10]. Clark views the site just like Allsworth-Jones, as an axe factory site that are found in some parts of Africa like Cameroon. He declined from giving a clear nod to the postulation that the site is an Acheulean. Infact both Clark [14] and Allsworth-Jones [10] in their publications reported that the conference paper presented on the Ugwuelle studies during the 1983 Pan-African Congress at Jos by Anozie and other prominent actors in the investigation, was not published as a full paper in the conference proceedings except the short abstract. But they (Clark and Allsworth-Jones) failed to inform the cause of this accidental exclusion of the paper from the preceding conference proceedings. 

The question now is, was it excluded for lack of merit? Baseless argument. Author’s decision?. Regional and/or continental bias?, Or academic sentiments and politics? This has opened up the need for the arguments and demands of this paper. Much have been said on the archaeological evidence at Ugwuele in Uturu area of Abia State, Nigeria, with respect to the evidence of existence of early industrial sites in the area owing to the discovery of early stone tools in large quantity at a particular area of the community that are not habited by the extant society but used occasionally as farm site by the community. Anozie F. N. led the first archaeological investigation of the site and concluded that the site was Acheulean. This view did not go well with that of Allsworth-Jones who profusely criticized this view from Anozie and maintained that the site could have been an ax factory site with a possible Holocene date [8, 10 & 11]. In this site, many stone tools similar to that of the Acheulian culture have been identified i.e. handaxes , cleavers and Picks revealing the possibility of the existence of a culture similar to the other Acheulean cultures known in the world Anozie, Chikwendu & Umeji [11]. The true nature of the site is still a vague as extensive investigation is still a mirage. “The only published but still avowedly preliminary description of the site has been given by the Late F. N Anozie who directed the UNN excavation at Ugwuele over an eight-week period during November 1977 to March 1978” [10]. However, the nature and location of these stone tools coupled with issues on human use and natural factors have formed major questions for cultural thoughts on the site and its position in archeological evidence and analysts of the early human settlement in Africa. These amongst other issues this paper tends to address.

In this study, ground reconnaissance enabled for the corpus collection of lithic samples from the site. This is coupled with detailed field observation and critical content analysis of previous contending literatures on the subject matter. During the ground reconnaissance, most of the broken lithic artifacts were randomly collected and sorted typographically. Furthermore, the entire site area and environs were walked round and many cultural and natural features like shrines, groves, caves and rock shelters which give clue to early human settlement in the area were observed. Site Catchment Analysis (SCA) of Ugwuelle site was conducted 5-6 kilometres radius or one hour work, to study the various landscapes as earlier mentioned. Among these were Ugwuogwu iron smelting site, Nnemchukwu cave, Okpuchukwu cave, Ogu-agor cave and rock shelter, the grove of Nwogba stream made up of a vegetation cover that consist of majorly of mat plants (pandamus pandam) which are also features possible early human settlement in the study area. Descriptive and evaluative methods of data analysis were employed for data analysis.

The Genesis of the Site Discovery

It all began in 1977 when a student in the Department of Geography, University of Nigeria, Nsukka, visited a quarry site in his home town of Ugwuele in the present Isuikwuato Local Government of Abia State, Nigeria. He saw many stone flakes in large quantity scattered over a large area of land (Figures 4 & 5). He thought of the academic relevance of the discovery, and decided to report it to Professor G.E.K Ofomata of the Department of Geography, University of Nigeria, Nsukka. Professor Ofomata immediately understood the archaeological implications of those stone flakes and took a wise decision of taking some of them to the Archaeological Laboratory of the University of Nigeria, Nsukka for professional analysis and interpretation. The site was later visited by professional archaeologists from the Department of History and Archaeology, University of Nigeria, Nsukka, in October, 1977 for a rescue excavation. It was recorded that during this excavation, two test pits of 2m by 2m each coupled with two trenches of 6m by 2m each were excavated. Apart from the Initial archaeological investigation of the site in 1977 led by F. N. Anozie of the blessed memory, another archaeological investigation was carried out in 1981 by a team from the University of Nigeria Nsukka, University of Ibadan and the Nigerian National Museum which is currently referred to as the National Commission for Museums and Monuments (NCMM) [8-10, 16-18]. 

At the end so many stone tools which included handaxes, cleavers, stone knives, picks, were discovered in industrial quantity. The discovered stone tools were made of dolerite [19]. Details of findings from these series of minor archaeological investigations of the site can be found in the publications of prominent actors in that exploration (i.e. Anozie et al. 1978; Anozie 1982; 1983; 1985; 1993; Andah & Derefaka 1983; Allsworth-Jones 1987; 2015; etc). It is not the intension of this paper to revisit the details of finds from those archaeological investigations on the site which have already been stated in many previous studies like the ones mentioned above, but this paper is more interested in the controversies that were generated as a result of these finds and the escape route towards establishing the true nature of the site devoid of any form of sentiments and prejudices.

As at the time of the most recent ground reconnaissance on the site, (between 19th – 23rd May 2014), the quarrying company was still going on with its quarrying activities in the site. Though they reserved some part of the site for future archaeological studies as they promised when the site was discovered in 1977, the site is faced with serious threat of destruction as tones of the materials were being quarried on daily basis and carried away for road construction and other uses. Anozie [9] informed that the site is not dated yet but can be undisputedly put at between 1.6 million and 95,000 years BP. He concluded that from the studies of Clark [20], the Ugwuele site (Figures 6-13) could belong to the later phase of Acheulean which has been dated to about 500,000 years BP. Anozie [9] went ahead to assert that “We are trying to obtain a more definite date using Carbon-14 and Potassium argon techniques of dating as suitable dating materials were found at the site during the excavation, although we have some problems with these two techniques. We have also invited a geologist and a palynologist to see if the site could be dated by other means”. This was in contrast to the accusations from Allsworth-Jones who reported that Anozie claimed to have taken the samples to a lab for dating.

Further Archaeological Questions

Evidences from the site at Ugwuelle in Uturu Area of Abia State and the arguments surrounding it motivated this research. This paper tends to reflect on Ugwuelle industrial site and its position further on the archeological map of Nigeria. Some cultural thoughts are necessary at this juncture towards preserving and promoting the archaeological understanding of the Ugwuelle industrial site. First reflationary point is on the nature of tools discovered at this site. It is quite understandable that stone tools discovered at the Ugwuelle industrial site are much like the famous Acheulean tools of the Middle Stone Age, a subsequent stone tool culture to the earliest Oldowan culture.

 These stone tools as can be seen in Figures 9-11 include hand axes, cleavers and picks of different sizes; most of which are in broken forms. Unfortunately, much of these tools are in fragments as a complete hand axe or cleaver like that of Mai Idontoro or Pingel in the Jos Plateau Acheulean cultures has not been found (Figures 14-17). This is evidenced from the reconnaissance conducted by the present researchers. This raises up a lot of questions like, (i) is Ugwuele truly Achulean? (ii) If Achulean, are the materials of primary or secondary workshop/redeposition? (iii) Were they preforms for Late Stone tools (ground/polished stone) axes as posited by Clark [15] and Allsworth-Jones [10] or not? From our experience through the archaeological reconnaissance conducted in the area, Ugwuele site is likely an Acheulean site as it contains all the lithic tools with which Acheulean sites are known all over the world [12, 21-25]. Surprisingly, 37 years after the first preliminary study (1977) was conducted on the site, lithic tools were still discovered through a focused ground reconnaissance as was conducted by the present authors in May, 2014. Finds of this recent reconnaissance were in harmony with those from the earlier preliminary investigations of the site as was published in the works of Anozie et al (1978), Anozie (1982), (1983), (1985), (1993), (2002), Andah and Derefaka (1983), Clark (1983), and Allsworth-Jones (1987 and 2015). It is an industrial site taking into consideration the abundance of raw materials in the form of dolerite stones and stone chips found within the vicinity. 

From our ground reconnaissance, we were of the opinion that the broken handaxes and the cleavers and the lack of complete ones could be that the makers selected the finished tools with which they hunt and dismember the animals killed and discarded the unfinished or broken ones only to re-visit the site when they run out or of tools. In addition, it is of primary workshop as there are no areas within the vicinity that such lithic raw material which breaks at a sharp edge could be found. Thus, natural environmental factors have a role to buttress this point. Down the slope of the hill is a stream which may have served as source of water to the workers/hunters. As for our last question, the Ugwuele site is not a direct preform or Late Stone Age in Africa. Though there is the appearance of Sangoan tools like picks, they occurred in small numbers when compared with the handaxes and the cleavers. No evidence of Late Stone Age tools (either of the lower or the upper) like the polished stone axes and the microliths of any form have so far been found in Ugwuele tool assemblage. It is our contention here that a further research outside the vicinity of Ugwuele in particular and Okigwe area in general may reveal where the finished products from Ugwuele were taken to. Furthermore, it is also our contention here that the tools were produced through chipping and flaking techniques and not the levallois technique as claimed by Anozie (1982). 

The technique of debiting carried out in the site can further add weight to this claim. Our reason for this lie on the fact that the raw material (dolerite stone and to some extent quartz materials used) are so hard to be worked on using bone as anvil and a hammer stone. Another call for thought is on the human remains. Hand axe culture is synonymous with Acheulean, Abbevillian and Chellean cultures (Balout, 1981). Evidence of human remains was recorded at these places in association with these stone tools. This was an indication of the manufacturers and/or users of these stone tools. Thorough studies at these sites made relevant inferences and premises in the existence and nature of humans at such sites. Such was not the case at Ugwuele owing to incomprehensive research. 

Stone tools discovered have not been associated with any human remain apart from the use of the cross-cultural dating and inferences by detailed and purposeful archeologists. This raises another reflationary point on the position of the Ugwuele industrial site in the world Archaeological Map. Moreover, another reflationary point is on the issue of systematic and comprehensive excavation. Anozie (2002) asserted that the Ugwuele Industrial site was discovered in July 1977 and had first archaeological visit in October 1977, for a rescue excavation. Also during this rescue excavation it was noted that only two test pits of 2m by 2m was dug coupled with two trenches that were dug on 6m by 2m each. These excavations revealed multiple stone tools in industrial quantity which include handaxes, cleavers, picks and stone knives (Anozie, Chikwendu & Umeji, 1981; Anozie, 2002). These rescue excavations shouldn’t have been sufficient for such a magnificent and historical archaeological site. In some other similar sites in some other parts of the world, a much comprehensive excavation had been conducted with many other ones in progress so as to maintain detailed and more accurate archaeological inferences.

However, there are also issues on substantive dating for this site. According to (Braq & Trump 1975, p.71) “time factor is obviously of paramount importance in archaeology and many methods of recording is employed”. This is amongst the supporting factors of archaeological discoveries and inferences. The dating of a site aids in preserving the archaeological relevance of the site in a world of faster development and subsequent destructions of heritage resources. Although the Ugwuele site has not been dated, Clark (1974) had already noted before the discovery of the site, that similar culture in the other parts of Africa are put between 1.6 million and 95,000years BP (in Anozie 2002). Anozie who was amongst the first excavators of the Ugwuele site in 1977, when discussing on the age of the site noted as thus; “At present, the Ugwuele site has not been precisely dated but the culture is well known in Africa and its time range is undisputedly put at between 1.6million and 95,000 years BP; so the age of Ugwuele is within this range... judging from the tools, it seems that the site belongs to a phase which in other parts of Africa (Clark 1974) has been dated to about 500,000 years BP. We are trying to obtain a more definite date using the Carbon-14 and the potassium argon techniques of dating as sustainable dating materials were found at the site during the excavation, although we have some problems with these two techniques. 

We have also invited a geologist and a palynologist to see if the site could be dated by other means (Anozie 2002, p.18). Datable materials were also recovered by Anozie in his text trench II at the depth of 1.2 metres in form of extensive hearth and charcoal which according to him (Anozie 1982) were sent to Groningen for C14 dating(but inexplicably so far without result). Also excavations and dating at Iwo Eleru revealed that the site is about 11,000BC and likely earlier at Ugwuele (Shaw & Daniels 1984). None of these have shown a substantive date for the Ugwuele industrial site. This factor has brought much segregation for this historic site in the world archaeological sequence and discuss. 

The nature of the site demands that proper dating will give more understanding and appreciation of historical and archaeological relevance of the site. Presently, most of the dates applied are from sites that are contiguous with Ugwuele. Finally, archaeological reflections are sacrosanct on the issue of surface collection in the site. During the recent ground reconnaissance on this industrial site at Ugwuele on the 19th to 23rd of May 2014, much of the stone tools (mostly in broken forms) (Figures 14 - 20) were still lying on the surface of the soil. Some of these stone tools were picked up and taken to the Archaeological museum of the Department of Archaeology and Tourism, University of Nigeria, Nsukka for further studies. The survival of these artifacts till date may be attributed to the fact that the site is not yet inhabited by people and the reserved areas have not been quarried. Presently, the community is using the area as farm site.

Conclusion

Allsworth-Jones [10] concluded his own view about the Ugwuelle site and its future in the following lines; I submit that the technological/typological profile of Ugwuelle and its stratigraphic context insofar as we know it fits far better with a Holocene workshop ‘model’ than it does with the kind of structure that we would expect in the Acheulean as detailed above. That the picture presents itself on the basis of the incomplete data we have at our disposal. What is needed now is a re-examination of all the evidence, coupled with an appraisal and possibly a fresh attempt to date the extant deposits at the site itself. Then we will be on a much surer footing [10] It is worthy to note that this study is a wakeup call to all relevant stakeholders in the field of archaeology. A detailed excavation is needed in the site which would help unravel some of the questions surrounding this site. It would also help in making a comprehensive study and inferences on the site like some other archaeological sites of similar cultures from other parts of the world. Series of test pits opened in the site by Anozie and his team during the initial discovery of the site, did not help in ascertaining the true nature of the site hence the current debate on its archaeological status. 

We propose in line with Okafor (1989) that an extensive and systematic excavation of six different pits of 10 x 15m in the site (which is currently under threat by the activities of SETRACO Querying Company) and a further reconnaissance survey of the site area. The depth of the six trenches should not just stop at the sterile layer but go beyond possible hiatus until no hiatus is further observed. Also, further Site Catchment Analysis (SCA) should equally be conducted on the landscape of the Uturu area of Abia State, Nigeria, to support findings from the excavation. This work should be executed by a conglomeration of seasoned archaeologists with members from Nigeria and some other parts of the world. Interestingly, some seasoned archaeologists from Nigeria, England and South Africa have already indicated interest in being part of this team. Departments of Archaeology in University of Nigeria and University of Ibadan in Nigeria should be fully involved since they are part of the history of the site. They are also expected to provide some of the equipment and human resources for the study. More importantly, a study of this kind, would need external funding for efficiency and unbiased report. This should be followed by series of systematic analysis, dating, interpretation and notable publications, which are expected to give answers to the critical questions raised in this paper. This is expected to dowse further debates on the archaeological relevance of the site since its discovery in 1977. Moreover, before the study, formal consultations and approvals should be sought after from the National Commissions for Museums and Monuments in Nigeria, coupled with the Commission’s support towards the success of the study. Orientation programmes should be organized for the members of the host community on the proposed plan; how it will benefit them and their expected role. This will not only help in promoting and preserving Ugwuele Industrial site as a rich cultural heritage center in Nigeria and Africa in a wider scale [26-28] but also boost the tourism potential of Ugwuele community and Abia State In general. This would have settled various contentions on the site which made Okafor [12] to conclude his study on the site in the following lines. How can the cultural association be determined since enough geological data concerning the site are available, we should concentrate on the archaeology. What is needed is a full trench excavation, at least 10 by 15m in size, in the decomposed bedrock area in order to expose the stratigraphic sequence. 

The area of the site that appears to be most promising is the undisturbed southern part of Reserve I, so the trench should be placed here. During the excavation, care should be taken to collect any available organic remains which could yield information on chronology, environment and ecological setting. The establishment of an adequate date for the site will settle all the arguments [12]. Finally, it is our contention here that from this research and evidences that turned up that Ugwuele archaeological site may be an industrial site and may have belonged to the Acheulean site as evidenced from the tools found in the area. The issue of accurate chronology of Ugwuele as we suggested awaits further archaeological researches through detailed archaeological excavations. It is earnestly recommended that this call for a total revisit to this site should be harkened to, through adequate collaborative efforts from relevant experts. As noted earlier, a research of this kind can only be funded by the National Commission for Museums and Monuments in Nigeria and other relevant funding agencies like UNESCO, with interest in culture and heritage preservation. The result of this research would answer most of the puzzling archaeological questions raised in this paper and also determine the value and position of the Ugwuele site in the world archaeological map.

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Thursday, April 8, 2021

Diffuse Large B-Cell Lymphoma of the Sphenoid Sinus Initially Presenting with Binocular Diplopia - Juniper Publishers

Neurology & Neurosurgery - Juniper Publishers 

Mini Review

A 59 year old man was referred by his neurologist with symptoms of twelve days of binocular, horizontal diplopia and decreased visual acuity. His medical history was notable for hypertension and hyperlipidemia, adequately controlled with medication. He was a former 1 pack per day smoker but had stopped smoking 20 years previously. He was recently hospitalized for work-up of his symptoms in a community affiliate hospital where a magnetic resonance angiogram of the head was performed, which was unremarkable. Visual acuity was 20/40 in the right eye and 20/30 in the left eye. In addition, he had a trace afferent pupillary defect of the right eye and 12 Prism Diopter (PD) esotropia and 10 PD hypertropia in primary gaze which increased to 20 PD esotropia and 20 PD hypertropia in right gaze. The remainder of the eye exam was normal. He was diagnosed with sixth nerve palsy versus skew deviation, advised to patch the eye for symptomatic relief, and return in 8 weeks.

The patient experienced decreasing vision of the right eye and developed right-sided headache and periorbital pain, prompting a follow-up visit two weeks later. His visual acuity had decreased to light perception, and his pupillary and motility exams remained unchanged. Dilated fundus exam was unremarkable. The differential diagnosis included ophthalmic artery occlusion, optic neuritis or giant cell arteritis, and he was admitted to the same community affiliate hospital and received high dose intravenous steroids. Computed tomography imaging revealed near complete opacification of the right sphenoid sinus and enhancement and thickening of the right optic nerve. On follow-up visit, his visual acuity in the right eye had improved to 20/400, but he still had an afferent pupillary defect and there was no improvement in ocular motility. He was then referred to a tertiary care hospital for dedicated Magnetic Resonance Imaging (MRI) of the brain and orbits and further evaluation and management. The MRI scan revealed a 3.6 x 2.2 x 2.8 cm enhancing sphenoid sinus mass, with extension through the right orbital apex and annulus of Zinn with 270 degrees of encasement and superior displacement of the right optic nerve (Figure 1). Subsequent sphenoid sinotomy and biopsy demonstrated diffuse large B-cell lymphoma with high proliferation index (Figure 2). The patient was referred to neuro-oncology for chemotherapy.

Diffuse large B cell lymphoma is the most common subtype of non-Hodgkin’s lymphoma but rarely arises from the paranasal sinuses [1,2]. The sphenoid sinus as site of origin is especially rare, with only 19 reports in English literature; incidence is slightly more common in Asian patients [1]. Yoshihara et al. reviewed 15 reports and found 13/15 (86.7%) presented initially with ptosis or diplopia caused by CN III, IV, or VI palsy [1]. This is the fourth report in the English literature to describe sphenoid lymphoma with orbital apex syndrome and optic neuropathy. Imaging findings that can be demonstrated with sphenoid lymphoma include permeative bone destruction, hemorrhage, or fibrous dysplasia [2]. As seen in our patient, lack of classical radiologic findings can lead to delay in diagnosis. Vision loss, diplopia affecting multiple cranial nerves, and an indolent course should alert clinicians to suspecting this entity. Prompt consultation with otolaryngology and medical oncology can afford the patient the greatest chance at preventing additional morbidity and mortality.

Material Science


Material Science

Tuesday, April 6, 2021

Incidence of Postoperative Agitated Behavior in Nerve Block and Neuraxial Anesthesia: Retrospective Observational Study - Juniper Publishers

 Anesthesia & Intensive Care Medicine - Juniper Publishers


Abstract

Background: Postoperative delirium exacerbates the prognosis of elderly surgical patients. Postoperative agitation or confusion is one of the symptoms of hyperactive delirium. We retrospectively evaluated the incidence of postoperative abnormal psychomotor behavior in elderly surgical patients according to different anesthetic methods: nerve block vs. neuraxial anesthesia.

Methods: The medical records of 288 patients older than 64 years who underwent surgery with regional anesthesia between January 2015 and December 2017 were divided into two groups, the nerve block group (n=209) and the neuraxial anesthesia group (n=79). The primary outcome was postoperative agitated behaviors, and the secondary outcomes were patient and anesthesia related factors.

Results: In elderly patients, the incidence of agitated behavior was lower in the nerve block group compared with the neuraxial anesthesia group (4 {1.3%} vs. 8 {2.8%}, P=0.004). Neuraxial anesthesia, older age and male gender were found to be significant factors for the occurrence of agitation in elderly patients.

Conclusions: This study suggests that nerve block, as compared with neuraxial anesthesia, may have a greater beneficial effect in reducing postoperative agitated behavior in surgical elderly patients.

Keywords: Nerve block, Neuraxial anesthesia, Postoperative agitated behavior, Hyperactive delirium

Abbreviations: ANCOVA: Analysis of Covariance, CAM-ICU: Confusion Assessment Method in The Intensive Care Unit, OAA/S: Observer’s Assessment of Alertness/Sedation, RASS: Richmond Agitation-Sedation Scale

Introduction

Postoperative delirium can exacerbate the prognosis of surgical patients, result in increased postoperative morbidity and mortality, and generate higher hospital costs [1-3]. Postoperative delirium is a common complication, especially in elderly patients, occurring in up to 60% of patients after major surgery [4]. The risk factors for postoperative delirium such as old age, hip surgery, and propofol use are known [5-7]. In addition, postoperative pain is an important factor related to postoperative delirium [8]. However, the pathophysiology of postoperative delirium has not been elucidated yet. A previous study reported that peripheral nerve blocks reduce side effects such as postoperative delirium via an opioid-sparing effect [9].

There have been many studies on the incidence of delirium in different types of anesthesia. However, most studies compared general anesthesia with neuraxial (spinal, epidural, or combined spino-epidural) anesthesia [10,11]. There are few studies comparing neuraxial anesthesia with peripheral nerve block in regional anesthesia.

There are three types of delirium: hypoactive, hyperactive, and mixed [12]. Although the hypoactive type is more common than the hyperactive type [13], the abnormal behavioral patterns of the hyperactive type, such as agitation or confusion, are considered harmful to patients and medical providers and need to be quickly managed.

In this study, based on the hypothesis that nerve block may reduce the incidence of abnormal psychomotor behavior compared with neuraxial anesthesia, we retrospectively investigated the incidence of postoperative agitated or anxious behavior with other risk factors in elderly patients who underwent surgery with regional anesthesia.

Methods

Study population and data collection

After obtaining an approval from the Institutional Review Board at Hanyang University Hospital (HYUH 2018-07-006), this study was registered at the Clinical Research Information Service (KCT0003279). The requirement for informed consent was waived. Electronic medical records from January 2015 to December 2017 were reviewed. Adult patients aged 65 and over who underwent surgery with neuraxial anesthesia or nerve block were listed for this study.

Anesthesia techniques: neuraxial anesthesia and nerve block

Patients were injected intramuscularly with midazolam 1-2mg and atropine 0.5mg for anti-anxiety and reduction of salivation at the ward and were transferred to the operating room. The neuraxial anesthesia technique included either spinal or combined spinal-epidural anesthesia, which was chosen according to the duration of operation. In our hospital, an optimal dose of 0.5% hyperbaric bupivacaine is used intrathecally with or without fentanyl (10-20μg). In lengthy surgeries, 0.75% ropivacaine is injected additionally through the epidural catheter placed for combined spinal-epidural anesthesia at 2 hours after surgical incision. The nerve block technique includes brachial plexus block, sciatic nerve block or combined sciatic and femoral nerve block, which are chosen according to the patient’s lesion. In our hospital, an optimal dose of 0.75% ropivacaine is used with or without 2% lidocaine under ultrasound guidance.

Intraoperative sedation

Sedation was provided to patients after confirming the proper regional anesthesia level and obtaining hemodynamic stability. The sedative agent was selected among propofol, dexmedetomidine, remifentanil, midazolam, mixed, or no agents depending on the anesthesiologist’s preference. Sedation was usually maintained to achieve an observer’s assessment of alertness/sedation (OAA/S) score of 3 or 4. For sedation, propofol (Fresofol®, Fresenius Kabi, Graz, Austria) was administered continuously via a targetcontrolled infusion device (Orchestra®, Fresenius vial, Brézins, France), and the effect-site concentration was maintained within 0.5-2.0μg/mL. Dexmedetomidine (PrecedexfM, Hospira Inc., Lake Forest, IL, USA) was diluted with 0.9% normal saline to a concentration of 4μg/mL. Dexmedetomidine of 1μg/kg was administered over a 10-min period as a loading dose and was then infused continuously at 0.1-0.5 μg/kg/h. Remifentanil (UltiAN®, Hanlim Pharm.co., LTD., Republic of Korea) was diluted with 0.9% normal saline to a concentration of 50μg/mL and then infused continuously at 0.05-0.1μg/kg/h. Midazolam (MIDAZOLAM Bukwang, Bukwang Pharrm. Co., LTD., Republic of Korea) was administered 0.5-1mg as needed according to the OAA/S score. In the case of the mixed method, midazolam and propofol or dexmedetomidine, or propofol and remifentanil, were administered.

Assessment of postoperative abnormal behavior

The Richmond agitation-sedation scale (RASS) was used to evaluate the presence of patient abnormal behaviors after surgery [14]. The postoperative daily progress notes and nursing notes were recorded regularly by doctors and nurses in charge. By evaluating these notes, we were able to determine which patients were documented with abnormal behaviors, including agitated, uncooperative, aggressive, confused, combative, violent, hallucination, delusion, or removal of catheters, plasters, or bandages. In addition, the recording of consultation for delirium with the Psychiatry Department was determined to be abnormal behavior. These descriptions of abnormal behavior corresponded roughly to RASS scores of +2, +3, or +4.

Other outcome variables

The following variables were further evaluated:

a. preoperative factors (age, gender, weight, height, body mass index, and American Society of Anesthesiologist (ASA) physical status classification)

b. intraoperative factors (surgery and anesthesia time, use of midazolam for premedication, and use of sedative drugs); and

c. postoperative factors (total admission period).

Statistical analysis

Data are presented as the mean plus or minus the standard deviation or a number (proportion). All continuous data were assessed for normality using the Shapiro-Wilk test. Incidence was analyzed by the chi-square test. The numerical data were assessed using independent t-tests, as appropriate. A binary logistic regression model was used to evaluate the predisposing factors for abnormal postoperative behavior. The dependent variable was the occurrence of abnormal postoperative behavior; and the independent variables were anesthesia method, age, gender, preoperative stroke history, preoperative depressive disorder history, use of sedative agents, and admission period. Analysis of covariance (ANCOVA) was performed to reduce the risk of confounder effects between the nerve block group and the neuraxial anesthesia group. The covariates were age, gender, preoperative stroke history, preoperative depressive disorder history, use of sedative agents, surgery type, and admission period. The dependent variable was the anesthesia method: nerve block or neuraxial anesthesia. Also, the incidence of abnormal postoperative behaviors according to the types of sedatives in elderly patients was analyzed by the Kruskal-Wallis test. All analyses were carried out using IBM® SPSS® Statistics version 22.0 (IBM Corporation, NY, USA). P<0.05 was considered statistically significant.

Results

A total of 916 patients were screened and 622 patients under 65 years old were excluded. Four cases were changed from regional anesthesia to general anesthesia due to incomplete anesthesia. Two cases were excluded due to duplicated surgery of the same patient. Nerve block and neuraxial anesthesia were performed for surgery in 209 and 79 patients, respectively (Figure 1).

Material Science

Patient characteristics and information regarding anesthesia are shown in Table 1. Demographic data were comparable between the two groups except age, gender, preoperative stroke, and depressive disorder histories, use of sedative agents, surgery type, and admission period. Preoperative stroke and depressive disorder histories were lower in the nerve block group than in the neuraxial anesthesia group (P<0.001 and P<0.001, respectively). The use of perioperative sedative agents was lower in the neuraxial anesthesia than in the nerve block group (P=0.034), and the effect of sedative agents was significantly different between the two groups (P<0.001). Surgery type was significantly different between two groups (P<0.001). Admission period was lower in the neuraxial anesthesia group than in the nerve block group (P=0.001). In order to reduce the risk of confounder effects between the two groups, ANCOVA was performed by setting age, gender, preoperative stroke history, preoperative depressive disorder history, use of sedative agents, surgery type, and admission period as covariance.

Material Science

Data are expressed as the mean±SD or the number of the patients (proportion). BMI: body mass index; ASA: American Society of Anesthesiologist classification

We found that there were significantly less postoperative agitated behaviors in the nerve block group than in the neuraxial anesthesia group (1.3% vs. 2.8%, P=0.004), which was corrected with the ANCOVA method. In the nerve block group, one of the 168 patients receiving the brachial plexus block and three of the 40 patients receiving sciatic nerve block had abnormal postoperative agitated behaviors (Table 2).

Material Science

Data are expressed as the mean±SD or the number of the patients (proportion).

The following parameters were confirmed as significant determinants for the occurrence of postoperative agitated behaviors by the binary logistic regression analysis (Table 3). Patients receiving neuraxial anesthesia were 65.26 (95% CI: 2.14- 1991.9, P=0.017) times more likely to experience postoperative agitated behaviors than patients receiving nerve block. Patients were 1.15 (95% CI: 1.03-1.29, P=0.016) times more likely to experience abnormal postoperative behaviors for each year increase in age. Men were 33.24 (95% CI: 4.24-260.7, P=0.001) times more likely to experience postoperative agitated behaviors than women.

The incidence of postoperative agitated behaviors according to the types of sedatives in elderly patients was not significantly different (p=0.217) (Table 4).

Material Science

OR: odds ratio; CI: confidence interval.

Material Science

Data are expressed as the mean±SD or the number of the patients (proportion).

Discussion

In this retrospective study, we found that surgical elderly patients under nerve block presented less postoperative agitation than those under neuraxial anesthesia. We believe that this is the first study to verify that type of regional anesthesia during surgery can affect postoperative behavioral pattern.

When assessing the data, our first consideration was whether postoperative agitated, anxious, or confused behavior was associated with postoperative delirium. Delirium can be divided into three types, hypoactive, hyperactive, or mixed type, according to the motor-activity profile [12]. Although the incidence of the hypoactive type of delirium is known to be more frequent, this study focused on symptoms of the hyperactive type. Agitation and confusion are major symptoms of hyperactive delirium. These symptoms can be a threat to patient prognosis and the safety of medical persons. Therefore, rapid diagnosis and multimodal approaches to actively prevent postoperative agitated behaviors are necessary.

Previous studies [10,11] compared general anesthesia with regional anesthesia and showed no difference in the incidence of postoperative delirium. However, the researchers did not investigate the types of regional anesthesia and the subtypes of delirium in detail. Our results specified that nerve block is associated with the reduction of agitated behavior presented in hyperactive delirium. The postoperative agitated state is related to patient safety. The type of anesthetic method is thought to be a modifiable factor, and according to our results, nerve block for surgery can be regarded as one of the preventive strategies for patients with a high possibility of postoperative hyperactive delirium.

To detect abnormal psychomotor behavior retrospectively, choosing the appropriate assessment tool is important. The confusion assessment method in the intensive care unit (CAMICU) is regarded as the standard tool for evaluating delirium [15]; however, in our study, checking CAM-ICU data retrospectively was challenging. Thus, we used RASS, which is a simpler scale than CAM-ICU, to detect any postoperative abnormal behavior. RASS was originally developed to assess the level of agitation and sedation [14]. RASS is composed of four levels of anxiety or agitation (+1 ~ +4) and 5 levels of sedation (-1 ~ -5) with a calm or alert state (0 point) as the center. Unfortunately, we were unable to prove whether the hypoactive subtype of delirium can be relieved by nerve block. Hypoactive delirium often cannot be recognized clinically, and there are limitations in evaluating the hypoactive state via a retrospective investigation [16,17]. Therefore, a precise and well-controlled prospective study may be required for this issue.

This study has a limitation to consider when interpreting its results. Because this study is retrospective in nature, the type of anesthetic method was not randomized. In addition, no specific sample size was determined. Based on a post-hoc power analysis, this study has 83.3% power with a type 1 error of 5% to detect the decreased incidence of postoperative agitated behavior in the nerve block group.

Conclusion

In conclusion, the nerve block method was associated with lowering the incidence of postoperative agitation in elderly patients undergoing surgery via regional anesthesia compared with neuraxial anesthesia. Thus, nerve block can be considered as one of the potential preventive strategies for postoperative hyperactive delirium.

Monday, April 5, 2021

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Thursday, April 1, 2021

Reversible Posterior Encephalopathy Syndrome Remission with the Complete Response in a Patient with Multiple Myeloma after Continuous Application of Bortezomib - Juniper Publishers

Juniper Online Journal of Case Studies - Juniper Publishers  


Abstract

Introduction: Bortezomib is the first generation of proteasome inhibitors and is a cornerstone drug approved for the treatment of multiple myeloma, recommended by the NCCN front-line (IA).

Case Presentation: A 61-year-old man was first attended to our hospital due to “low back and rib pain for 3 months”. He had renal insufficiency (creatinine 357μmol/L, urea nitrogen 18.8 mmol/L). After bortezomib therapy, he had altered mental status, seizures and aphasia. He was diagnosed with multiple myeloma IgG- λ light chain stage III B (DS staging) III (ISS staging), acute renal injury; posterior reversible encephalopathy syndrome. Electrocardiogram monitoring, oxygen inhalation, mannitol for dehydration were administrated. Sodium bicarbonate tablets (1mg bid), and the hydration treatment were still given to the patient, and he was suggested to drink proper water considering his poor heart and renal function.

Discussion: Proteasome inhibitors have previously been reported to cause reversible posterior encephalopathy syndrome, but the mechanism is not clear. However, we consider that the complication in this patient is caused by many factors, proteasome may not be the cause of the disease. After persistent application, the disease has been alleviated, and the reversible posterior encephalopathy syndrome has been improved. Furthermore, he exhibited very good response (VGPR) under continued bortezomib (iv once a week) therapy based on our follow-up.

Established Facts Proteasome inhibitors have previously been reported to cause reversible posterior encephalopathy syndrome, these cases all stopped application of bortezomib, and their conditions deteriorated as evidenced by a period of follow up.

Novel Insights Not all cases of PRES were caused by bortezomib. This is the first report of a patient that does not withdraw or replace bortezomib when facing PRES, and owing to bortezomib, his MM condition got clinical remission, and was accompanied by concomitant improvement in the renal function miraculously

Keywords: Bortezomib; PRES; Remission; Multiple myeloma

Introduction

Bortezomib is a cornerstone drug approved for the treatment of multiple myeloma (MM), recommended by the NCCN front-line (IA) and widely used at home and abroad [1,2]. The most common adverse reaction is peripheral neuropathy, which attracts great attention in clinical practice [3]. However, there are few reports of central nervous system lesions, posterior reversible encephalopathy syndrome (PRES) is one of them. The clinical manifestations of PRES comprise unexplained headache, blurred or low level of consciousness, visual changes, epileptic seizures, intractable hypertension, and characteristic neuroimaging manifestations of posterior white matter edema [4].

We herein report on a PRES case occurred in the bortezomib therapy of multiple myeloma. Clinicians should weigh and consider the balance of risks and benefits, as we look forward to a wider and safer application of bortezomib in hematological disease.

Case Presentation

In August 2018, a 61-year-old man was first attended to our hospital due to “low back and rib pain for 3 months”. He had hypertension for 20 years, peak blood pressure could reach 180/110mmHg, and has taken metoprolol tartrate tablets 25mg twice a day for a long-term administration, his blood pressure was controlled at 150/70mmHg for a long time. He had diabetes mellitus for 5 years, and now takes metformin 1000mg 6AM, but was not well controlled. He has mitral valve prolapse with regurgitation for 5 years but wasn’t given special treatment. Atrial fibrillation for more than 3 years, with no anticoagulant drug. Physical examination after admission showed clear mind. The tremors could be touched in the precordial area. Abdomen is soft, but tenderness and rebound pain exist in the left lower abdomen. Laboratory evaluation suggested that the patient had hypercalcemia (calcium 3.64mmol/L), renal insufficiency (creatinine 357μmol / L, urea nitrogen 18.8mmol / L), hyperuricemia (uric acid 814μmol / L), hyperglycemia (glucose 12.0mmol/L), moderate anemia and thrombocytopenia. Serum IgG 41.40g/L, IgA 0.15g/L, IgM 0.11g/L, complement C30.78g / L, κ light chain 1.36g/L, λ light chain 24.90g/L, urine κ and λ light chain were undetectable, blood immunofixation electrophoresis (IFE) showed IgG-λ monoclonal band and a light chain λ monoclonal band. Urinary IFE showed a monoclonal band of free light chain λ. Bone marrow biopsy showed CD38+ plasma cells 34.8%, expressing CD45dim, CD38, clambdaCD138, PCR showed MAGE-C1/CT7(+), bone marrow showed immature plasma cells 93%. Echocardiography showed LVEF was 66%. FISH result (CCND1, 1q21, p53, 13q-, FGFR3, MAF) was normal.

The patient was diagnosed as multiple myeloma IgG- λ light chain stage III B (DS staging) III (ISS staging); acute renal dysfunction; hypertension grade 3 (very high risk); type 2 diabetes mellitus; atrial fibrillation and hypercalcemia. In light of the diagnosis and echocardiographic results, we decided to treat this patient with PAD plan, that is bortezomib (1.3mg/m2, 2.5mg weekly i.v.) in combination with dexamethasone (40mg, d1-4, i.v.) and liposome doxorubicin (40mg, d1, i.v.), which started on August 7th, 2018. At the same time, Sodium bicarbonate tablets (1mg bid), low-molecular-weight heparin and the hydration treatment were given to the patient, and he was suggested to drink proper water during the day.

On August 12th, five days after the first infusion of bortezomib, he acutely developed altered mental status, drowsiness, accompanied by intermittent restlessness and expression indifferent. A neurological examination showed aphasia, adjustment and convergence reflexes disappearing. Laboratory test revealed hypercoagulable state of blood (fibrinogen 133.6mg/ dl, D-Dimer 0.55mg/l FEU). Cerebral computed tomography (CT) scan was failed to perform due to his restlessness. On August 13th, the vital signs were stable, but the mental status did not improve significantly, accompanied by occasionally cough. Physical examination showed sleepiness, delirium and failing to communicate. No seizures had been observed and his blood pressure fluctuation was between 140-152/80-96mmHg. There was no obvious abnormality in the blood ammonia, electrolytes level and imaging examination. Nuchal rigidity was present, and 3 fingers were engraved onto the chest. Cranial CT showed multiple bone destruction of skull with small nodules at the top of the skull, considering MM metastasis, and senile brain changes. Craniocerebral magnetic resonance imaging (MRI) plain scan plus diffusion showed senile brain changes and multiple bone destruction of skull. The imaging examination above demonstrated no new lesions compared with before in the year of 2018. In view of the urgent need for the treatment of multiple myeloma, after fully communicating with family members, the second dose of bortezomib was still given on August 14th. Dramatically, over two preceding days, his state of mind and spirit improved day by day, and the vital signs were stable until 16th. Physical examination showed mental clarity, but he was found to have a right deviation of the tongue. Previous data exhibited that there were reports of disturbance of consciousness caused by drug-induced white matter lesions, so chemotherapy was suspended, and then the changes of the patient’s condition were closely observed. On the 19th, cranial MRA showed no obvious abnormality. Whereas a repeat examination of the cranial MRI suggested mild white matter degeneration. During this period, the symptoms had improved a lot except for the deviating tongue, and patient’s family agreed to continue the chemotherapy, so we gave the third dose of bortezomib in this course of treatment. The creatinine of the patients was significantly lower than that before admission. He achieved clinical remission after 3 cycles of regimen and had clear speech, however, his right tongue did not recover.

Discussion

PRES is a rare but fatal clinic-radiological syndrome associated with reversible nervous system impairment and typical imaging alterations, was first put forward by Hinchey in 1996 [5]. However, its pathophysiological mechanism is the subject of ongoing investigation. Causes include accelerated hypertension (most common); all kinds of serious kidney diseases (acute glomerulonephritis, chronic renal failure); employment of immunosuppressive agents or cytotoxic drugs, such as immunoglobulin, interferon, cyclosporine, after organ transplantation; and so on [6]. It can be visible at any age, more often in young females. Clinical features contain a sudden elevation of blood pressure; headache; visual disturbance; seizures and altered mental status [7]. CT scan lacks specificity, MRI shows angiogenetic edema in both posterior cerebral hemispheres [8]. Diagnosis depends on predisposing factor, reversible symptoms and radiography. Delay of recognition diagnosis and treatment would result in permanent sequelae, so prompt diagnosis and treatment are of great clinical importance.

Bortezomib is the first generation of proteasome inhibitors with antiangiogenic and proapoptotic properties, while carfilzomib, newly appears on the market, is the second, they both have been reported to associated with PRES, of which plasma hematological diseases account for eleven cases, one was Waldenström macroglobulinaemia, a kind of inert small granulocyte lymphoma, the other ten were all MM (including this case).

The characteristics of total eleven cases related to bortezomib reported are outlined in Table 1 & 2 [9-18]. Among these cases, male only account for 3/11; all experienced hypertension during PRES attacks; a half mentioned had varied degrees of renal injury; all of them had specific clinical features and imaging changes. Their treatment for PRES was essentially symptomatic, such as anti-hypertension and sedatives. Improvement or complete resolution of changes on repeat neuroimaging and clinical status are relatively constant findings.

We herein present a newly diagnosed and treated MM patient who had headache, visual disturbance and an altered mental status five days after the first dose of bortezomib use. CT and MRI excluded the possibility of intracranial space occupying lesion, cerebral hemorrhage and infarction. A presumptive diagnosis of PRES was made due to the typical symptoms and mild white matter lesions of MRI. Optical microscope morphological observation and Hoechst33258 nuclear fluorescence staining results showed bortezomib of 0.03μM, 0.3μM and 3μM could dose-dependently induce apoptosis in primary cultured cerebral cortical neurons of rats [19], suggesting that bortezomib could go through the blood brain barrier and accumulate in the brain, damaging the nervous system. Considering the high correlation in time and the nervous system damage of bortezomib, bortezomib has become a key suspect in causing this comorbidity.

We thought in-depth what was the real causes of this patient’s PRES? Most of PRES occur when the overall conditions of patients are poor. In the same time, it needs to be taken into account that first, this patient had MM, free light chain, uric acid and calcium might deposited in kidney, leading to a high level of creatinine, but we didn’t pay close attention to hydration at the same time of chemotherapy, resulting in progressive deterioration of renal function. Second, this patient had a long term of hypertension, his blood pressure fluctuated at around 150/90mmHg during hospitalization. They are all stablished causes of PRES. Although PRES occurred after the use of bortezomib, the drug seemed to act as the last straw of the occurrence of PRES. We assume that the past diseases mentioned above together with the additional effects of bortezomib synthetically contributed to the occurrence of PRES.

Generally speaking, the clinical process of PRES is reversible and the prognosis is good. The overall prognosis depends on the condition of underlying diseases [20,21]. Through literature review, we found that there were 4 cases that didn’t have further treatment for MM during the recovery of PRES, their conditions deteriorated as evidenced by a period of follow up, unfortunately, they ultimately passed away from progressive myeloma. Based on these considerations, we intended to continue to use bortezomib to treat MM in this case, after communicating with his family the risks and benefits of bortezomib, his family agreed to continue the drug. When we continue to use bortezomib, his nervous symptom became remission, so bortezomib might not be the arch-criminal of PRES.

In contrast to the other ten cases, this case is unique in continuation treatment of bortezomib after recovery of clinical symptoms. This is the first report of a patient that does not withdraw or replace bortezomib when facing PRES. Since then, the symptom resolved except for right deviation of the tongue and MRI performed 7 months later still had white matter lesion in bilateral lateral ventricle. The cause of not completely recover might be contributed to the continuation of bortezomib or other factors mentioned above, it is a comprehensive outcome that couldn’t blame on the use of bortezomib. But these irreversible symptoms don’t influence patient’s daily life, and owing to bortezomib, his MM condition got clinical remission, and was accompanied by concomitant improvement in the renal function miraculously. For patients who are first diagnosed with PRES, especially accompanied by renal failure, doctors should keep a careful eye on the lipid intake and output and give prompt administration of hydration to prevent excessive blood drug concentration. Continuous administration under effective control is advised because bortezomib is a very efficient drug for MM.

Conclusion

Programs comprising bortezomib are increasingly being used in treatment for plasma cell disorders, so physicians, as well as pharmacists, should be alert to the complication caused by bortezomib and be aware of the relationship between PRES and bortezomib. PRES is caused by comprehensive factors, doctors need to screen carefully whether PRES is associated with bortezomib or not. Bortezomib should not be rudely rejected, so that patients cannot get relief from the disease.

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