Breakdown of Relations: American Expansionism, the Great Plains, and the Arikara People, 1823-1957

Arikara people had been adapting their tribal structures to European influences since Europeans first arrived on the northern Plains in the early seventeenth century. Their sedentary lifestyle, focused on agriculture and hunting, increasingly included trade with French, British, and American trappers by the seventeenth century. The goods procured from European traders, such as firearms and other metallurgical works, began to upset the balance of geopolitical power on the Plains, setting the stage for the violence and political realignments at the center of this thesis. As my research reveals, by the time of the Lewis and Clark expedition, tensions between the frontiersmen and the Indigenous people across the northern Plains reached new heights. As Arikara oral histories, United States diplomatic records, ethnological sources – such as travel writings – and correspondence from frontier settlers and soldiers reveal, the Arikara tribe struggled to innovate and reshape their societies in the face of colonial expansionism and hostilities with other Indigenous polities

Altering the Regiospecificity of C6 Indole Prenyltransferase Enzymes Towards Drug Development

Prenyltransferase (PT) biocatalysts are late-stage tailoring enzymes that modify natural products. PTs catalyze the attachment of prenyl moieties to natural product acceptors using pyrophosphate donors. This prenyl modification in small molecules leads to changes in structural and biological activities. Understanding the structural insights as well as the mechanisms by which PTs function allows us to utilize PTs as a unique approach towards drug development. PriB PT is an example of aromatic PTs that has been characterized previously as a L-tryptophan (L-Trp) C6 C-prenyltransferase (C6-C-PT). Analysis of PriB binding pocket, highlighted key residues that might play an important role in determining the regiospecificity of the enzyme and their mechanisms. Hence, we hypothesized that site-directed mutagenesis of one of these residues will alter the enzyme regiospecificity and/or its permissiveness leading to variation in the pharmacokinetics and biological activities of small molecules. Site-directed mutagenesis approach was used to engineer PriB PT as a model for C6-PTs and the purified mutant proteins were produced and purified. In vitro reactions of the purified engineered proteins have shown altered regiospecificity toward substrate acceptors when compared to wild type. The long-term goal for this study is to utilize the permissiveness of PriB enzyme for drug diversification and determine the activity of the mutant PriB enzymes. This study will also shed some light on the mechanistic insights of aromatic C6-PTs

Manejo quirúrgico del miembro superior en la artrogriposis múltiple congénita

Se realiza un estudio de carácter retrospectivo descriptivo sobre el manejo quirúrgico que recibieron 16 pacientes con artrogriposis múltiple congenita en un período de 10 años, desde enero de 1983 a diciembre de 1993. Se observó que el sexo predominante fue el masculino en una proporción de 2:1. La edad media en el momento de la intervención fue de 5 años. Las operaciones fueron realizadas con mayor frecuencia en los dedos, seguidas de las practicadas en las muñecas, codo y hombro. Las intervenciones en el codo fueron todas destinadas a corregir la ausencia de flexión mediante transferencia del pectoral mayor al radio acompañadas de la estabilización del hombro mediante la transferencia del trapecio al deltoides. El tratamiento de los problemas en el miembro superior por artrogriposis deben enfocarse desde un punto multidisciplinario procurando en el paciente mayor independencia personal y adaptación social.A retrospective study was undertaken to review the surgeries performed in upper limbs of arthrogryphotic children in a period of 10 years, from January 1983 to December 1993 on a total of 16 patients. Sex ratio was 2:1, male:female. Mean age at surgery was 5 years. Operations were performed predominantly in fingers, followed by wrist, elbow and shoulder. At the elbow, surgeries were made to adquire active flexion by muscle traslocation. The operations performed arc analized and results discussed. Some recomendations for treatment are given

Exploring the Support Needs of Family Caregivers of Patients with Brain Cancer Using the CSNAT: A Comparative Study with Other Cancer Groups

A substantial burden is placed on family caregivers of patients diagnosed with brain cancers. Despite this, the support needs of the caregivers are often under-recognised and not addressed adequately in current routine and patient centred clinical care. The Care Support Needs Assessment Tool (CSNAT) is a validated instrument designed to systematically identify and address caregiver needs. It has been trialled in an Australian palliative care community setting using a stepped wedge cluster design involving 322 family carers of terminally ill patients. The current article reports on a subset from this trial, 29 caregivers of patients with primary brain cancer, and compares their profile and outcomes to those of other cancer groups. Caregiver strain was assessed using the Family Appraisal of Caregiving Questionnaire, caregiver physical and mental wellbeing using SF12 and caregiver workload using a questionnaire on support with activities of daily living (ADL). In comparison to caregivers of patients with all other cancers, the primary brain cancer group had significantly higher levels of caregiver strain, lower levels of mental wellbeing and a higher level of ADL workload. Their physical wellness also deteriorated significantly over time.An action plan approach led to practical solutions for addressing highlighted concerns. Four themes evolved from the family caregivers’ feedback interviews: The extremely challenging caregiver experience with brain cancer; the systematic and practical approach of the CSNAT during rapid changes; connection with health professionals, feeling acknowledged and empowered; and timely advice and assurance of support during the caregiving journey. This preliminary study has demonstrated that the CSNAT provides a practical and useful tool for assessing the support needs of family caregivers of patients with brain cancer and has provided the basis for a larger scale, longitudinal study that allows a more detailed characterisation of the evolving caregiver needs at different stages of the disease

Why and how the work of Motor Neurone Disease Associations matters before and during bereavement: a consumer perspective

Background: Studies on the experiences of consumers with Motor Neurone Disease Associations at end of life and bereavement are lacking, and their role and capability within the broader sectors of health and disability are unknown. Objectives: To ascertain the experiences and views of bereaved motor neurone disease caregivers with Motor Neurone Disease Associations about service gaps and needed improvements before and during bereavement and to propose a model of care that fits with consumer preferences and where Motor Neurone Disease Associations are effective enablers of care. Methods: A national bereavement survey was facilitated in 2019 by all Motor Neurone Disease Associations in Australia. A total of 363 respondents completed the section on support provided by Motor Neurone Disease Associations. A mixed-method design was used. Results: Respondents were generally positive about support received before bereavement (73-76%), except for emotional support (55%). Positive experiences related to the following: information, equipment advice/provision, advocacy/linking to services, showing empathy/understanding, personal contact and peer social support. Negative experiences included lack of continuity in case management and contact, perceived lack of competence or training, lack of emotional support and a lack of access to motor neurone disease services in rural areas. Suggested improvements were as follows: more contact and compassion at end of life and postdeath; better preparation for end of life; option of discussing euthanasia; providing referrals and links for counseling; access to caregiver support groups and peer interaction; provision of a genuine continuum of care rather than postdeath abandonment; guidance regarding postdeath practicalities; and more access to bereavement support in rural areas. Conclusion: This study provides consumer perspectives on driving new or improved initiatives by Motor Neurone Disease Associations and the need for a national standardised approach to training and service delivery, based on research evidence. A public health approach to motor neurone disease end-of-life care, of international applicability, is proposed to address the needs and preferences of motor neurone disease consumers, while supporting the capability of Motor Neurone Disease Associations within a multidisciplinary workforce to deliver that care

Product Service System Innovation in the Smart City

Product service systems (PSS) may usefully form part of the mix of innovations necessary to move society toward more sustainable futures. However, despite such potential, PSS implementation is highly uneven and limited. Drawing on an alternate socio-technical perspective of innovation, this paper provides fresh insights, on among other things the role of context in PSS innovation, to address this issue. Case study research is presented focusing on a use orientated PSS in an urban environment: the Copenhagen city bike scheme. The paper shows that PSS innovation is a situated complex process, shaped by actors and knowledge from other locales. It argues that further research is needed to investigate how actors interests shape PSS innovation. It recommends that institutional spaces should be provided in governance landscapes associated with urban environments to enable legitimate PSS concepts to co-evolve in light of locally articulated sustainability principles and priorities

Frequency of Drug Resistance Gene Amplification in Clinical Leishmania Strains

Experimental studies about Leishmania resistance to metal and antifolates have pointed out that gene amplification is one of the main mechanisms of drug detoxification. Amplified genes code for adenosine triphosphate-dependent transporters (multidrug resistance and P-glycoproteins P), enzymes involved in trypanothione pathway, particularly gamma glutamyl cysteine synthase, and others involved in folates metabolism, such as dihydrofolate reductase and pterine reductase. The aim of this study was to detect and quantify the amplification of these genes in clinical strains of visceral leishmaniasis agents: Leishmania infantum, L. donovani, and L. archibaldi. Relative quantification experiments by means of real-time polymerase chain reaction showed that multidrug resistance gene amplification is the more frequent event. For P-glycoproteins P and dihydrofolate reductase genes, level of amplification was comparable to the level observed after in vitro selection of resistant clones. Gene amplification is therefore a common phenomenon in wild strains concurring to Leishmania genomic plasticity. This finding, which corroborates results of experimental studies, supports a better understanding of metal resistance selection and spreading in endemic areas

Hospital postdischarge intervention trialled with family caregivers of older people in Western Australia: potential translation into practice

There is lack of a suitable assessment tool that can be used routinely and systematically by hospital staff to address family caregivers' (FCs') support needs. This paper describes a novel approach to identifying and addressing FCs' needs following hospital discharge of the older person receiving care. SETTING AND PARTICIPANTS: FC recruitment occurred on the patient's discharge from a tertiary hospital in Western Australia; 64 completed the study; 80% were female; mean age 63.2 years. INTERVENTION: The Further Enabling Care at Home (FECH) programme was delivered over the telephone by a specially trained nurse and included: support to facilitate understanding of the patient's discharge letter; caregiver support needs assessment and prioritisation of urgent needs; and collaborative guidance, from the nurse, regarding accessing supports. RESULTS: Sixty-four FCs completed the FECH programme. The top three support needs identified by the FCs were: knowing what to expect in the future (52%), knowing who to contact if they were concerned (52%) and practical help in the home (36%). The telephone-based outreach service worked well and was convenient for the nurse and the FCs, and saved on transport, time and money. Most of the FCs appreciated the systematic approach to identify and articulate their needs and were satisfied with the support they received, mainly navigation through the systems, problem solving, self-care strategies, explanation of illness, symptoms and medication and access to after-hours services. CONCLUSIONS: In order to guide services which may consider adopting this systematic approach to supporting FCs and integrating it into their routine practice, this evaluation of the FECH programme has described the processes implemented and highlighted the factors that hindered or facilitated these processes to engage caregivers with appropriate services in a timely manner. Positive feedback indicated that the programme was a useful addition to hospital discharge planning. TRIAL REGISTRATION NUMBER: ACTRN12614001174673; Results

Structure-Guided Mutagenesis Reveals the Catalytic Residue that Controls the Regiospecificity of C6-Indole Prenyltransferases

Indole is a significant structural moiety and functionalization of the C−H bond in indole-containing molecules expands their chemical space, and modifies their properties and/or activities. Indole prenyltransferases (IPTs) catalyze the direct regiospecific installation of prenyl moieties on indole-derived compounds. IPTs have shown relaxed substrate flexibility enabling them to be used as tools for indole functionalization. However, the mechanism by which certain IPTs target a specific carbon position is not fully understood. Herein, we use structure-guided site-directed mutagenesis, in vitro enzymatic reactions, kinetics and structural-elucidation of analogs to verify the key catalytic residues that control the regiospecificity of all characterized regiospecific C6 IPTs. The presented results also demonstrate that substitution of PriB_His312 to Tyr leads to the synthesis of analogs prenylated at different positions than C6. This work contributes to understanding of how certain IPTs can access a challenging position in indole-derived compounds