Novel insights into the role of the GABAB receptor in depression and anxiety

The GABAB receptor is a functional heterodimer comprising the GABAB1 and GABAB2 subunits, with the GABAB1 subunit displaying two major isoforms, GABAB(1a) and GABAB(1b). Preclinical findings have strongly implicated the GABAB receptor in stress-related psychiatric disorders, however, the precise contribution of the GABAB receptor in depression and anxiety disorders remains unknown. Emerging data suggest that the interaction between adverse environmental conditions, such as early life stress, and a specific genetic composition can increase the risk to develop psychiatric disorders in adulthood. This thesis investigated the role of the GABAB receptor alone or in combination with early-life stress (maternal separation), in modulating antidepressant like and anxiety-related behaviours. Pharmacological blockade of the GABAB receptor with CGP52432 had antidepressant-like behavioural effects. Moreover, mice lacking the GABAB(1b) receptor subunit isoform exhibited antidepressant-like behaviours in adulthood but anxiety-like behaviour in early-life. In response to maternal separation, GABAB(1a)-/- mice exhibited early-life stress-induced anhedonia, a core symptom of depression, while GABAB(1b)-/- mice exhibited a more resilient phenotype. Moreover, when compared with wildtype or GABAB(1a)-/- mice, GABAB(1b)-/- mice that underwent maternal separation exhibited enhanced stressinduced neuronal activation in the hippocampus and in the nucleus accumbens (NAcc), a critical area for anhedonia thus suggesting that enhanced stress-induced neuronal activation in the hippocampus and NAcc in GABAB(1b)-/- mice may be important for their antidepressant-like phenotype and their resilience to stress-induced anhedonia. Pharmacological blockade of GABAB receptor and GABAB(1b) receptor subunit isoform loss of function increased adult hippocampal cell proliferation, thus suggesting that increased hippocampal neurogenesis could be a potential mechanism for the antidepressant-like effects of GABAB receptor antagonists and GABAB(1b) receptor subunit isoform disruption. Finally, this thesis investigated whether the expression of several genes involved in hippocampal neurogenesis or the antidepressant response were altered in the mouse hippocampus following chronic treatment with a GABAB receptor antagonist.

Vascular calcification and mineral bone disorder in chronic kidney disease

Chronic Kidney Disease (CKD), osteoporosis and mild hyponatremia are all prevalent chronic conditions that may coexist and are often under-recognized. Mineral-Bone Disorder begins early in the natural history of CKD and results in complex abnormalities of bone which ultimately confers a well-established increased risk of fragility fractures in End Stage Kidney Disease. Hyponatremia is a novel, usually renal mediated metabolic perturbation, that most commonly occurs independently of the stage of renal dysfunction but which may also predispose to increased fracture risk. The extent -if any- to which either early stages of renal dysfunction or the presence of hyponatremia contribute to fracture occurrence in the general population, independently of osteoporosis, is unclear. Renal transplantation is the treatment of choice for ESKD and although it restores endogenous renal function it typically fails to normalize either the long term cardiovascular or fracture risk. One potential mechanism contributing to these elevated long-term risks and to diminished Health Related Quality of Life is persistent, post-transplant hyperparathyroidism. In this study we retrospectively examine the association of renal function and serum sodium with Bone Mineral Density and fracture occurrence in a retrospective cohort of 1930 female members of the general population who underwent routine DXA scan. We then prospectively recruited a cohort of 90 renal transplant recipients in order to examine the association of post transplant parathyroid hormone (PTH) level with measures of CKD Mineral Bone Disorder, including, DXA Bone Mineral Density, Vascular Calcification (assessed using both abdominal radiography and CT techniques, as well as indirectly by carotid-femoral Pulse Wave Velocity) and Quality of Life (using the Short Form-12 and a PTH specific symptom score). In the retrospective DXA cohort, moderate CKD (eGFR 30-59ml/min/1.73m2) and hyponatremia (<135mmol/L) were associated with fracture occurrence, independently of BMD, with an adjusted Odds Ratio (95% Confidence Interval), of 1.37 (1.0, 1.89) and 2.25 (1.24, 4.09) respectively. In the renal transplant study, PTH was independently associated with the presence of osteoporosis, adjusted Odds Ratio (95% Confidence Interval), 1.15 (per 10ng/ml increment), (1.04, 1.26). The presence of osteoporosis but not PTH was independently associated with measures of vascular calcification, adjusted ß (95% Confidence Interval), 12.45, (1.16, 23.75). Of the eight quality-of-life domains examined, post-transplant PTH (per 10ng/ml increment), was only significantly and independently associated with reduced Physical Functioning, (95% Confidence Interval), 1.12 (1.01, 1.23). CKD and hyponatremia are both common health problems that may contribute to fracture occurrence in the general population, a major on-going public health concern. PTH and decreased Bone Mineral Density may signal sub-optimal long-term outcomes post renal transplantation, influencing bone and vascular health and to a limited extent long term Health Related Quality of Life

Fas ligand expression and tumour immune evasion; the role of prostaglandin E2 and the EP1 receptor

Background and Aim: During carcinogenesis, tumours develop multiple mechanisms to evade the immune system and suppress the anti-tumour immune response. Upregulation of Fas Ligand (FasL/CD95L) expression may represent one such mechanism. FasL is a member of the tumour necrosis factor superfamily that triggers apoptotic cell death following ligation to its receptor Fas. Numerous studies have demonstrated upregulated FasL expression in tumor cells, with FasL expression associated with numerous pro-tumorigenic effects. However, little is known about the mechanisms that regulate FasL expression in tumours. The cyclooxgenase (COX) signalling pathway may play an important role in colon carcinogenesis, via the production of prostaglandins, in particular PGE2. PGE2 signals through four different receptor subtypes, EP1 – EP4. Thus, the aim of this study was to investigate the effect of targeting the PGE2-FasL signaling pathway. Results: (i) PGE2 induces FasL expression via the EP1 receptor in colon cancer cells. (ii) Suppression of FasL expression in colon tumour cells in vivo significantly delays and reduces tumour growth. (iii) Blocking EP1 receptor signaling, or suppression of the EP1 receptor in colon tumour cells, reduces tumour growth in vivo. Suppression of tumour growth correlates in part with suppression of FasL expression. (iv) The reduction in tumour growth is associated with an improved anti-tumour immune response. Tumour infiltration by Treg cells and macrophages was reduced, and the cytotoxic activity of CTL generated from splenocytes isolated from these mice increased. Conclusion: 1) Targeting FasL expression by blocking PGE2-EP1 receptor signalling reduces tumour development in vivo. 2) The mechanism is indirect but is associated with an increased anti-tumour immune response. Thus, unraveling the mechanisms regulating FasL expression and the pro-tumorigenic effects of the EP1 receptor may aid in the search for new therapeutic targets against colon cancer.

College adjustment, depressive symptoms and peer support among undergraduate university students

Background: College adjustment is a developmental milestone that can be stressful and may lead to mental health problems such as depression. Support during this adjustment period is seen as essential, however it is unknown if informal peer support from fellow students has any impact on either college adjustment or depressive symptoms. Aim: To identify levels of social and personal college adjustment, depressive symptoms and peer support among students, and to examine the relationship between the variables. Design: A quantitative correlational design was used Instruments: Data were collected using two subscales of the Student Adaptation to College Questionnaire; the Centre for Epidemiology Depressive Symptoms Scale and a subscale of the Peer Support Evaluation Inventory. Sample: The sample consisted of 417, first (n=188), second (n=134) and fourth (n=94) year nursing and midwifery students from one University in Ireland. Findings: The findings indicated that 20% of participants were poorly personally adjusted and 9% poorly socially adjusted. Furthermore, 34% of participants experienced significant depressive symptoms. Most students had good levels of peer support. Statistically significant relationships were found between all key variables, the strongest of which were between personal adjustment and depressive symptoms and social adjustment and depressive symptoms. Differences in adjustment and depressive symptom scores were found based on year of study, with second year students experiencing more depressive symptoms and having poorer personal adjustment scores. Participants who had poor relationships with their father’s experienced greater depressive symptoms and had more difficulties personally and socially adjusting to college. The alcohol consumption of participants had a statistically significant correlation with college adjustment, depressive symptoms and peer support, with higher consumption having a positive impact on the variables.

Accommodating interruptions: a grounded theory of young people with asthma

Background: Accommodating Interruptions is a theory that emerged in the context of young people who have asthma. A background to the prevalence and management of asthma in Ireland is given to situate the theory. Ireland has the fourth highest incidence of asthma in the world, with almost one in five Irish young people having asthma. Although national and international asthma management guidelines exist it is accepted that the symptom control of asthma among the young people population is poor. Aim: The aim of this research is to investigate the lives of young people who have asthma, to allow for a deeper understanding of the issues affecting them. Methods: This research was undertaken using a Classic Grounded Theory approach. It is a systematic approach to allowing conceptual emergence from data in generating a theory that explains behaviour in resolving the participant’s main concern. The data were collected through in-depth interviews with young people aged 11-16 years who had asthma for over one year. Data were also collected from participant diaries. Constant comparative analysis, theoretical coding and memo writing were used to develop the theory. Results: The theory explains how young people resolve their main concern of being restricted, by maximizing their participation and inclusion in activities, events and relationships in spite of their asthma. They achieve this by accommodating interruptions in their lives in minimizing the effects of asthma on their everyday lives. Conclusion: The theory of accommodating interruptions explains young people’s asthma management behaviours in a new way. It allows us to understand how and why young people behave the way they do in order minimise the effect of asthma on their lives. The theory adds to the body of knowledge on young people with asthma and challenges some viewpoints regarding their behaviours.

An investigation into mechanisms of visceral pain in rodents

Visceral pain is a debilitating symptom of irritable bowel syndrome (IBS), a disorder affecting up to 30% of adults. A better understanding of the mechanisms underlying visceral hypersensitivity may facilitate development of more targeted therapies, improving the quality of life of these individuals. The studies performed in this thesis were designed to investigate important factors of visceral pain, including early-life manipulations, genetic predisposition and sex hormones. Maternal separation (MS) consistently reproduces visceral hypersensitivity and altered anxiety-like behaviours in rats, symptoms associated with IBS. It has been found that 5-HT2B receptor antagonism blocks visceral pain but no difference in relative 5-HT2B receptor mRNA expression was found in hippocampus, amygdala and colon. The neuronal activation patterns of prefrontal cortex and amygdala of MS rats were then investigated. MS animals are characterised by differential activation of the prefrontal cortex (anterior cingulate cortex (ACC), infralibic cortex, prelimbic cortex) as well as the central nucleus of the amygdala (CeA). Genetic factors also contribute to pain syndromes such as IBS. We utilised the Wistar Kyoto (WKY) rat, a stress-sensitive strain, as an animal model of brain-gut axis dysfunction. WKY rats have a lower expression of the glutamate transporter EAAT2 and mGlu4 receptor in the ACC. Another early-life factor that can increase susceptibility to functional gastrointestinal symptoms later life is disruption of the gut microbiota, thus early-life antibiotic treatment was used to assess this effect. Antibiotic treatment induced visceral hypersensitivity in adulthood and may be related to observed reductions in spinal cord alpha-2A adrenoreceptor (adra2A) mRNA. Lastly, we investigated sex differences in visceral sensitivity. EAAT1 & 2 mRNA levels are lower in females, potentially increasing glutamatergic concentration at the symaptic level. Moreover, NR1 and NR2B subunits mRNA of NMDA receptor were increased in caudal ACC of females. These findings may account for sex differences in visceral sensitivity.

A study of the regulation of Trib family members expression in normal and malignant haematopoiesis

The Tribbles family of genes consist of three members; TRIB1, TRIB2 and TRIB3. Trib1 and Trib2 have been identified as oncogenes that can induce AML in mice. However little is known about how the expressions of the Tribbles family genes are controlled in the cell during haematopoiesis or leukaemogenesis. To investigate the Tribbles genes in leukaemia a bioinformatics approach was used. TRIB2 expression was found to be elevated in T-ALL and ALL with t(1;19). TRIB1 was found not to be significantly elevated in any leukaemic subtypes. Analyses of the TRIB1 and TRIB2 gene signatures in both leukaemic and normal haematopoietic cells identified pathways and transcription factors associated with these signatures. Pathways enriched for the TRIB1 signature included TLR signalling pathways and NF-κB pathways. Transcription factors enriched for this signature include C/EBP and SRF. Enriched for the TRIB2 signature includes T cell signalling pathways and Notch signalling pathways. Transcription factors enriched for this signature include E2F and ETS. Further investigation in vitro confirmed the finding that E2F1 was as a potential regulator of TRIB2 expression. E2F1 is able to directly bind to the TRIB2 promoter region and induce TRIB2 expression. C/EBPα p42 was found to inhibit E2F1 and the p30 isoform was found to cooperate with E2F1 induced activation of the TRIB2 promoter. Indicating the potential presence of a regulatory loop involved in the regulation of the TRIB2 gene. In conclusion we have investigated the Tribbles gene signatures in both normal haematopoietic and leukaemic cells. This has led to the identification of a number of pathways and transcription factors associated with these genes. We have also identified a family of transcription factors directly responsible for the regulation of TRIB2 expression. This regulatory pathway has the potential to be targeted in the treatment of leukaemia with a high TRIB2 signature.

Cancer related fatigue and self-care while undergoing chemotherapy: patients' perspectives

Background: Cancer related fatigue (CRF) is considered the most severe, debilitating and under-managed symptom of cancer. Patients receiving chemotherapy experience high levels of CRF which profoundly impacts on their lives. Aim: 1). To explore and measure CRF and determine the most effective self-care strategies used to combat CRF in a cohort of patients with a diagnosis of cancer (breast cancer, colorectal cancer, Hodgkin’s and Non-Hodgkin’s lymphoma) 2). To explore self-care agency and its relationship to CRF. Method: A mixed methods study which incorporated a descriptive, comparative, correlational design and qualitative descriptions of patients’ (n=362) experiences gleaned through open ended questions and use of a diary. The study utilised The Revised Pipers Fatigue Scale, the Appraisal of Self-Care Agency and a researcher developed Fatigue Visual Analogue Scale, Fatigue Self-Care Survey, and Diary. Findings: Having breast cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma; using the strategies of counselling, taking a 20–30 minute nap, resting and sleeping, self-monitoring and complementary therapies were all associated with increased odds of developing fatigue. Increased self-care agency; being in the divorced / separated cohort; being widowed; increased length of time since commencement of chemotherapy; engagement in exercise, and socializing were associated with a reduced risk of developing fatigue. Females had 20% higher fatigue levels than males (p=<.001). Receiving support was the strategy used most frequently and rated most effective. Fatigue was very problematic and distressing, four key qualitative categories emerged: the behavioural impact, affective impact, the sensory impact, and the cognitive impact. Keeping a diary was considered very beneficial and cathartic. Conclusions: Fatigue severely impacted on the daily lives of patients undergoing chemotherapy. There are a range of self-care strategies that patients should be encouraged to use e.g. exercise, socializing, and enhancement of psychological well-being. The enhancement of self-care agency and use of diaries should also be considered.

Cancer associated malnutrition: prevalence of cachexia, sarcopenia and impact on treatment outcomes, survival and health related quality of life

Malnutrition, sarcopenia and cancer cachexia (CC) are prevalent among cancer patients and can have detrimental effects on clinical outcomes such as quality of life (QoL) and overall survival. Cachexia is associated with lower tolerance for chemotherapy, which limits the total dose that can be delivered, the number of symptomatic responses and any survival advantage that might be accrued. Moreover, for the majority who do not respond, cachexia may be exacerbated by systemic chemotherapy, thus increasing the net symptom burden experienced by patients. The multitude of interactions between cancer location, treatments, nutritional status and QoL has never been thoroughly explored in an Irish cancer cohort. The objectives of this thesis were to further understand nutritional status, especially body composition in ambulatory cancer patients and determine the relationship between nutritional status using different assessment criteria and QoL, chemotherapy toxicity and survival among cancer patients undergoing chemotherapy. Results aimed to identify baseline factors that may be predictive of poor outcome, toxicities to chemotherapy and disease-free and overall survival. This thesis broadly divides into two sections. The first section (Chapters 3 & 4) focuses on improving our knowledge of the nutritional status of Irish cancer outpatients using a cross sectional study design. A study of 517 patients referred for chemotherapy was conducted using computed tomography (CT) imaging (body composition) and a survey that documented oncologic data, weight loss (WL) data and QoL data. We revealed that a significant proportion of Irish cancer patients undergoing chemotherapy experience unintentional WL over the previous 6 months (62%), sarcopenia (45%) and CC (43%), and the distribution of WL and nutritional risk were associated with site of primary tumour and treatment intent. Patients that had sarcopenia, nutritional risk, or CC had significantly reduced functional abilities, more symptoms and adverse global QoL. In the second section of this thesis (Chapters 5 & 6) the potential link between developing toxicity to antineoplastic regimens in patients with sarcopenia was conducted by way of retrospective studies. A retrospective serial CT analysis defined the prevalence of sarcopenia in patients with metastatic renal cell carcinoma (mRCC) and metastatic castrate resistant prostate cancer (mCRPC), which was then correlated with dose limiting toxicities of sunitinib and docetaxel respectively. Sarcopenia was prevalent in patients with mRCC and mCRPC, was an occult condition in patients with normal/high BMI, was associated with less treatment days, was a significant predictor of DLT in patients receiving sunitinib and a significant predictor of neutropenia and neurosensory toxicities in patients receiving docetaxel. This thesis attempted to address the underlying research deficiencies in Irish oncology nutritional data at national level. The findings from this thesis have implications for the planning of cancer care interventions and indicate that further research is required to improve nutritional screening, in particular for CC and sarcopenia, in the hope that timely intervention can improve both patient-centered and oncologic outcomes.

Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organization for Research and Treatment of Cancer Randomized Study with cross-over.

PURPOSE: To compare the efficacy of paclitaxel versus doxorubicin given as single agents in first-line therapy of advanced breast cancer (primary end point, progression-free survival ¿PFS) and to explore the degree of cross-resistance between the two agents. PATIENTS AND METHODS: Three hundred thirty-one patients were randomized to receive either paclitaxel 200 mg/m(2), 3-hour infusion every 3 weeks, or doxorubicin 75 mg/m(2), intravenous bolus every 3 weeks. Seven courses were planned unless progression or unacceptable toxicity occurred before the seven courses were finished. Patients who progressed within the seven courses underwent early cross-over to the alternative drug, while a delayed cross-over was optional for the remainder of patients at the time of disease progression. RESULTS: Objective response in first-line therapy was significantly better (P =.003) for doxorubicin (response rate ¿RR, 41%) than for paclitaxel (RR, 25%), with doxorubicin achieving a longer median PFS (7.5 months for doxorubicin v 3.9 months for paclitaxel, P <.001). In second-line therapy, cross-over to doxorubicin (91 patients) and to paclitaxel (77 patients) gave response rates of 30% and 16%, respectively. The median survival durations of 18.3 months for doxorubicin and 15.6 months for paclitaxel were not significantly different (P =.38). The doxorubicin arm had greater toxicity, but this was counterbalanced by better symptom control. CONCLUSION: At the dosages and schedules used in the present study, doxorubicin achieves better disease and symptom control than paclitaxel in first-line treatment. Doxorubicin and paclitaxel are not totally cross-resistant, which supports further investigation of these drugs in combination or in sequence, both in advanced disease and in the adjuvant setting.

Patient-based outcome assessment instruments in acupuncture research.

BACKGROUND: Outcome assessment can support the therapeutic process by providing a way to track symptoms and functionality over time, providing insights to clinicians and patients, as well as offering a common language to discuss patient behavior/functioning. OBJECTIVES: In this article, we examine the patient-based outcome assessment (PBOA) instruments that have been used to determine outcomes in acupuncture clinical research and highlight measures that are feasible, practical, economical, reliable, valid, and responsive to clinical change. The aims of this review were to assess and identify the commonly available PBOA measures, describe a framework for identifying appropriate sets of measures, and address the challenges associated with these measures and acupuncture. Instruments were evaluated in terms of feasibility, practicality, economy, reliability, validity, and responsiveness to clinical change. METHODS: This study was a systematic review. A total of 582 abstracts were reviewed using PubMed (from inception through April 2009). RESULTS: A total of 582 citations were identified. After screening of title/abstract, 212 articles were excluded. From the remaining 370 citations, 258 manuscripts identified explicit PBOA; 112 abstracts did not include any PBOA. The five most common PBOA instruments identified were the Visual Analog Scale, Symptom Diary, Numerical Pain Rating Scales, SF-36, and depression scales such as the Beck Depression Inventory. CONCLUSIONS: The way a questionnaire or scale is administered can have an effect on the outcome. Also, developing and validating outcome measures can be costly and difficult. Therefore, reviewing the literature on existing measures before creating or modifying PBOA instruments can significantly reduce the burden of developing a new measure.

Dual-energy computed tomography with advanced postimage acquisition data processing: improved determination of urinary stone composition.

INTRODUCTION: The characterization of urinary calculi using noninvasive methods has the potential to affect clinical management. CT remains the gold standard for diagnosis of urinary calculi, but has not reliably differentiated varying stone compositions. Dual-energy CT (DECT) has emerged as a technology to improve CT characterization of anatomic structures. This study aims to assess the ability of DECT to accurately discriminate between different types of urinary calculi in an in vitro model using novel postimage acquisition data processing techniques. METHODS: Fifty urinary calculi were assessed, of which 44 had >or=60% composition of one component. DECT was performed utilizing 64-slice multidetector CT. The attenuation profiles of the lower-energy (DECT-Low) and higher-energy (DECT-High) datasets were used to investigate whether differences could be seen between different stone compositions. RESULTS: Postimage acquisition processing allowed for identification of the main different chemical compositions of urinary calculi: brushite, calcium oxalate-calcium phosphate, struvite, cystine, and uric acid. Statistical analysis demonstrated that this processing identified all stone compositions without obvious graphical overlap. CONCLUSION: Dual-energy multidetector CT with postprocessing techniques allows for accurate discrimination among the main different subtypes of urinary calculi in an in vitro model. The ability to better detect stone composition may have implications in determining the optimum clinical treatment modality for urinary calculi from noninvasive, preprocedure radiological assessment.

Establishing a regional, multisite database for quality improvement and service planning in community-based palliative care and hospice.

BACKGROUND: Outpatient palliative care, an evolving delivery model, seeks to improve continuity of care across settings and to increase access to services in hospice and palliative medicine (HPM). It can provide a critical bridge between inpatient palliative care and hospice, filling the gap in community-based supportive care for patients with advanced life-limiting illness. Low capacities for data collection and quantitative research in HPM have impeded assessment of the impact of outpatient palliative care. APPROACH: In North Carolina, a regional database for community-based palliative care has been created through a unique partnership between a HPM organization and academic medical center. This database flexibly uses information technology to collect patient data, entered at the point of care (e.g., home, inpatient hospice, assisted living facility, nursing home). HPM physicians and nurse practitioners collect data; data are transferred to an academic site that assists with analyses and data management. Reports to community-based sites, based on data they provide, create a better understanding of local care quality. CURRENT STATUS: The data system was developed and implemented over a 2-year period, starting with one community-based HPM site and expanding to four. Data collection methods were collaboratively created and refined. The database continues to grow. Analyses presented herein examine data from one site and encompass 2572 visits from 970 new patients, characterizing the population, symptom profiles, and change in symptoms after intervention. CONCLUSION: A collaborative regional approach to HPM data can support evaluation and improvement of palliative care quality at the local, aggregated, and statewide levels.

Entorhinal cortex volume in older adults: reliability and validity considerations for three published measurement protocols.

Measuring the entorhinal cortex (ERC) is challenging due to lateral border discrimination from the perirhinal cortex. From a sample of 39 nondemented older adults who completed volumetric image scans and verbal memory indices, we examined reliability and validity concerns for three ERC protocols with different lateral boundary guidelines (i.e., Goncharova, Dickerson, Stoub, & deToledo-Morrell, 2001; Honeycutt et al., 1998; Insausti et al., 1998). We used three novice raters to assess inter-rater reliability on a subset of scans (216 total ERCs), with the entire dataset measured by one rater with strong intra-rater reliability on each technique (234 total ERCs). We found moderate to strong inter-rater reliability for two techniques with consistent ERC lateral boundary endpoints (Goncharova, Honeycutt), with negligible to moderate reliability for the technique requiring consideration of collateral sulcal depth (Insausti). Left ERC and story memory associations were moderate and positive for two techniques designed to exclude the perirhinal cortex (Insausti, Goncharova), with the Insausti technique continuing to explain 10% of memory score variance after additionally controlling for depression symptom severity. Right ERC-story memory associations were nonexistent after excluding an outlier. Researchers are encouraged to consider challenges of rater training for ERC techniques and how lateral boundary endpoints may impact structure-function associations.

Neutralization activity in a geographically diverse East London cohort of human immunodeficiency virus type 1-infected patients: clade C infection results in a stronger and broader humoral immune response than clade B infection.

The array of human immunodeficiency virus (HIV) subtypes encountered in East London, an area long associated with migration, is unusually heterogeneous, reflecting the diverse geographical origins of the population. In this study it was shown that viral subtypes or clades infecting a sample of HIV type 1 (HIV-1)-positive individuals in East London reflect the global pandemic. The authors studied the humoral response in 210 treatment-naïve chronically HIV-1-infected (>1 year) adult subjects against a panel of 12 viruses from six different clades. Plasmas from individuals infected with clade C, but also plasmas from clade A, and to a lesser degree clade CRF02_AG and CRF01_AE, were significantly more potent at neutralizing the tested viruses compared with plasmas from individuals infected with clade B. The difference in humoral robustness between clade C- and B-infected patients was confirmed in titration studies with an extended panel of clade B and C viruses. These results support the approach to develop an HIV-1 vaccine that includes clade C or A envelope protein (Env) immunogens for the induction of a potent neutralizing humoral response.