Peptide-MHC-based nanovaccines for the treatment of autoimmunity: a “one size fits all” approach?

Nanotechnology offers enormous potential in drug delivery and in vivo imaging. Nanoparticles (NPs), for example, are being extensively tested as scaffolds to deliver anti-cancer therapeutics or imaging tags. Our recent work, discussed herein, indicates that an opportunity exists to use NPs to deliver ligands for, and trigger, cognate receptors on T lymphocytes as a way to induce therapeutic immune responses in vivo. Specifically, systemic delivery of NPs coated with Type 1 diabetes (T1D)-relevant peptide-major histocompatibility complex molecules triggered the expansion of cognate memory autoregulatory (disease-suppressing) T cells, suppressed the progression of autoimmune attack against insulin-producing beta cells, and restored glucose homeostasis. This therapeutic avenue exploits a new paradigm in the progression of chronic autoimmune responses that enables the rational design of disease-specific “nanovaccines” capable of blunting autoimmunity without impairing systemic immunity, a long sought-after goal in the therapy of these disorders. Here, we discuss the research paths that led to the discovery of this therapeutic avenue and highlight the features that make it an attractive approach for the treatment, in an antigen-specific manner, of a whole host of autoimmune diseases.     

Transfusion in sub‐Saharan Africa: does a Western model fit?

This review examines the current state of transfusion services in sub-Saharan Africa and presents the argument for and against the Western model of a centralised blood service with 100% voluntary non-remunerated blood donors as advocated by the World Health Organization. The current practice of family replacement donors in hospital-based blood service is the most economical option, but in the face of high child and maternal mortality rates the blood supply has proved to be insufficient. With estimates of 5-10% of HIV transmission in Africa being the result of contaminated blood transfusions, there is a need to improve testing for transfusion transmissible diseases and the selection of blood donors. Of major concern, with respect to testing, is the quality of kits being used and the continuity of supply. The need to produce components is discussed in the context of the transfusion needs in sub-Saharan Africa. The running costs of establishing and maintaining centralised blood services need careful consideration as such projects need to be sustainable in the future. It is concluded that both options are viable while centralised programmes are being developed, and a pragmatic approach should be taken to ensure that the patients' needs are met and that resources are suitably utilised to ensure sustainability.     

Unexplained infertility: does it really exist?

Recent medical literature has quite extensively addressed the use of various terminologies within the field of reproductive medicine. This discussion has, however, so far overlooked the fact that one of the most frequently made diagnosis, so-called unexplained infertility (UI), not only didactically but, even more importantly, clinically, appears unsustainable as an independent diagnosis. The arguments in support of such a contention are manifold. The diagnosis of UI is highly subjective. It is dependent on which diagnostic tests have been performed (or have been omitted) and at what level of quality. Paradoxically, a diagnosis of UI will, therefore, be more often reached if the diagnostic workup is incomplete or of poor quality. Supported by evidence from the literature, the argument is made that the conditions, most frequently misdiagnosed as UI, are endometriosis, tubal infertility (especially distal and peritubal disease), premature ovarian ageing and immunological infertility. Because of the obvious unreliability of a diagnosis of UI and the widely reported unevenness in diagnostic criteria, we recommend the abandonment of UI as a formal infertility diagnosis. Better efforts to reach infertility diagnoses more accurately should improve the diagnostic accuracy of hitherto frequently missed diagnoses, which often falsely have led to a diagnosis of UI.     

What does the MMPI dependency scale really measure?

Examined the mean DY score of various clinical and nonclinical groups (N = 855). It was significantly higher for females, whether patients or nonpatients; nonpatients with a high total score and high scores on several subscales of the Crown Crisp Experiential Index of neurotic symptomatology; psychiatric patients in general; patients and nonpatients with a high modified Zung depression score; neurotic as opposed to endogenous depressives; suicide attemptors, especially non-serious ones; Ss with early bereavement or separation particularly if followed by poor replacement care; Ss with poor quality marriages and husband dominant marriages as measured by the Ryle Marital Patterns Test. The DY Scale relates directly with the PT and D Scales and inversely with the Do Scale. Separation of the test items into those that were and were not predominantly depressive revealed that most, though not all, significant associations were due to the depressive component, which it was suggested should be markedly diminished.     

HIV diversity, recombination and disease progression: how does fitness "fit" into the puzzle?

HIV appears to have diverged into several lineages upon multiple zoonotic introductions from the nonhuman primates. The HIV-2 and HIV-1 groups M, N, and O likely represent different cross-species transmission events. The radial evolution of group M in multiple clades or subtypes is likely due to adaptation and expansions in the human hosts. It is not well understood why HIV strains such as HIV-1 subtype C in particular or group M in general have spread disproportionately as compared to other subtypes, groups, or types, which often remained geographically constrained to local epidemics. Host genetic effects, transmission bottlenecks, social/behavioral and environmental limitations, founder effect and other viral factors could have contributed to variable spread through the human population. Even after transmission, viruses evolve at different rates during disease progression. Recent studies have explored phenotypic differences between HIV types, groups, and subtypes in attempts to explain or understand this radial evolution and expansion. This review explores some of the important aspects relating to fitness during disease progression, during global distribution of different HIV subtypes, and related to circulation of recombinant forms in the epidemic.     

Ultrasound-guided fine-needle aspiration of thyroid nodules: does the size limit its efficiency?

Purpose: The management criterion of thyroid nodules is to evaluate the risk of malignancy, based on cytological examinations. Ultrasound-guided fine-needle aspiration biopsy (US-FNAB) has a highly diagnostic value for thyroid nodules. The aim of this study was to compare the efficacy of US-FNAB for thyroid nodules with different sizes. Material and methods: From August 2013 to November 2013, 344patients with thyroid nodules who had undergone US-FNAB were divided into three groups, according to the largest diameter of their nodules (group A, ≤ 5.0 mm; group B, 5.1-10.0 mm; group C, > 10.0 mm). All the nodules were subsequently verified by histology or follow-up findings. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value of aspiration cytology in each group was compared. Results: Among 344 thyroid nodules diagnosed by cytology, the cytology was classified as nondiagnostic or unsatisfactory for 53 (15.4%) lesions, benign for 144 (41.9%) lesions, atypia of undetermined significance or follicular lesion of undetermined significance for 20 (5.8%) lesions, follicular neoplasm or suspicious for a follicular neoplasm for 26 (7.6%) lesions, suspicious for malignancy for 36 (10.5%) lesions, malignant for 65 (18.9%) lesions. There were 243 benign and 101 malignant nodules confirmed by the pathological or follow-up ultrasound. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were confirmed to be 87.5% (14/16), 92.5% (37/40), 91% (51/56), 82.3% (14/17), and 94.8% (37/39) in group A; 92.3% (36/39), 96.9% (94/97), 95.5% (130/136), 92.3% (36/39), and 96.9% (94/97) in group B; and 91.3% (42/46), 93.4% (99/106), 92.7% (141/152) 85.7% (42/49), and 96.1% (99/103), in group C. There were no statistical differences in accuracy, sensitivity, specificity, false positive accuracy, false negative rate of fine needle aspiration of thyroid nodules with different sizes (P > 0.05). Conclusion: US-FNAB has similar diagnostic efficacy to thyroid nodules with different sizes.     

What does matrix metalloproteinase-1 expression in patients with breast cancer really tell us?

Many patients with asthma have poorly controlled symptoms, and particularly for those with severe disease, there is a clear need for improved treatments. Two recent therapies licensed for use in asthma are omalizumab, a humanized monoclonal antibody that binds circulating IgE antibody, and bronchial thermoplasty, which involves the delivery of radio frequency energy to the airways to reduce airway smooth muscle mass. In addition, there are new therapies under development for asthma that have good potential to reach the clinic in the next five years. These include biological agents targeting pro-inflammatory cytokines such as interleukin-5 and interleukin-13, inhaled ultra long-acting β₂-agonists and once daily inhaled corticosteroids. In addition, drugs that block components of the arachidonic acid pathway that targets neutrophilic asthma and CRTH2 receptor antagonists that inhibit the proinflammatory actions of prostaglandin D₂ may become available. We review the recent progress made in developing viable therapies for severe asthma and briefly discuss the idea that development of novel therapies for asthma is likely to increasingly involve the assessment of genotypic and/or phenotypic factors.     

Migraine: where and how does the pain originate?

Migraine is a complex neurological disease with a genetic background. Headache is the most prominent and clinically important symptom of migraine but its origin is still enigmatic. Numerous clinical, histochemical, electrophysiological, molecular and genetical approaches form a puzzle of findings that slowly takes shape. The generation of primary headaches like migraine pain seems to be the consequence of multiple pathophysiological changes in meningeal tissues, the trigeminal ganglion, trigeminal brainstem nuclei and descending inhibitory systems, based on specific characteristics of the trigeminovascular system. This contribution reviews the current discussion of where and how the migraine pain may originate and outlines the experimental work to answer these questions. This contribution is dedicated to the author’s academic teacher, Robert F. Schmidt.