Regulation of protein synthesis: Activation by double-stranded RNA of a protein kinase that phosphorylates eukaryotic initiation factor 2

Incubation of reticulocyte lysates or isolated crude ribosomes with low levels of double-stranded RNA (0.1-10 ng/ml) induces the formation of an inhibitor of protein synthesis initiation similar to that observed in heme deficiency. The inhibitor is associated with a cyclic AMP-independent protein kinase activity (ATP:protein phosphotransferase, EC 2.7.1.37) that phosphorylates the small polypeptide (38,000 daltons) of the eukaryotic initiation factor eIF-2. Activation of the inhibitor requires ATP in addition to double-stranded RNA and is accompanied by the phosphorylation of a 67,000-dalton polypeptide of unknown function. The inhibitor remains associated with the ribosomes during high-speed sedimentation. Once formed, the ribosome-associated inhibitor phosphorylates eIF-2 and inhibits protein synthesis in the absence of double-stranded RNA. Inhibition is prevented by exogenous eIF-2. The bound inhibitor can be solubilized by extraction with 0.5 M KCl. The soluble inhibitor preparation retains the ability to phosphorylate the small polypeptide of eIF-2 and to inhibit protein synthesis. Untreated crude ribosomes also contain cyclic AMP-independent protein kinase activities that phosphorylate the middle polypeptide (49,000 daltons) of eIF-2 and several polypeptide subunits of eIF-3 (160,000, 125,000, and 65,000 daltons); these kinase activities are not affected by double-stranded RNA and do not inhibit protein synthesis.     

Placebo use in vaccine trials: Recommendations of a WHO expert panel

Vaccines are among the most cost-effective interventions against infectious diseases. Many candidate vaccines targeting neglected diseases in low- and middle-income countries are now progressing to large-scale clinical testing. However, controversy surrounds the appropriate design of vaccine trials and, in particular, the use of unvaccinated controls (with or without placebo) when an efficacious vaccine already exists. This paper specifies four situations in which placebo use may be acceptable, provided that the study question cannot be answered in an active-controlled trial design; the risks of delaying or foregoing an efficacious vaccine are mitigated; the risks of using a placebo control are justified by the social and public health value of the research; and the research is responsive to local health needs. The four situations are: (1) developing a locally affordable vaccine, (2) evaluating the local safety and efficacy of an existing vaccine, (3) testing a new vaccine when an existing vaccine is considered inappropriate for local use (e.g. based on epidemiologic or demographic factors), and (4) determining the local burden of disease.     

Motor speech disorders associated with primary progressive aphasia

Background: Primary progressive aphasia (PPA) and conditions that overlap with it can be accompanied by motor speech disorders. Recognition and understanding of motor speech disorders can contribute to a fuller clinical understanding of PPA and its management as well as its localisation and underlying pathology.

Aims: To review the types of motor speech disorders that may occur with PPA, its primary variants, and its overlap syndromes (progressive supranuclear palsy syndrome, corticobasal syndrome, motor neuron disease), as well as with primary progressive apraxia of speech.

Main Contribution: The review should assist clinicians’ and researchers’ understanding of the relationship between motor speech disorders and PPA and its major variants. It also highlights the importance of recognising neurodegenerative apraxia of speech as a condition that can occur with little or no evidence of aphasia.

Conclusion: Motor speech disorders can occur with PPA. Their recognition can contribute to clinical diagnosis and management of PPA and to understanding and predicting the localisation and pathology associated with PPA variants and conditions that can overlap with them.     

Pharmacogenetic interactions between angiotensin-converting enzyme inhibitor therapy and the angiotensin-converting enzyme deletion polymorphism in patients with congestive heart failure

OBJECTIVES: We evaluated the interaction of angiotensin-converting enzyme (ACE) inhibitor therapy with the effect of the ACE D/I polymorphism on heart failure survival. BACKGROUND: The ACE deletion allele, ACE-D, is associated with increased ACE activity. The utilization of ACE genotyping to predict the impact of ACE inhibitor dose has not been previously evaluated. METHODS: We prospectively studied 479 subjects with systolic dysfunction (left ventricular ejection fraction 0.25 +/- 0.08). Subjects were divided on the basis of ACE inhibitor therapy into low dose (50%, n = 201), or those receiving angiotensin receptor antagonists (n = 51). Patients were genotyped for the ACE D/I polymorphism, followed to the end point of death or cardiac transplantation, and transplant-free survival compared by genotype. RESULTS: The ACE-D allele was associated with an increased risk of events (p = 0.026). In analysis by ACE inhibitor dose, this effect was primarily in the low-dose group (1-year percent event-free survival: II/ID/DD = 86/77/71,2-year = 79/66/59, p = 0.032). In the standard-dose group, the impact was markedly diminished (1-year: II/ID/DD = 91/81/80, 2-year: 77/70/71, p = 0.64). The impact of beta-blockers and high dose ACE inhibitors was greatest in subjects with the ACE DD genotype (p = 0.001) and was less apparent with the II and ID genotypes (p = 0.38). CONCLUSIONS: Higher doses of ACE inhibitors diminished the impact of the ACE-D allele, and the benefits of beta-blockers and high-dose ACE inhibitors appeared maximal for DD patients. Determination of ACE genotype may help target therapy for patients with heart failure.     

Groundhog Day for Medical Artificial Intelligence

Following a boom in investment and overinflated expectations in the 1980s, artificial intelligence entered a period of retrenchment known as the “AI winter.” With advances in the field of machine learning and the availability of large datasets for training various types of artificial neural networks, AI is in another cycle of halcyon days. Although medicine is particularly recalcitrant to change, applications of AI in health care have professionals in fields like radiology worried about the future of their careers and have the public tittering about the prospect of soulless machines making life‐and‐death decisions. Medicine thus appears to be at an inflection point—a kind of Groundhog Day on which either AI will bring a springtime of improved diagnostic and predictive practices or the shadow of public and professional fear will lead to six more metaphorical weeks of winter in medical AI.     

Artificial Intelligence and Black‐Box Medical Decisions: Accuracy versus Explainability

Although decision‐making algorithms are not new to medicine, the availability of vast stores of medical data, gains in computing power, and breakthroughs in machine learning are accelerating the pace of their development, expanding the range of questions they can address, and increasing their predictive power. In many cases, however, the most powerful machine learning techniques purchase diagnostic or predictive accuracy at the expense of our ability to access “the knowledge within the machine.” Without an explanation in terms of reasons or a rationale for particular decisions in individual cases, some commentators regard ceding medical decision‐making to black box systems as contravening the profound moral responsibilities of clinicians. I argue, however, that opaque decisions are more common in medicine than critics realize. Moreover, as Aristotle noted over two millennia ago, when our knowledge of causal systems is incomplete and precarious—as it often is in medicine—the ability to explain how results are produced can be less important than the ability to produce such results and empirically verify their accuracy.     

Spastic paretic hemifacial contracture related to multiple sclerosis: a rare and under-recognized entity

We describe an additional case of spastic paretic hemifacial contracture, an uncommon condition characterized by sustained unilateral contraction of the facial muscles associated with mild ipsilateral facial paresis. This entity has only rarely been associated with multiple sclerosis (MS) and can be mistaken for hemifacial spasm. Early consideration of MS in the differential diagnosis of young patients admitted with these symptoms is essential.     

Immune-mediated neurological syndromes in SARS-CoV-2-infected patients

Journal of Neurology - Evidence of immune-mediated neurological syndromes associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is limited. We therefore...     

Mastery,Intimacy, and Stress Resistance during War

The relationship between war-related stressors and emotional and behavioral adjustment during the Israel-Lebanon war was studied on a sample of 220 Israeli students, many of whom had been in combat. Mastery had direct effects on the well-being of both sexes. There was limited support for the stress-buffering effect of intimacy for men, such that those who had less intimate ties were increasingly negatively affected by greater exposure to war-related stressors, whereas those with more intimate relationships were relatively unaffected; the buffering effect applied both to emotions and behavior. No stress-buffering effect of intimate ties was found for women, but women were not affected by war-related stress at this time. The diagnosis post-traumatic stress disorder is examined in terms of the fact that normally healthy populations may be at increased risk of long-term adjustment difficulties following exposure to extreme stress if the threat of recurrence of the stressor continues. Implications for Vietnam veterans are also discussed.