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Polyketides such as the clinically-valuable antibacterial agent mupirocin are constructed by architecturally-sophisticated assembly lines known as trans-acyltransferase polyketide synthases. Organelle-sized megacomplexes composed of several copies of trans-acyltransferase polyketide synthase assembly lines have been observed by others through transmission electron microscopy to be located at the Bacillus subtilis plasma membrane, where the synthesis and export of the antibacterial polyketide bacillaene takes place. In this work we analyze ten crystal structures of trans-acyltransferase polyketide synthases ketosynthase domains, seven of which are reported here for the first time, to characterize a motif capable of zippering assembly lines into a megacomplex. While each of the three-helix LINKS (Laterally-INteracting Ketosynthase Sequence) motifs is observed to similarly dock with a spatially-reversed copy of itself through hydrophobic and ionic interactions, the amino acid sequences of this motif are not conserved. Such a code is appropriate for mediating homotypic contacts between assembly lines to ensure the ordered self-assembly of a noncovalent, yet tightly-knit, enzymatic network. LINKS-mediated lateral interactions would also have the effect of bolstering the vertical association of the polypeptides that comprise a polyketide synthase assembly line., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The resurgence of the use of LSD by a young, inexperienced population increases the likelihood of the occurrence of adverse psychedelic reactions. While the treatment of choice remains supportive, nonjudgmental talkdown, intramuscular lorazepam and haloperidol offer invaluable and specific adjuncts to care.

At the Haight-Ashbury Free Medical Clinics in San Francisco, the recreational use of cocaine is on a precipitous incline of popularity. Intensified symptoms of intoxication and the possibility of overdose parallel the current fad of smoking "freebase." We examined the "cocaine reaction," an adrenergic storm affecting CNS, respiratory and cardiovascular systems, which may proceed to generalized collapse and death within minutes. The physiologic and pharmacologic mechanisms of the reaction are elaborated, and a logical algorithm of treatment is outlined. The psychodynamics of the "armed" cocaine personality is discussed, as is the proper psychological approach to these patients. A specific indicated technical and pharmacologic approach, as well as several caveats of therapy that have been clinically developed in the treatment of several hundred cases of cocaine overdose, are presented.

Subjective discomfort caused by nausea and hot, pruritic skin has been described in patients after ingestion of therapeutic dosages of niacin is shown by this study to be alleviated by propranolol HC1. A dosage of 2 mg, I.V., given incrementally, in a clinical trial of six patients is described. The peripheral vasodilator effects of niacin were attenuated in some subjects but not in others. However, all subjects reported relief of unpleasant symptoms. Serial vital signs were taken and no significant changes were found. It is postulated that propranolol HC1 exerts a calmative effect at the CNS level. In a series that utilized doses of 40 and 80 mg of propranolol HC1 taken orally 30 min prior to the ingestion of 500 or 1000 mg of niacin, a progressive increase in the onset of the niacin flush was observed. It is proposed that as the available plasma level of propranolol HC1 falls, the ratio of niacin to propranolol HC1 increases, exceeding the threshold at which the flush occurs. Both these studies suggest that further work is indicated to establish the possible therapeutic efficacy of propranolol HC1.

In a large series of patients who have abused a variety of commercially available "amphetamine-like" agents as well as "street drugs" with CNS stimulant activity, the specific lytic effects of propranolol (Inderal) were utilized to reverse the dangerous hyperkinetic cardiovascular and frightening CNS phenomena noted in these non-comatose individuals. Presented here is a logical and clinically proven mode of therapy by which the authors have consistently, successfully, and safely managed such patients in "adrenergic crisis" by judicious titration of electrolytes, propranolol, and diazepam.

Phencyclidine (PCP) is a potent sympathomimetic and hallucinogenic dissociative anesthetic agent. As an abused street drug, it is most often smoked, thus allowing the user to titrate the dose. The clinical signs of PCP intoxication can be viewed in three dose-related stages, but waxing and waning of signs through the three stages is not uncommon. Treatment protocols for each stage address drug therapy and both clinical and psychological supportive measures.

A specific arousal therapy with NAGD (Naloxone, Activated Charcoal, Glucagon, Doxapram) is outlined for victims of drug overdose in comatose and semi-comatose states. Several direct benefits accrue if early awakening or lightening of such patients is safely accomplished. There are: 1) elimination of need for prolonged intubation or tracheostomy; 2) patient's ability to tell which drug(s) were taken; 3) excessively frantic and vigorous supportive treatment is obviated; and 4) the overall hospital stay is shortened. The NAGD regimen has been found to effectively, safely, and predictably reverse coma. Therapy consists of: naloxone 0.8 mg to 1.6 mg intravenously; large-bore orogastric tube instillation of 100 gm to 120 gm activated charcoal slurry; glucagon 1 mg to 2 mg intravenously; and, in selected cases, doxapram 1 mg/kg to 2 mg/kg intravenously.

The use of methadone in the treatment of heroin addiction continues to be controversial. Propoxyphene napsylate (Darvon N(R)) is a possible alternative and a pilot study was conducted to test its acceptability, safety and clinical efficacy in treating long term, "multi-relapse" heroin addicts. Findings indicate that propoxyphene napsylate suppresses many of the symptoms associated with opioid withdrawal phenomena. It should be viewed as a very promising therapeutic tool to be used in conjunction with psychological counseling and socio-vocational rehabilitation in detoxification and maintenance therapy for heroin or methadone addiction.

The respiratory stimulant doxapram hydrochloride has long been shunned in the United States because of a perpetuated fear of the alleged side effects of hypertension and tachycardia with attendant hypermetabolism and increased oxygen consumption. This study reports the results of the administration of doxapram alone, and of doxapram in conjunction with the beta-blocker propranolol on the blood pressure, heart rate, and respiratory rate of 12 healthy unanesthetized volunteer subjects. Results showed an augmentation in blood pressure (especially diastolic), a significant decrease in heart rate, and an unexpected actual increase in respiratory rate in the doxapram/propranolol group. Subtleties of sympathetic balance, as well as proposed future studies are discussed.

We report a case of successful resuscitation and clinical management in a 31-year-old man who allegedly ingested 20 g of cocaine hydrochloride. The physiologic and pharmacologic mechanisms of cocaine toxicity are reviewed. The use of labetalol in resolving the cardiovascular crisis is specifically detailed.

Acute heroin and methadone overdose reactions are seen with increasing frequency in E.R.s servicing middle-class white suburbia. The authors give step-by-step procedures for the management of this life-threatening medical emergency.