Chemistry-based molecular signature underlying the atypia of clozapine.

The central nervous system is functionally organized as a dynamic network of interacting neural circuits that underlies observable behaviors. At higher resolution, these behaviors, or phenotypes, are defined by the activity of a specific set of biomolecules within those circuits. Identification of molecules that govern psychiatric phenotypes is a major challenge. The only organic molecular entities objectively associated with psychiatric phenotypes in humans are drugs that induce psychiatric phenotypes and drugs used for treatment of specific psychiatric conditions. Here, we identified candidate biomolecules contributing to the organic basis for psychosis by deriving an in vivo biomolecule-tissue signature for the atypical pharmacologic action of the antipsychotic drug clozapine. Our novel in silico approach identifies the ensemble of potential drug targets based on the drug's chemical structure and the region-specific gene expression profile of each target in the central nervous system. We subtracted the signature of the action of clozapine from that of a typical antipsychotic, chlorpromazine. Our results implicate dopamine D4 receptors in the pineal gland and muscarinic acetylcholine M1 (CHRM1) and M3 (CHRM3) receptors in the prefrontal cortex (PFC) as significant and unique to clozapine, whereas serotonin receptors 5-HT2A in the PFC and 5-HT2C in the caudate nucleus were common significant sites of action for both drugs. Our results suggest that D4 and CHRM1 receptor activity in specific tissues may represent underappreciated drug targets to advance the pharmacologic treatment of schizophrenia. These findings may enhance our understanding of the organic basis of psychiatric disorders and help developing effective therapies.

Successful management of trifurcation injuries.

Vascular injuries to the distal popliteal artery and its primary division(s) (trifurcation) combined with fracture(s) were analyzed for the years 1978 to 1983 at the Charity Hospital of Louisiana at New Orleans and Tulane Medical Center affiliates. This article does not include reports of isolated popliteal artery injuries. Thirty-six male patients with a mean age of 24 (16 to 47) years experienced 20 tibiofibular fractures and 16 tibial plateau fractures. Twenty-four injuries were secondary to penetrating trauma; the remaining 12 vascular injuries were the result of blunt trauma. All patients were angiographed preoperatively, resuscitated, treated with tetanus toxoid and antibiotics, and brought to the operating room in an average of 95 (30 to 244) minutes from entry to the emergency departments. Eight (22%) definitive below-knee amputations (BKA) (six [17%] with blunt trauma) and 28 (78%) reconstructive procedures were done initially. Twenty-four of the 28 (86%) patients had associated venous injury; 16 were repaired. Twenty of the 28 (71%) patients received fasciotomies There were eight late amputations in addition to the eight early definitive BKA; five secondary to related neurologic injury. Twenty of the 28 (71%) patients had successful repair of their arterial injury and total rehabilitation.

Classical heatstroke: clinical and laboratory assessment.

We reviewed the clinical and laboratory characteristics of 34 patients who had classical heatstroke during the Kansas City heat wave of 1980. The patients were elderly, predominantly black, and of low socioeconomic class. Overall mortality was 18%, with 9% of patients exhibiting severe residual neurologic deficit; 73% had full recovery. Patients with coma, temperature greater than or equal to 108 F (42.2 C), severe hypotension, coagulopathy, and need for respiratory assistance were at highest risk of death. Associated disease was common (67%), with hypertension (32%), diabetes (21%), and alcoholism (21%) being most frequent. Medications known to predispose to heatstroke were used by 56% of patients. Hematologic abnormalities were nonspecific, and clinical evidence of renal or hepatic failure was rare. Hyponatremia, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, and elevated levels of creatine phosphokinase and glucose were frequent but did not correlate with outcome. The predominant arterial blood gas abnormality was metabolic acidosis or a combined metabolic acidosis and respiratory alkalosis.