The role of 5-HT1A receptors in mediating acute negative effects of antidepressants: implications in pediatric depression.

Acute antidepressant exposure elevates the frequency of impulsive behavior and suicidal thoughts in children and adolescents with major depressive disorder (MDD). Long-term antidepressant treatment, however, is beneficial for pediatric MDD, so it is necessary to explore novel treatments that prevent the potentially dangerous consequences of acute antidepressant initiation. In the present study, a treatment strategy designed to reverse the acute negative behavioral effects of antidepressants was tested in rodents. Co-administration of the 5-HT1A receptor (5-HT1AR) antagonist WAY-100635 reversed the negative effects of acute fluoxetine, a serotonin reuptake inhibitor, but not reboxetine, a norepinephrine reuptake inhibitor, supporting the involvement of 5-HT1AR in mediating the negative consequences of acute selective serotonin reuptake inhibitor (SSRI) treatment. No 5-HT1AR antagonists are currently approved for use in pediatric populations, so alternative strategies should be explored. One such strategy was suggested based on the hypothesis that the rate of 5-HT1AR activation and the subsequent inhibition of serotonergic neuron activity caused by acute SSRI administration is proportional to the loading rate of an antidepressant. Existing pharmacological data were examined, and significant correlations were observed between the half-life of antidepressants and the rate of suicide-related events (SREs). Specifically, antidepressants with longer half-lives have lower rates of SREs. On the basis of these data, novel dosing strategies were developed for five antidepressants to mimic the pharmacological profile of the antidepressant with the longest half-life, fluoxetine. These dosing strategies could be used to decrease the rate of SREs associated with acute antidepressant treatment in pediatric MDD until an improved pharmacological treatment is developed.

Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition.

Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.

Pseudomonas osteomyelitis of the metatarsal sesamoid bones.

It is unusual for osteomyelitis of the sesamoid bones to occur after a puncture wound to the foot. When the puncture occurs through tennis shoes, the risk of Pseudomonas infection is increased. Pseudomonas was the causative organism in 7 of 22 cases reported in the literature. This report will explore the causes and natural history, as well as the treatment, of these infections. Initially, basic wound care principles should be adhered to when treating these wounds. Patient awareness and close follow-up is important to ensure complete healing. Treatment of this case involved intravenous antibiotics and medial sesamoidectomy. Foot deformities can occur with sesamoid osteomyelitis and sesamoid excision. Hallux valgus deformity was noted to occur with the osteomyelitis and worsen with sesamoid excision. Preservation of surrounding structures during excision is important to prevent deformity.

Mechanical effects of sodium fluoride on bovine cortical bone.

Seventeen 5 to 6-month-old Holstein heifer calves were divided into three groups and fed either a control ration alone or a control ration with sufficient sodium fluoride added to furnish an additional 30 or 50 p.p.m. fluoride based on total dry matter intake. After 6 years of the feedings, mean (SEM) fluoride concentrations in the metacarpals were found to be 594.6 (66.2), 2663.8 (319.2), and 4500.0 (417.8) p.p.m. Bone mineral density and mechanical evaluations were also conducted on the harvested metacarpals after the 6-year period. Using dual energy X-ray absorptiometry, mean (SEM) bone mineral densities of 3.030 (0.26), 2.801 (0.34), and 2.456 (0.19) g cm(-2) for the control group, the group receiving 30 p.p.m. fluoride, and the group receiving 50 p.p.m. respectively were found. For the mechanical testing, specimens were cut and tested in compression parallel to the long axis of the metacarpals. Mean (SEM) ultimate stress of 204.53 (3.63), 208.83 (5.25), and 205.93 (5.12) MPa and mean (SEM) Young's elastic moduli of 20.82 (1.52), 22.68 (2.38), and 21.55 (1.60) GPa for the control, the 30 p.p.m., and the 50 p.p.m. fluoride groups respectively were determined. No significant differences were found between control and treatment groups for either mechanical properties or bone mineral density.

Pollution aerosol in the northeast: northeastern-midwestern contributions.

In recent years, atmospheric scientists have been endeavoring to determine the relative contributions of local and distant sources to pollution aerosol in eastern North America. Elemental analysis of aerosol from various sites in the northeastern United States has revealed a persistent northeastern "foreground" upon which pulses of midwestern aerosol are superimposed every few days, in response to large-scale meteorological features. Regional apportionment of tracer element and sulfate in summer and winter samples from Narragansett, Rhode Island, and Underhill, Vermont, shows that most of the elements come predominantly from northeastern sources. Notable exceptions include arsenic and indium, for which Canadian nonferrous smelters are important sources, and sulfur and selenium, for which the Midwest is an important source. During 1982 and 1983, the Northeast and the Midwest contributed comparably to aerosol sulfate at Narragansett and Underhill, in spite of the fact that the emissions of sulfur dioxide in the Midwest were ten times those in the Northeast; Canadian smelters accounted for less than 10 percent of the total sulfate. During a major pollution episode in July 1982, northeastern and midwestern sources produced comparable sulfate concentration in Rhode Island, whereas midwestern sources dominated northeastern sources in Vermont. Thus, although distant midwestern sources affect the quantity of pollution aerosol in the Northeast and may dominate episodically, nearer northeastern sources are comparably important on the long term.

Elemental tracers of distant regional pollution aerosols.

A seven-element tracer system shows that regional pollution aerosols of both North America and Europe have characteristic signatures that can be followed into remote areas up to several thousand kilometers downwind. In aerosols of mixed origin, regional contributions to the tracer elements can be resolved by least-squares procedures. After transport of several hundred kilometers, secondary sulfate can also be apportioned satisfactorily. Regional elemental tracers thus offer a way to determine the sources of pollution aerosol in important areas such as the northeastern United States, Scandinavia, and the Arctic.

Sources of northeast pollution.

In the article, "Amplification and adaptation in regulatory and sensory systems" by D. E. Koshland, Jr., A. Goldbeter, and J. B. Stock (16 July, p. 220), the following errors should be corrected. On page 221, the ordinate on figure 1 was incorrect. The correct figure is given below. On page 223, in the first column, 23 lines from the bottom, the number 9 should be replaced by the number 7. [See Figure in the PDF file]

Tropospheric halogen gases: inorganic and organic components.

Inorganic and organic components of the gaseous tropospheric halogens chlorine, bromine, and iodine have been simultaneously measured. At four diverse remote locations the organic component contained the bulk of the halogen mass, varied less than the inorganic component, and was comparable in concentration to the independently measured halocarbon component.