Anxiety disorders of childhood, Implications for adult psychopathology

Although the exact path of acquisition remains incompletely understood, research supports the association between anxiety disorders in children and psychopathologic conditions in adults. This article addresses this relationship; reviews findings on the temperamental profile and behavioral inhibition, which may be an early identifiable childhood predictor of later anxiety disorders; and discusses the importance of early intervention.     

Development of technologies aiding large-tissue engineering

Apoptosis associated oligonucleosomal fragmentation of DNA can result from the activation of endonucleases that exhibit different pH optima and are either sensitive or insensitive to divalent cations. DNA fragmentation due to activation of cation sensitive endonucleases occurs in the absence of a change in intracellular pH whereas intracellular acidification is a feature of apoptosis characterized by activation of cation insensitive acidic endonuclease. We have reported earlier that somatostatin (SST) induced DNA fragmentation and apoptosis is signaled in a receptor subtype selective manner uniquely via human somatostatin receptor subtype 3 (hSSTR3). In the present study we investigated the pH dependence and cation sensitivity of endonuclease induced in hSSTR3 expressing CHO-K1 cells by the SST agonist octreotide (OCT) and its effect on intracellular pH. We show that OCT induced apoptosis is associated with selective stimulation of a divalent cation insensitive acidic endonuclease. The intracellular pH of of cells undergoing OCT induced apoptosis was 0.9 pH units lower than that of control cells. The effect of OCT on endonuclease and pH was inhibited by orthovanadate as well as by pretreatment with pertussis toxin, suggesting that hSSTR3 initiated cytotoxic signaling is protein tyrosine phosphatase mediated and is G protein dependent. These findings suggest that intracellular acidification and activation of acidic endonuclease mediate wild type p53 associated apoptosis signaled by hormones acting via G protein coupled receptors.     

Synthesis and biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.     

L-thiocitrulline. A stereospecific, heme-binding inhibitor of nitric-oxide synthases

Nitric-oxide synthase (NOS) catalyzes the oxidation of L-arginine to citrulline and nitric oxide (NO). The enzyme is inhibited by a variety of N omega-monosubstituted L-arginine analogs, and some of these compounds are useful in reversing pathologies associated with the overproduction of NO (e.g. the hypotension of septic shock). We report here that L-thiocitrulline (gamma-thioureido-L-norvaline) is a potent, stereospecific inhibitor of the constitutive brain and endothelial isoforms of NOS as well as the isoform induced in vascular smooth muscle cells by lipopolysaccharide and interferon-gamma. Steady state kinetic studies show L-thiocitrulline inhibition is competitive with L-arginine (Ki approximately 4-20% of KArgm), indicating that initial binding is as a substrate/product analog. In contrast to L-arginine and N omega-methyl-L-arginine, the prototypic NOS inhibitor, L-thiocitrulline binding elicits a "Type II" difference spectrum, indicating a high spin to low spin transition of the iron in the heme cofactor. This finding suggests that L-thiocitrulline is contributing the sixth ligand to heme iron, probably through the thioureido sulfur. Such interaction with heme iron neither stimulates nor inhibits the direct flavin-mediated cytochrome c reduction activity of the enzyme, but it does inhibit heme-dependent superoxide formation. In vivo, L-thiocitrulline is a potent pressor agent in both normal and endotoxemic rats, the latter finding suggesting utility in treating the hypotension of septic shock.     

Renal amyloidosis in a drug abuser

Drug abusers, particularly those who inject drugs s.c. ("skin popping"), may develop amyloidosis. Chronic infections are thought to play a pathogenetic role in this setting. A patient is presented who had a history of "skin popping" cocaine and heroin and developed nephrotic syndrome, with an elevated serum creatinine and a creatinine clearance of 61 mL/min. Renal biopsy demonstrated amyloidosis. Treatment with colchicine was initiated, and proteinuria decreased to near normal levels after 12 months. Concomitant with the decrease in proteinuria, creatinine clearance improved, although a repeat renal biopsy failed to show any significant improvement in amyloid burden. These observations suggest that colchicine may be a useful treatment in reversing the proteinuria of renal amyloidosis associated with drug abuse. Furthermore, clinical improvement may occur before any demonstrable regression in the amyloidosis.     

Importance of participation rate in sampling of data in population based studies, with special reference to bone mass in Sweden

OBJECTIVE: To study the effects of participation rate in sampling on "normative" bone mass data. DESIGN: This was a comparison between two randomly selected samples from the same population. The participation rates in the two samples were 61.9% and 83.6%. Measurements were made of bone mass at different skeletal sites and of muscle strength, as well as an assessment of physical activity. SETTING: Malm?, Sweden. SUBJECTS: There were 230 subjects (117 men, 113 women), aged 21 to 42 years. RESULTS: Many subjects participated in both studies (163). Those who took part only in the study with the higher participation rate (67) almost invariably had higher values for bone mass density at the sites measured (up to 7.6% for men) than participants in the study with the lower participation rate. No differences in muscle strength were recorded. CONCLUSION: A high degree of compliance is important to achieve a reliable result in determining normal values in population based studies.     

A negative association of schizophrenia with an allele of the HLA DQB1 gene among African-Americans

The present study investigated the relationship between the time of nocturnal onset of urinary 6-sulfatoxymelatonin (aMT6s) secretion, and the timing of the steepest increase in nocturnal sleepiness ("sleep gate"), as determined by an ultrashort sleep-wake cycle test (7 min sleep, 13 min wake). Twenty-nine men (mean age 23.8 +/- 2.7 years) participated. The ultrashort sleep-wake paradigm started at 0700 hr after a night of sleep deprivation and continued for 24 hr until 0700 hr the next day. Electrophysiological recordings were carried out during the 7-min sleep trials, which were then scored conventionally for sleep stages. Urinary aMT6s was measured every 2 hr. The results showed that the timing of the sleep gate was significantly correlated with the onset of aMT6s secretion. These results are discussed in light of the possible role of melatonin in sleep-wake regulation.     

Voltage sensitivity of the osteoclast calcium receptor

We demonstrated previously that osteoclasts possess a divalent cation-sensitive "receptor", the Ca2+ receptor. Activation of the Ca2+ receptor by the surrogate cation Ni2+ was shown to elicit an increase in cytosolic [Ca2+] to a peak value followed by an exponential decline. In the present study we examined the influence of surface membrane voltage on the kinetics of Ca2+ receptor inactivation. The K+ ionophore, valinomycin was applied to intercept the declining phase of the cytosolic [Ca2+] transient elicited by application of between 50 microM- and 5 mM-[Ni2+]. This resulted in a sustained elevation of cytosolic [Ca2+] or even a 'hump' followed by a gradual decline. Such a kinetic alteration persisted in a Ca(2+)-free solution, but was abolished in high extracellular [K+] (105 mM). Thus, we demonstrate for the first time to our knowledge, a modulatory effect of membrane potential on the function of the osteoclast Ca2+ receptor.