Diagnostic blocks: a truth serum for malingering

Malingering is not a diagnosis. It is a behavior for which there are no established diagnostic criteria. Guidelines have been published according to which malingering might be suspected, but those guidelines do not discriminate between patients who are malingering and ones with genuine sources of chronic pain. In such patients, malingering cannot be proven, but it can be refuted if a genuine source of pain can be established. In patients with no apparent cause of pain, the source of that pain can be established using controlled diagnostic blocks. A positive response to diagnostic blocks demonstrates that the complaint of pain is genuine and, by implication, refutes any contention that the patient is malingering. When positive, diagnostic blocks provide objective data by which disputes based on opinion can be resolved, as to whether a patient is malingering or not. Negative responses do not exclude a genuine complaint of pain, for patients may have a source of pain that is not amenable to testing with diagnostic blocks. Diagnostic blocks have proved particularly useful in the investigation of spinal pain for which the cause is not evident on conventional medical imaging. They can also confirm or refute purported mechanisms of certain clinical features in complex regional pain syndromes.     

Genomics and proteomics tools for compound mode-of-action studies in drug discovery

A broad range of genomics and proteomics technologies are increasingly being integrated into emerging research fields such as pharmacogenomics, pharmacoproteomics, chemogenomics, chemical genetics, and chemical biology. Here we review applications of genomic and proteomic technologies to drug mechanism-of-action studies and how these are beginning to impact the drug discovery process.     

Clonidine increases caspase-3 mRNA level and DNA fragmentation in the developing rat brainstem

The densities of alpha2-adrenergic receptors, labeled by 3H-clonidine or 3H-RX821002, reach a peak in the rat brainstem during the first week of its life. This enables the agonist of alpha2-adrenergic receptor clonidine, which is used as a component of anaesthetic solution in infants and children, to have specific effects in this structure of the developing brain. Clonidine was injected into the fetal brain (5 microg in 5 microl of saline) or subcutaneously to the pups (1, 10 microg in 50 microl of saline) 3 days before investigation. Clonidine increased the level of apoptotic enzyme caspase-3 mRNA expression, as measured by RT-PCR and enhanced the DNA fragmentation, as determined by gel electrophoresis, in the brainstem of the 21-day-old fetuses and 8-day-old rats. In the cortex of 8-day-old rat, the alpha2-adrenergic receptors are at a much lower level than the brainstem. Clonidine treatment had no evident effects on caspase-3 mRNA level and DNA fragmentation in the cortex of an 8-day-old rat. The data suggest that clonidine facilitates cell death in the developing brainstem. This drug effect provides a potential mechanism whereby clonidine during early life could induce long-lasting alterations in brain neurochemistry, autonomic functions and behavior.     

Naltrexone for heroin dependence treatment in St. Petersburg, Russia

Naltrexone may be more effective for treating opioid (heroin) dependence in Russia than in the U.S. because patients are mostly young and living with their parents, who can control medication compliance. In this pilot study we randomized 52 consenting patients who completed detoxification in St. Petersburg to a double blind, 6-month course of biweekly drug counseling and naltrexone, or counseling and placebo naltrexone. Significant differences in retention and relapse favoring naltrexone were seen beginning at 1 month and continuing throughout the study. At the end of 6 months, 12 of the 27 naltrexone patients (44.4%) remained in treatment and had not relapsed as compared to 4 of 25 placebo patients (16%; p<0.05). Since heroin dependence is the main way HIV is being spread in Russia, naltrexone is likely to improve treatment outcome and help reduce the spread of HIV if it can be made more widely available.     

Effects of modafinil on working memory processes in humans

Rationale Modafinil is a well-tolerated psychostimulant drug with low addictive potential that is used to treat patients with narcolepsy or attention deficit disorders and to enhance vigilance in sleep-deprived military personal. So far, understanding of the cognitive enhancing effects of modafinil and the relevant neurobiological mechanisms are incomplete.Objectives The aim of this study was to investigate the effects of modafinil on working memory processes in humans and how they are related to noradrenergic stimulation of the prefrontal cortex.Methods Sixteen healthy volunteers (aged 20–29 years) received either modafinil 200 mg or placebo using a double blind crossover design. Two computerized working memory tasks were administered, a numeric manipulation task that requires short-term maintenance of digit-sequences and different degrees of manipulation as well as delayed matching task that assesses maintenance of visuo-spatial information over varying delay lengths. The battery was supplemented by standardized paper pencil tasks of attentional functions.Results Modafinil significantly reduced error rates in the long delay condition of the visuo-spatial task and in the manipulation conditions, but not in the maintenance condition of the numeric task. Analyses of reaction times showed no speed-accuracy trade-off. Attentional control tasks (letter cancellation, trail-making, catch trials) were not affected by modafinil.Conclusions In healthy volunteers without sleep deprivation modafinil has subtle stimulating effects on maintenance and manipulation processes in relatively difficult and monotonous working memory tasks, especially in lower performing subjects. Overlapping attentional and working memory processes have to be considered when studying the noradrenergic modulation of the prefrontal cortex.     

Long-term prognostic significance of HER-2/<Emphasis Type="Italic">neu</Emphasis> in untreated node-negative breast cancer depends on the method of testing

Introduction  

The prognostic significance of HER-2/neu in breast cancer is a matter of controversy. We have performed a study in 101 node-negative breast cancer patients with long-term follow-up not treated in the adjuvant setting, and analysed the prognostic significance of immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH), both separately and in combination, in comparison with traditional prognostic factors.     

Different proliferative and apoptotic activity in peripheral versus central parts of human uterine leiomyomas

OBJECTIVE: To determine whether there are differences in proliferative and apoptotic activity and in expression of sex steroid receptors between central and peripheral parts of human uterine leiomyomas in different menstrual cycle phases. METHODS: Biopsy specimens of the myometrium and peripheral and central parts of uterine leiomyomas were obtained from 15 women in the proliferative phase and 8 women in the secretory phase. Mitotic cells were detected by immunohistochemical staining for Ki67. Apoptotic cells were detected by the TUNEL method. Mitotic and apoptotic indexes were calculated. Tissue levels of oestrogen and progesterone receptors were measured using a commercial monoclonal receptor enzyme immunoassay kit. RESULTS: During the secretory phase the mitotic index was significantly higher in the peripheral than in the central parts of the leiomyomas. During the proliferative phase the apoptotic index was significantly higher in the peripheral compared with the central parts. These differences were not reflected by differences in receptor expression. CONCLUSIONS: The results of this study suggest that the growth of a human uterine leiomyoma mainly occurs in the peripheral parts of the tumour, during the secretory phase of the menstrual cycle. The findings emphasise the importance of being consistent when taking samples for research work.     

Postsynaptic application of a cAMP analogue reverses long-term potentiation in hippocampal CA1 pyramidal neurons

The molecular mechanisms that underlie the maintenance of long-term potentiation (LTP) remain unclear. We have examined the influence of postsynaptic cAMP-dependent processes on LTP maintenance in CA1 hippocampal cells. After LTP induction, drugs affecting cAMP-dependent processes were perfused into the cell through a patch pipette. A cAMP analogue, Rp-cAMPS (4 mM), dramatically decreased the amplitude of potentiated synaptic responses. The amplitude of responses in the control pathway was also decreased but to a lesser extent, indicating a specific effect on the potentiation process. This specific effect was not due to the larger amplitude of potentiated responses, was not use-dependent and, unlike other factors that affect LTP maintenance, did not depend on the delay (2, 10, or 25 min) of drug application after LTP induction. Lower concentrations of Rp-cAMPS (1.0 and 0.4 mM) also produced an inhibitory effect but reduced the LTP and control pathways comparably. One possible action of Rp-cAMPS is competitive inhibition of protein kinase A (PKA). Surprisingly, a potent and noncompetitive PKA inhibitor, regulatory type II subunit of PKA, produced only a weak depression of potentiated and control responses indicating there must be other targets for Rp-cAMPS. Moreover, Sp-8-OH-cAMPS, which is an activator of PKA, and Rp-8-OH-cAMPS, which is a weak inhibitor of PKA, both produced effects similar to those of Rp-cAMPS. We conclude that there are postsynaptic cyclic nucleotide-dependent processes that can specifically alter the mechanisms that maintain LTP and that are not primarily dependent on PKA.