Abeta(1-42)-induced JNK and ERK activation in rabbit hippocampus is differentially regulated by lithium but is not involved in the phosphorylation of tau

Administration of Abeta(1-42) into the rabbit brain induces apoptosis and phosphorylation of tau. These Abeta effects correlate with the activation of JNK and ERK, but not of p38. Treatment with 7 mM lithium inhibits apoptosis, modulates JNK and ERK and does not affect the phosphorylation of tau. Our results demonstrate that lithium, at this dose, effectively inhibits the Abeta-induced apoptosis but has no effect on tau phosphorylation, and that MAP kinases are not involved in the phosphorylation of tau.     

Substance abuse-related P300 differences in response to an implicit memory task

The current study examined electrophysiological measures of cognitive efficiency in alcoholics and controls using a negative priming paradigm derived from DeSchepper and Treisman (J. Exp. Psychol. Learn. Mem. Cog. 22 (1996) 27). In this task, sets of novel shapes were presented: Two overlapping green and red shapes on the left and a single white shape on the right. Participants were instructed to ignore the red shape, but to determine whether the green shape was the same as or different from the white shape. On primed trials, previously red (to be ignored; i.e., irrelevant) shapes became green (relevant) shapes in a second component of the task. Participants who were capable of ignoring irrelevant stimuli were expected to experience more difficulty in the primed condition. Therefore, we predicted that, if alcohol-related impairment in cognitive efficiency is due to inability to respond "appropriately" (i.e., ignore irrelevant stimuli), alcoholics would experience less negative priming than normal controls. Both amplitude and latency of the P300 component of the event-related potential were measured in response to each trial condition. Using a 2 x 2 (group x condition) ANOVA with repeated conditions, a significant pattern of group x condition interactions was observed at right frontal, F4 (p=.05) and central parietal, Pz (p=.03) electrode sites on measures of P300 amplitude. A significant group x condition latency interaction was observed at the central parietal electrode, Pz (p=.006). Overall, controls exhibited increased P300 amplitude and latency in response to negatively primed trials. As predicted, alcoholics did not demonstrate this pattern, a finding consistent with alcohol-related cognitive inefficiency.     

Identification of a novel urokinase receptor splice variant and its prognostic relevance in breast cancer

The cellular receptor for urokinase-type plasminogen activator, uPAR, plays a central role in both cell surface-associated proteolysis and cellular adhesion. In the present study, we systematically searched for splice variants of uPAR mRNA in human cells and tumor tissues by qualitative RT-PCR using specific primers for uPAR exons 1 and 6. Beside the wild-type (wt) uPAR mRNA and the previously described splice variant lacking exon 5 (uPAR-del5), a novel splice variant lacking both exons 4 and 5 (uPAR-del4/5) was found predominantly in various cancer cell lines. To elucidate whether alternatively spliced uPAR mRNA may be translated and post-translationally processed, we generated stably transfected Chinese hamster ovary cells, which harbor expression plasmids of wt uPAR and various uPAR variants including uPAR-del5 and uPAR-del4/5. By ELISA, flow cytofluorometry, and Western blot analysis, we confirmed synthesis and secretion of wt uPAR and the uPAR variants by the use of domain-specific monoclonal antibodies against uPAR. For quantification of uPAR mRNA variants, we established two highly sensitive real-time RT-PCR assays based on LightCycler technology. Study of their expression in a representative set of breast cancer tissues indicated that the novel mRNA variant uPAR-del4/5 was expressed very frequently and independently of uPAR mRNA variants covering exon 4 (uPAR-wt and uPAR-del5). Higher uPAR-del4/5 expression was significantly associated with shorter disease-free survival (p = 0.0004) of breast cancer patients. These results suggest that uPAR-del4/5 mRNA may serve as a novel prognostic marker in breast cancer.     

Vpr R77Q is associated with long-term nonprogressive HIV infection and impaired induction of apoptosis

The absence of immune defects that occurs in the syndrome of long-term nonprogressive (LTNP) HIV infection offers insights into the pathophysiology of HIV-induced immune disease. The (H[F/S]RIG)(2) domain of viral protein R (Vpr) induces apoptosis and may contribute to HIV-induced T cell depletion. We demonstrate a higher frequency of R77Q Vpr mutations in patients with LTNP than in patients with progressive disease. In addition, T cell infections using vesicular stomatitis virus G (VSV-G) pseudotyped HIV-1 Vpr R77Q result in less (P = 0.01) T cell death than infections using wild-type Vpr, despite similar levels of viral replication. Wild-type Vpr-associated events, including procaspase-8 and -3 cleavage, loss of mitochondrial transmembrane potential (deltapsi(m)), and DNA fragmentation factor activation are attenuated by R77Q Vpr. These data highlight the pathophysiologic role of Vpr in HIV-induced immune disease and suggest a novel mechanism of LTNP.     

A prospective study on the implications of a base deficit during fluid resuscitation

An excessive base deficit (BD) and elevated serum lactate are increasingly recognized as important markers of a malperfusion state during the resuscitation of thermally injured patients. In a previous retrospective study, we found that patients with a BD less than -6 mmol/l during fluid resuscitation developed more severe systemic inflammatory response syndrome (SIRS), more frequent acute respiratory distress syndrome (ARDS), and more severe multiple organ dysfunction syndrome (MODS). The object of this study was to reexamine prospectively the relationship between the BD during fluid resuscitation and the subsequent development of SIRS, ARDS, and MODS by undertaking a prospective observational study of a cohort of consecutive burn patients. Analysis was completed on 38 patients with a mean age of 39 +/- 17 years and a mean %TBSA burn of 36 +/- 15%. The mean BD in the first 24 hours was less than -6 mmol/l in five patients (BD24 < -6 group), and was greater than -6 mmol/L in 33 patients (BD24 > -6 group). Patients in both groups were resuscitated to nearly identical endpoints of urinary output (1.2 ml/kg/hr in the BD24 < -6 group vs 1.3 ml/kg/hr in the BD24 > -6 group). Patients in the BD24 < -6 group had a trend toward a greater number of SIRS signs on the first postburn day, had a significantly higher incidence of ARDS (P =.02), and had significantly more severe MODS (P <.001) than patients in the BD24 > -6 group. The results concur with those of our previous retrospective study. Despite resuscitation to an acceptable urinary output, some burn patients develop a more extreme BD and go on to experience more severe organ dysfunction than do patients who do not generate a BD. The effect of specific correction of the BD during fluid resuscitation is not known at this time.     

Does synchronous nasal surgery increase the risk of post-operative haemorrhage in adult patients undergoing tonsillectomy?

Otolaryngologists occasionally perform simultaneous procedures on their patients, the indication being co-existent pathology. This is not a universally accepted practice as some feel that the post-operative morbidity is increased in such patients. Tonsillectomy is a common otolaryngological procedure and the main life-threatening complication, haemorrhage is easily identifiable. This study compares the incidence of post-operative haemorrhage requiring admission in patients undergoing tonsillectomy alone with that in patients undergoing tonsillectomy and nasal surgery. A retrospective study was undertaken of all adult patients undergoing tonsillectomy alone or tonsillectomy and synchronous nasal surgery in Aberdeen Royal Infirmary. Seventy-one patients (34 male) with a mean age of 23 years underwent tonsillectomy and synchronous nasal surgery over a nine-year period 1991-1999. The commonest nasal procedure was reduction of the inferior turbinates (in 48 cases). Three hundred and ninety-eight patients (131 male) with a mean age of 23 years underwent tonsillectomy alone over a nine-month period, July 1998 to April 1999. The incidence of post-tonsillectomy haemorrhage in the synchronous nasal surgery group was 12.7 per cent (9 out of 71) compared with four per cent (16 out of 398) in the tonsillectomy alone group (p <0.01, Chi-squared test). There was no difference in hospital stay between the two groups (mean two days). Synchronous nasal surgery increases the incidence of post-tonsillectomy haemorrhage.     

Spinal 5-HT(2) and 5-HT(3) receptors mediate low, but not high, frequency TENS-induced antihyperalgesia in rats

Transcutaneous electrical nerve stimulation (TENS) is a form of non-pharmacological treatment for pain. Involvement of descending inhibitory systems is implicated in TENS-induced analgesia. In the present study, the roles of spinal 5-HT and alpha(2)-adrenoceptors in TENS analgesia were investigated in rats. Hyperalgesia was induced by inflaming the knee joint with 3% kaolin-carrageenan mixture and assessed by measuring paw withdrawal latency (PWL) to heat before and 4 h after injection. The (1). alpha(2)-adrenergic antagonist yohimbine (30 microg), (2). 5-HT antagonist methysergide (5-HT(1). and 5-HT(2). 30 microg), one of the 5-HT receptor subtype antagonists, (3). NAN-190 (5-HT(1A), 15 microg), (4). ketanserin (5-HT(2A), 30 microg), (5). MDL-72222 (5-HT(3), 12 microg), or (6). vehicle was administered intrathecally prior to TENS treatment. Low (4 Hz) or high (100 Hz) frequency TENS at sensory intensity was then applied to the inflamed knee for 20 min and PWL was determined. Selectivity of the antagonists used was confirmed using respective agonists administered intrathecally. Yohimbine had no effect on the antihyperalgesia produced by low or high frequency TENS. Methysergide and MDL-72222 prevented the antihyperalgesia produced by low, but not high, frequency TENS. Ketanserin attenuated the antihyperalgesic effects of low frequency TENS whereas NAN-190 had no effect. The results from the present study show that spinal 5-HT receptors mediate low, but not high, frequency TENS-induced antihyperalgesia through activation of 5-HT(2A) and 5-HT(3) receptors in rats. Furthermore, spinal noradrenergic receptors are not involved in either low or high frequency TENS antihyperalgesia.     

Combined risk factors contributing to cerebral venous thrombosis in a young woman

Cerebral venous thrombosis is a rare condition affecting predominantly adolescents or young adults. The presentation is often non-specific, and delay in diagnosis is common. The otolaryngologist may be consulted about the radiological findings of lateral sinus thrombosis and mastoid changes. The association of congenital thrombophilia with unusual presentations of venous thrombosis, especially in young individuals is now well documented. We present a case of lateral and sagittal sinus thrombosis complicated by cerebral venous infarction in a girl with protein C deficiency and masked mastoiditis. Unusual forms of venous thrombosis, including cerebral venous thrombosis may develop in association with a single risk factor for thrombosis, but additional risk factors should be sought especially when thrombosis presents in very young individuals. This case draws attention to the multi-causal nature of cerebral venous thrombosis in young adults, and highlights the issue of masked mastoiditis. A coordinated approach by otolaryngological and haematological teams is recommended in such cases.