Affective learning in adults with intellectual disability: an experiment using evaluative conditioning.

BACKGROUND: Evaluative conditioning is a form of affective learning in which initially neutral stimuli acquire an affective value through association with negative or positive stimuli. Recent research shows an important role for cognitive resources in this type of learning. This form of affective learning has rarely been studied in intellectual disability (ID). METHOD: We examined evaluative conditioning in 16 adults with mild to moderate ID compared to age- and gender-matched control participants. Neutral shapes and symbols were repeatedly paired with positive, neutral or negative unconditioned stimuli (faces or International Affective Picture System images). There was also an extinction phase. RESULTS: There was significant acquisition of conditioning in both groups. Stimuli paired with positive images were evaluated more positively, and stimuli paired with negative images were evaluated more negatively. Post-extinction ratings however show that these novel affective associations were not maintained by individuals with ID as much as by individuals in the control group. CONCLUSIONS: We conclude that ID modulates some aspects of affective learning but not necessarily initial preference acquisition.

The pre-hospital epidemiology and management of spinal cord injuries in New South Wales: 2004-2008.

CONTEXT: Patients who have sustained a traumatic spinal cord injury require appropriate management in the immediate post-injury period for both survival and to reduce the chances of costly and disabling permanent neurological deficits. Emerging time-critical neuroprotective therapies require the prompt recognition and transfer of patients to a specialised centre for early intervention. METHODS: The Ambulance Research Institute, with the New South Wales State Spinal Cord Injury Service retrospectively linked prehospital data to spinal cord injury unit (SCIU) outcome data for all 324 patients transported by ambulance and subsequently admitted to a SCIU with a persisting traumatic spinal cord injury (SCI) between January 2004 and June 2008, with the aim of identifying factors that impact on the provision of timely and appropriate care. RESULTS: Paramedics appropriately managed 88% of SCI patients. Only 4.9% of patients had initial vital signs potentially indicative of neurological injury. The median time to a SCIU was 12h, with 60% of patients undergoing multiple transfers. The odds of reaching a SCIU in over 24h were 1.71 times greater for patients injured in a major city (95% CI 1.00-2.90) in comparison to other areas of NSW. More SCI patients with multiple trauma experienced delays in reaching a SCIU (59%), compared to patients with isolated SCI (40%; p=0.039). Patients initially transported to a designated major trauma centre were more likely to be delayed in reaching a SCIU, regardless of whether their injury was an isolated SCI or associated with multiple trauma, compared with other patients. Patients who took greater than 24h to reach a SCIU were 2.5 times more likely to develop a secondary complication (95% CI 1.51-4.17, p=0.0004). Patients who sustained their SCI as a result of a low fall were older and less likely to have their SCI identified and treated early, with less than half of this group reaching a SCIU within 24h compared with other SCI patients (OR 0.42, 95% CI 0.19-0.93, p=0.004). CONCLUSION: Early recognition, appropriate prehospital management, triage, timely and appropriate interfacility transfers of all SCI patients are critical for access to specialised care and reducing preventable complications. Elderly fallers present particular challenges to early identification.

Noninvasive hemodynamic monitoring in the emergency department.

PURPOSE OF REVIEW: Emergency department patients are frequently undifferentiated, need accurate risk assessment and stratification, and are time-critical in their need for diagnosis and resuscitation. Valid, noninvasive hemodynamic monitoring modalities are essential to differentiate high from low risk patients, and to perform goal-directed management. This review analyses recent literature, which describes innovation in the range of noninvasive monitoring tools and places them in the emergency medicine context. RELEVANT FINDINGS: A range of noninvasive measures of hemodynamic status are both commonly used, or are in the research and development phase. Pulse oximetry waveforms, electrocardiogram-based heart rate variability, Doppler and B-mode ultrasound, echocardiography, transthoracic bioimpedance, pressure pulse waveform analysis and near-infrared spectroscopy all have potential value in diagnosis and monitoring of hemodynamics, particularly used to explore autonomic nervous system control of cardiovascular function and by extension the early phases of compensation for illness and injury. Noninvasive techniques coupled with advances in data visualization and pattern recognition bring the potential for revolution to emergency department hemodynamic monitoring. SUMMARY: Noninvasive measures of hemodynamic status and function are increasingly being used, although much still remains in the research domain. Noninvasive measures may not only offer similar variables to traditional vital signs, but add a new dimension of hemodynamic descriptors.

Expression of the WASP verprolin-homologues (WAVE members) in human breast cancer.

BACKGROUND: The WASP family proteins have been indicated to play a vital role in the formation of membrane protrusions required for cell locomotion. WAVE proteins are an important subfamily that also plays a crucial role in actin polymerisation, which is vital to cell migration. However, not much is known about the clinical significance of this subfamily in cancers. We report, for the first time, the expression of the WAVE molecules, at protein and mRNA levels, in human breast cancer. MATERIALS AND METHODS: The expression of the 3 WAVE molecules at the mRNA and protein levels in a cohort of 122 human breast cancers and 32 normal breast tissues were analysed and correlated with the patients' pathological and clinical information as well as outcome (120 months follow-up). RESULTS: All 3 WAVE molecules were detected in mammary tissues. WAVE2 transcripts were expressed in high levels in all breast tumours. Over-expression of WAVE2 was seen in node-positive cases as well as in moderately and poorly differentiated tumours. Also, high levels of WAVE2 expression were associated with death due to disease (p = 0.02) at follow-up. No distinct associations were found between the WAVE1 and WAVE3 transcripts and the breast cancer cells.

A selenopyrylium photosensitizer for photodynamic therapy related in structure to the antitumor agent AA1 with potent in vivo activity and no long-term skin photosensitization.

Cationic chalcogenopyrylium dyes 5 were synthesized in six steps from p-aminophenylacetylene (9), have absorption maxima in methanol of 623, 654, and 680 nm for thio-, seleno-, and telluropyrylium dyes, respectively, and generate singlet oxygen with quantum yields [Phi((1)O(2))] of 0.013, 0.029, and 0.030, respectively. Selenopyrylium dye 5-Se was phototoxic to cultured murine Colo-26 and Molt-4 cells. Initial acute toxicity studies in vivo demonstrate that, at 29 mg (62 micromol)/kg, no toxicity was observed with 5-Se in animals followed for 90 days under normal vivarium conditions. In animals given 10 mg/kg of 5-Se via intravenous injection, 2-8 nmol of 5-Se/g of tumor was found at 3, 6, and 24 h postinjection. Animals bearing R3230AC rat mammary adenocarcinomas were treated with 10 mg/kg of 5-Se via tail-vein injection and with 720 J cm(-2) of 570-750-nm light from a filtered tungsten lamp at 200 mW cm(-2) (24 h postinjection of 5-Se). Treated animals gave a tumor-doubling time of 9 +/- 4 days, which is a 300% increase in tumor-doubling time relative to the 3 +/- 2 days for untreated dark controls. Mechanistically, the mitochondria appear to be a target. In cultured R3230AC rat mammary adenocarcinoma cells treated with 0.1 and 1.0 microM 5-Se and light, mitochondrial cytochrome c oxidase activity was inhibited relative to cytochrome c oxidase activity in untreated cells. Irradiation of isolated mitochondrial suspensions treated with 10 microM dye 5-Se inhibited cytochrome c oxidase activity. The degree of enzyme inhibition was abated in a reduced oxygen environment. Superoxide dismutase, at a final concentration of 30 U, did not alter the photosensitized inhibition of mitochondrial cytochrome c oxidase by dye 5-Se. The data suggest that singlet oxygen may play a major role in the photosensitized inhibition of mitochondrial cytochrome c oxidase.

Water-soluble, core-modified porphyrins as novel, longer-wavelength-absorbing sensitizers for photodynamic therapy.

Water-soluble, core-modified 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-dithiaporphyrin (1) and 5,10,15, 20-tetrakis(4-sulfonatophenyl)-21,23-diselenaporphyrin (2) were prepared as the tetrasodium salts by the sulfonation of 5,10,15, 20-tetraphenyl-21,23-dithiaporphyrin (3) and -21, 23-diselenaporphyrin (4), respectively, with sulfuric acid. Compounds 3 and 4 were prepared by the condensation of pyrrole with either 2,5-bis(phenylhydroxymethyl)thiophene (5) or 2, 5-bis(phenylhydroxymethyl)selenophene (6) in propionic acid. The addition of benzaldehyde to 2,5-dilithiothiophene or 2, 5-dilithioselenophene gives 5 or 6, respectively, as a nearly equimolar mixture of meso- and d,l-diastereomers. Careful crystallization of 5 gives a single diastereomer by removing the crystalline product from the equilibrating mixture of diastereomers in solution. Photodynamic therapy (PDT) with 1 has an LD(50) of less than 25 microg/mL against Colo-26 cells in culture and exhibits a lethal dose for 90% or more at concentrations greater than 50 microg/mL. In contrast, PDT with 5,10,15, 20-tetrakis(4-sulfonatophenyl)porphyrin (TPPS(4)) requires concentrations of greater than 100 microg/mL to achieve LD(50). Neither 1 nor TPPS(4) shows significant photoactivity against the murine T-cell line, MOLT-4, above the dark toxicity. Sensitizer 1 shows no toxicity or side effects in BALB/c mice observed for 30 days following a single intravenous injection of 10 mg (9.1 micromol)/kg. Distribution studies show that sensitizer 1 accumulates in the tumors of BALB/c mice bearing Colo-26 or EMT-6 tumors with sensitizer concentration roughly doubling as the dosage of 1 increased from 5 to 10 mg/kg. In vivo studies show that PDT with sensitizer 1 at both 3.25 and 10 mg/kg with 135 J cm(-2) of 694-nm light is effective against Colo-26 tumors in BALB/c mice.

Synthesis and evaluation of chalcogenopyrylium dyes as potential sensitizers for the photodynamic therapy of cancer.

A series of thiopyrylium (2), selenopyrylium (3), and telluropyrylium dyes (4) was prepared via the addition of Grignard reagents to either 2, 6-di(4-dimethylamino)phenylchalcogenopyran-4-ones (5a) or 2-[4-(dimethylamino)phenyl]-6-phenylchalcogenopyran-4-ones (5b) followed by elimination and ion exchange to give the chloride salts. The absorption spectra and quantum yields for singlet oxygen generation of these dyes suggested that the dyes would have utility as sensitizers for PDT. Selenopyrylium dyes 3a and 3d with quantum yields for singlet oxygen generation of 0.040 and 0.045, respectively, were phototoxic to Colo-26 cells in culture. The toxicity of the dyes 2-4 was evaluated in clonogenic assays of human carcinoma cell lines. Importantly, the presence of a sulfur, selenium, or tellurium heteroatom in the molecules had no predictable impact on the toxicity of any particular dye set. Substituents at the 2-, 4-, and 6-positions of the dye had a much greater impact on cytotoxicity. The IC(50) values determined in the clonogenic assays did not correlate with chemical properties in the dye molecules such as reduction potential or lipophilicity. Initial in vivo toxicity studies showed no toxicity for these dyes at dosages between 7.2 and 38 micromol/kg in BALB/c mice.

Recombinant human osteogenic protein 1 is a potent stimulator of the synthesis of cartilage proteoglycans and collagens by human articular chondrocytes.

OBJECTIVE: To study the effects of recombinant human osteogenic protein-1 (rHuOP-1; bone morphogenetic protein-7) on proteoglycan and collagen synthesis by human articular chondrocytes. METHODS: Articular chondrocytes from fetal, adolescent, and adult human donors were cultured in alginate beads for 4 days in a mixture of Ham's F-12, Dulbecco's modified Eagle's medium, 10% fetal bovine serum (FBS), then for an additional 3-10 days in the presence and absence of rHuOP-1, with and without FBS. Chondrocyte synthetic activity was measured as the amount of incorporation of 35S-sulfate into proteoglycans and 3H-proline into hydroxyproline. Sieve chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were performed to identify specific proteoglycans and collagens. RESULTS: Recombinant human OP-1 markedly stimulated the synthesis of proteoglycans (mostly aggrecan) and collagens (predominantly type II) by all chondrocyte preparations. This did not require the presence of FBS and was associated with continued expression of the chondrocyte phenotype. CONCLUSION: Recombinant human OP-1 is a more potent stimulator of the synthesis of cartilage-specific molecules by human articular chondrocytes than are other factors tested for comparison, including TGF beta 1 and activin A.

Doxycycline inhibits type X collagen synthesis in avian hypertrophic chondrocyte cultures.

Doxycycline, a member of the tetracycline family, has been shown to reduce a type X collagen epitope as detected by immunohistochemistry with a monoclonal antibody in an avian explant culture system (). It was also shown to decrease collagenase and gelatinase activities and thus matrix degradation. This study investigates the effect of doxycycline on type X collagen synthesis in monolayer cultures of hypertrophic chondrocytes. Protein synthesis was evaluated by radioisotopic labeling during doxycycline, tetracycline, or minocycline treatment. Radiolabeled proteins were analyzed by gel electrophoresis, and total collagen was quantitated by hydroxyproline analysis. Additionally, the synthesis of type X collagen was measured by immunoprecipitation. Doxycycline was found to inhibit type X production more effectively than either of the other tetracyclines at comparable dose levels. Furthermore, type X collagen was inhibited more than other collagens, non-collagenous proteins and proteoglycans, with maximal inhibition at 80 microg/ml and an IC50 of 7 microg/ml. This inhibition by doxycycline was specific for type X collagen at 10 microg/ml, and the pattern was distinct from cycloheximide, a recognized inhibitor of protein translation. This suppression of type X collagen could not be overcome by excess extracellular calcium, conditions that have been demonstrated to induce synthesis of this protein (2).

Systemic lupus erythematosus and the obstetrical patient--implications for the anaesthetist.

Systemic lupus erythematosus (SLE) is a multisystem, chronic inflammatory disease characterized by autoantibody production. The disease is most frequently found in women of childbearing age and therefore may co-exist with pregnancy. The clinical manifestations of the disease are variable and depend on the severity of damage to organ systems such as musculoskeletal, renal, haematological, neurological, cardiac, and respiratory. Many patients require drugs such as aspirin or prednisone. The pregnant patient may experience exacerbations of the disease, neonatal loss, and obstetrical complications such as pre-eclampsia. Patients with the Lupus Anticoagulant are at risk for an abnormal perinatal course. The anaesthetic management will depend on the patient's clinical status and the well-being of the fetus. The patient should be examined to determine the extent of end organ damage, current medications, and the health of the fetus. Laboratory investigations such as a coagulation screen and tests of renal function should be performed before anaesthetic intervention if time permits. A multidisciplinary approach to care of the patient and resources to manage complications are essential to optimize the outcome for both mother and newborn.

Alprazolam in the treatment of panic disorders.

An open clinical trial of alprazolam therapy of patients with panic disorder or agoraphobia with panic attacks was undertaken to clarify certain issues not resolved by previous studies. These included the proportion of patients who significantly improve with alprazolam; the relative time courses for improvement in panic attacks, anticipatory anxiety, and phobic avoidance; whether successful alprazolam treatment alters vulnerability to panic with sodium lactate infusion; and what factors predict response to alprazolam in panic patients. Thirty patients meeting DSM-III criteria for panic disorder or agoraphobia with panic attacks completed a 12-week open clinical trial, and 22 were considered responders. In responders, panic attacks showed rapid improvement, whereas improvement of anticipatory anxiety and phobic avoidance was more variable. Successful alprazolam therapy appeared to block lactate vulnerability. High pretreatment Hamilton Anxiety Scale scores were associated with poor treatment response. The data suggest that alprazolam is an effective treatment for panic disorder and agoraphobia with panic attacks, and acts by directly blocking panic attacks.