D1/NMDA Receptors and Concurrent Methamphetamine+HIV-1 Tat Neurotoxicity

The interactive effects of HIV-1 infection and methamphetamine (METH) abuse in producing cognitive dysfunction represent a serious medical problem; however, the neural mechanisms underlying this interactive neurotoxicity remain elusive. In this study, we report that a combination of low, sub-toxic doses of METH + HIV-1 Tat 1-86 B, but not METH + HIV-1 gp120, directly induces death of rodent midbrain neurons in vitro. The effects of D1- and NMDA-receptor specific antagonists (SCH23390 and MK-801, respectively) on the neurotoxicity of different doses of METH or HIV-1 Tat alone and on the METH + HIV-1Tat interaction in midbrain neuronal cultures suggest that the induction of the cell death cascade by METH and Tat requires both dopaminergic (D1) and N-methyl D-aspartate (NMDA) receptor-mediated signaling. This interactive METH+Tat neurotoxicity does not occur in cultures of hippocampal neurons, which are predominately glutamatergic, express very low levels of dopamine receptors, and have no functional dopamine transporter (DAT). Thus, the presence of a subpopulation of neurons capable of dopamine release/uptake is essential for METH+Tat induction of the cell death cascade. Overall, our results support the hypothesis that METH and HIV-1 Tat disrupt the normal conjunction of signaling between D1 and NMDA receptors, resulting in neural dysfunction and death.     

α-terpineol reduces mechanical hypernociception and inflammatory response

α‐Terpineol (TPN), a volatile monoterpene alcohol, is relatively non‐toxic and one of the major components of the essential oils of various plant species. In this study, we tested for the antihypernociceptive activity of TPN (25, 50 or 100 mg/kg, i.p.) in mice using mechanical models of hypernociception induced by carrageenan (CG, 300 μg/paw) and the involvement of important mediators of its cascade signalling, such as tumour necrosis factor‐α (TNF‐α, 100 pg/paw), prostaglandin E₂ (PGE₂, 100 ng/paw) or dopamine (DA, 30 μg/paw). We also investigated the anti‐inflammatory effect of TPN on the model of carrageenan‐induced pleurisy and the LPS‐induced nitrite production in murine macrophages. Pre‐systemic treatment with TPN (25, 50 or 100 mg/kg, i.p.) inhibited the development of mechanical hypernociception induced by CG or TNF‐α. A similar effect was also observed upon PGE₂ and DA administration. In addition, TPN significantly inhibited the neutrophil influx in the pleurisy model. TPN (1, 10 and 100 μg/mL) also significantly reduced (p < 0.01) nitrite production in vitro. Our results provide information about the antinociceptive and anti‐inflammatory properties of TPN on mechanical hypernociception and suggest that this compound might be potentially interesting in the development of new clinically relevant drugs for the management of painful and/or inflammatory disease.     

Drug use and sexual behaviors reported by adults: United States, 1999-2002

This report presents prevalence estimates for self-reported adult drug use and sexual behaviors in the United States. Data are from the National Health and Nutrition Examination Survey (NHANES) collected from 1999 to 2002. NHANES surveys a stratified multistage probability sample of the civilian noninstitutionalized population of the United States. Tables included in this report present estimates for use of cocaine, including crack or freebase, or other street drugs, and sexual behavior by selected sociodemographic characteristics among adults 20-59 years of age.     

Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders

Background

Although adverse neuropsychological and neurological health effects are well known among workers with high manganese (Mn) exposures in mining, ore‐processing and ferroalloy production, the risks among welders with lower exposures are less well understood.

Methods

Confined space welding in construction of a new span of the San Francisco–Oakland Bay Bridge without adequate protection was studied using a multidisciplinary method to identify the dose–effect relationship between adverse health effects and Mn in air or whole blood. Bridge welders (n = 43) with little or no personal protection equipment and exposed to a welding fume containing Mn, were administered neurological, neuropsychological, neurophysiological and pulmonary tests. Outcome variables were analysed in relation to whole blood Mn (MnB) and a Cumulative Exposure Index (CEI) based on Mn‐air, duration and type of welding. Welders performed a mean of 16.5 months of welding on the bridge, were on average 43.8 years of age and had on average 12.6 years of education.

Results

The mean time weighted average of Mn‐air ranged from 0.11–0.46 mg/m³ (55% >0.20 mg/m³). MnB >10 µg/l was found in 43% of the workers, but the concentrations of Mn in urine, lead in blood and copper and iron in plasma were normal. Forced expiratory volume at 1s: forced vital capacity ratios (FEV₁/FVC) were found to be abnormal in 33.3% of the welders after about 1.5 years of welding at the bridge. Mean scores of bradykinesia and Unified Parkinson Disease Rating Scale exceeded 4 and 6, respectively. Computer assisted tremor analysis system hand tremor and body sway tests, and University of Pennsylvania Smell Identification Test showed impairment in 38.5/61.5, 51.4 and 88% of the welders, respectively. Significant inverse dose–effect relationships with CEI and/or MnB were found for IQ (p⩽0.05), executive function (p⩽0.03), sustaining concentration and sequencing (p⩽0.04), verbal learning (p⩽0.01), working (p⩽0.04) and immediate memory (p⩽0.02), even when adjusted for demographics and years of welding before Bay Bridge. Symptoms reported by the welders while working were: tremors (41.9%); numbness (60.5%); excessive fatigue (65.1%); sleep disturbance (79.1%); sexual dysfunction (58.1%); toxic hallucinations (18.6%); depression (53.5%); and anxiety (39.5%). Dose–effect associations between CEI and sexual function (p<0.05), fatigue (p<0.05), depression (p<0.01) and headache (p<0.05) were statistically significant.

Conclusions

Confined space welding was shown to be associated with neurological, neuropsychological and pulmonary adverse health effects. A careful enquiry of occupational histories is recommended for all welders presenting with neurological or pulmonary complaints, and a more stringent prevention strategy should be considered for Mn exposure due to inhalation of welding fume.Manganese (Mn) exposure through welding fume has been reported to cause parkinsonian syndrome, sometimes described as welding fume‐related parkinsonism and often misdiagnosed as Parkinson''s disease because of similarities in neurological features including tremor, masked facies and generalised bradykinesia.¹ However, important differences in movement disturbance between Mn‐induced parkinsonism (also called manganism) and idiopathic Parkinson''s disease (IPD) include an awkward high‐stepping dystonic gait in manganism, which is in stark contrast with the typical shuffling gait in patients with IPD, and the tendency to lose balance by falling backward in IPD and forward in manganism. Additionally, tremor characteristics are different, usually resting tremor in IPD and postural intention tremor in manganism.¹ Magnetic resonance imaging (MRI) may be used to differentiate IPD from Mn‐induced parkinsonism if a patient has had excess Mn exposure within the previous 6 months.² Positive MRIs can show cerebral Mn²⁺ deposition in both animals and humans, especially in the globus pallidus (possibly in the striatum), by exhibiting a T₁‐weighted signal hyperintensity.³ IPD, however, is associated with lesions in the substantia nigra pars compacta, and does not exhibit MRI abnormality in the globus pallidus. Two other key features differentiating between Mn‐induced parkinsonism and IPD are: (1) a younger age of onset for Mn‐exposed workers and (2) little or no response to l‐dopa among Mn‐induced parkinsonism cases.^4,5 Case reports of neurological findings in career welders exposed to Mn have shown dystonia bilaterally in the shoulders and four distal limbs, as well as other parkinsonian features—for example, tremor and postural instability.^5,6Welders have been reported to be exposed to “a wide variety of potential respiratory hazards”,^7,8 although earlier studies did not show increases in chronic bronchitis.⁹ However, shipyard welders have been reported to have a higher standardised mortality ratio for lung cancer, a finding which was also supported by the California Occupational Mortality Survey, after adjustment for smoking and asbestos exposure. Sjögren presented evidence of a causal relationship between exposure to stainless steel welding and lung cancer.¹⁰Diagnosis of Mn intoxication in workers actively exposed to excessive Mn in welding fumes can be further supported by biomarkers of exposure indicating increased internal Mn concentrations—for example, in whole blood and to a lesser extent in plasma/serum or urine. Sjögren et al¹¹ reported a mean concentration of 8.4 μg/l for whole blood Mn (MnB) in welders, whereas in other industrial settings the mean MnB ranged from 8.1 to 25.3 µg/l. No clear cutoff value of MnB is currently agreed upon, but HAR postulates that any values >10 µg/l is of concern.Mn air levels (Mn‐air) as reported in a few welder studies indicate that aerosols in welding operations (external exposure) usually contain <0.5 mg Mn/m³ (total dust), but sometimes they are >1 mg Mn/m³. A paramount feature of welding fume is that most of the airborne particles are in the respirable fraction (particle size <10 µm).¹² It is astonishing that reliable levels of respirable Mn particulate have rarely been reported, given the importance of the pulmonary uptake of Mn via the alveoli and its significance for Mn distribution to and effects on the central nervous system.¹³ It should be pointed out that inhalation exposure to Mn is for most of the jurisdictions regulated on the basis of total (or inhalable) dust: however, in the particular case of welding, a permissible exposure level established on the respirable fraction would enhance health prevention strategies.Neuropsychological testing methods used over the past two decades have successfully differentiated Mn‐exposed welders from unexposed controls.^4,6,11 There have been 13 reports on welders showing deficits for motor, tremor, memory and neurocognitive domains, as well as for sleep, sexual function and vision. Although not all reports dealt with all of these domains, 11 studies indicated slowing of motor speed/efficiency^{4,6,11,14,15,16,17,18,19,20,21} and tremor^{3,4,6,14,15,16,17,19,20,21,22}; eight found loss of neurocognitive functioning^{4,6,11,14,16,18,19,21}; and six reported diminished memory function.^{4,6,11,14,18,21} Six studies reported sleep disturbances^{4,6,11,14,15,17} and three sexual problems.^4,6,14 Vision was assessed in only two studies, and both found loss of colour vision associated with Mn exposure.^6,14Welders exposed to Mn‐containing welding fumes and dust have rarely been investigated by clinical neuropsychologists using an epidemiological study design in which actual measurements of internal and external exposure to Mn are studied in relation to outcome variables of a comprehensive test battery (including measures of IQ). Therefore, in the latter part of 2004, we decided to evaluate a welder group with health complaints, identified as employees on the reconstruction project of the San Francisco–Oakland Bay Bridge, which was damaged during the 1989 earthquake. The work on a vulnerable portion of the East span of the bridge began in 2003, requiring confined space welding of 28 anchoring foundations or piers, consisting of steel piles and footing boxes. The welding operations took place below the Bay''s surface in unpressurised cofferdams. During the first 1.5 years of welding on the support piers for the new bridge, welders began to express concerns of ill health feared to be the result of exposure to fumes due to confined space welding. During this period the welders were not required to wear personal protective equipment, and ventilation was minimal or ineffective. After receiving health complaints from almost 90% of the welders employed on the project, workers'' compensation evaluations were enacted, which supported their report of adverse health effects. A multidisciplinary study group took advantage of this “natural experiment” for undertaking additional clinical evaluations (1) to assess the extent of neurological, neuropsychological, neurophysiological and pulmonary effects, (2) to explore whether these effects were associated with internal and/or external measures of Mn exposure and (3) to define a tentative permissible exposure level for Mn in welding fume.     

The Centers for Disease Control and Prevention's Healthy Days Measures – Population tracking of perceived physical and mental health over time

To promote the health and quality of life of United States residents, the U.S. Department of Health and Human Services' Centers for Disease Control and Prevention (CDC) - with 54 state and territorial health agencies - has supported population surveillance of health-related quality of life (HRQOL). HRQOL was defined as "perceived physical and mental health over time." Commonly-used measures of health status and activity limitation were identified and a set of "Healthy Days" HRQOL measures was developed and validated. A core set of these measures (the CDC HRQOL-4) asks about self-rated general health and the number of recent days when a person was physically unhealthy, mentally unhealthy, or limited in usual activities. A summary measure combines physically and mentally unhealthy days. From 1993 to 2001, more than 1.2 million adults responded to the CDC HRQOL-4 in each state-based Behavioral Risk Factor Surveillance System (BRFSS) telephone interview. More than one fifth of all BRFSS respondents also responded to a set of related questions - including five items that assess the presence, main cause and duration of a current activity limitation, and the need for activity-related personal and routine care; as well as five items that ask about recent days of pain, depression, anxiety, sleeplessness, and vitality.     

Cell Cycle Arrest and Apoptosis Induction by an Anticancer Chalcone Epoxide

Safe and effective chemotherapeutic agents for the treatment of pancreatic cancer remain elusive. We found that chalcone epoxides (1,3‐diaryl‐2,3‐epoxypropanones) inhibited growth in two pancreatic cancer cell lines, BxPC‐3 and MIA PaCa‐2. Three compounds were active, with GI₅₀ values of 5.6 to 15.8 µM. Compound 4a , 1,3‐bis‐(3,4,5‐trimethoxyphenyl)‐2,3‐epoxypropanone, had an average GI₅₀ of 14.1 µM in the NCI 60‐cell‐line panel. To investigate the mode of action, cell cycle analyses of BxPC‐3 cells were carried out. Treatment of cells with 50 µM 4a resulted in dramatic accumulation at G2/M (61% after 12 h for 4a vs. 15% for untreated cells). The cells rapidly entered apoptosis. After 12 h, 26% of cells treated with 50 µM 4a had entered apoptosis vs. 4% for cells treated with 100 µM etoposide and 2% for untreated cells. Compound 4a interfered with paclitaxel enhancement of tubulin polymerization, suggesting microtubules as the site of action. Reaction of thiol nucleophiles with 4a under basic conditions resulted in epoxide ring‐opening and retroaldol fragmentation, yielding alkylated thiol. MALDI mass spectrometry showed that retroaldol reaction occurred upon treatment of β‐tubulin with 4a . The site of alkylation was identified as Cys³⁵⁴. Chalcone epoxides warrant further study as potential agents for treatment of cancer.     

Assessment of long-term glycemia in type I diabetes using multiple blood glucose values stored in a memory-containing reflectometer

The relationship between repetitive hemoglobin A₁ values and daily blood glucose tests performed by 20 insulin-dependent diabetic outpatients was assessed over a six-week period using a modified reflectance meter capable of storing blood glucose determinations automatically. An average of four and a half determinations per subject per day was recorded with a range of average blood glucose values between 82 ± 2 mg/dl and 316 ± 5 mg/dl (mean ± SE). The relationship between average blood glucose and hemoglobin A₁ values was significant when hemoglobin A₁ values at the end of the six-week period were correlated with the mean blood glucose level over that period (r = 0.55, p <0.02), but improved when a more remote hemoglobin A₁ value obtained at 10 weeks was used (r = 0.64, p <0.005). Hemoglobin A₁ values covering two-week intervals were extremely poor in reflecting average glycemia. The average fasting blood glucose level in these subjects was highly correlated with the overall daily blood glucose values (r = 0.89, p <0.0001), although the coefficients of variation of these parameters averaged 43 ± 3 percent and 47 ± 2 percent, respectively, and were greater than that of the hemoglobin A₁ values over six weeks (10 ± 2 percent). It is concluded that labile blood glucose control in patients with insulin-dependent diabetes is accurately reflected by the average fasting blood glucose level, although multiple determinations must be employed. Satisfactory assessment may be made by use of hemoglobin A₁ value provided that the hemoglobin A₁ determination follows a sufficiently long period of time, presumably related to the turnover of glycosylated hemoglobin.