Excitation by dopamine of rat subthalamic nucleus neurones in vitro-a direct action with unconventional pharmacology

Recent anatomical and physiological studies have pointed to a functional innervation of the subthalamic nucleus by dopamine. This nucleus has a pivotal role in basal ganglia function and voluntary movement control and the possibility that dopamine, and dopaminergic medication used in Parkinson's disease, might directly influence its activity is of considerable interest. We have evaluated electrophysiologically the action and pharmacology of dopamine on single subthalamic neurones in rat brain slices. Dopamine increased firing rate to up to a mean of 60% in 98% of the 261 neurones tested when examined using extracellular single-unit recording. This excitation was unaffected by the GABA antagonist picrotoxin, and the glutamate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione, and persisted in a low Ca(2+)/raised Mg(2+) solution, indicative of a direct action, independent of synaptic transmission. Of the 33 cells examined using whole patch-clamp recording, only 13 showed measurable increases in firing rate and/or depolarisations in response to dopamine. Dopamine-responsive cells displayed significantly greater access resistance, suggesting that an unidentified cytoplamic constituent, removed by whole-cell dialysis, was required for the response. Using extracellular recording, the D2-like dopamine receptor agonists quinpirole and bromocryptine, but not the D1-like receptor agonist 1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol, also consistently caused an excitation. This was mimicked by the catecholamine releaser amphetamine in 60% of cells tested. However, the dopamine excitation was not significantly reduced either by the D1-like receptor antagonist 7-chloro8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine or the D2-like receptor antagonists (-)-sulpiride, eticlopride and (+)-butaclamol, and the quinpirole excitation was also unaffected by (-)-sulpiride. In contrast, (-)-sulpiride, eticlopride and (+)-butaclamol all abolished the D2-like receptor-mediated inhibition by dopamine of substantia nigra pars compacta neurones. The alpha-adrenoceptor antagonist phentolamine was a weak antagonist of dopamine excitations, but not of those caused by quinpirole. Dopamine excitations also showed weak sensitivity to the 5-HT(2) antagonist ritanserin, but were unaffected by the alpha(1)-adrenoceptor antagonist prazocin and the beta-adrenoceptor antagonist propranolol. The pharmacology of this dopamine excitation is inconsistent with an action on any known catecholamine receptor. However, the effect of amphetamine indicates that an unidentified monamine--possibly dopamine--can be released within the subthalamic nucleus to cause an excitation. The anomalies of its pharmacological characterisation do not strongly support a physiologically relevant direct action of dopamine in the rat subthalamic nucleus.     

A case of enterolith small bowel obstruction and jejunal diverticulosis

We reported a case of 79-year old woman with known large bowel diverticulosis presenting with small bowel obstruction due to stone impaction - found on plain abdominal X-ray. Contrast studies demonstrated small bowel diverticulosis. At laparotomy, the gall bladder was normal with no stones and no abnormal communication with small bowel - excluding the possibility of a gallstone ileus. Analysis of the stone revealed a composition of bile pigments and calcium oxalate. This was a rare case of small bowel obstruction due to enterolith formation - made distinctive by calcification (previously unreported in the proximal small bowel).     

A preliminary study of multidimensional pain inventory profile differences in predicting treatment outcome in a heterogeneous cohort of patients with chronic pain

OBJECTIVE: The objective was to evaluate whether the Multidimensional Pain Inventory (MPI) is effective for predicting response to interdisciplinary treatment in a heterogeneous group of patients with chronic pain. Changes in patients' profiles to a predominantly adaptive coping status after treatment also were assessed. DESIGN: A prospective study was conducted of patients with an array of pain conditions. A standard evaluation battery, including measures of self-reported pain and disability, psychosocial functioning, helpfulness of the program, and medication use, was used for all patients before and after treatment. The MPI status of patients was evaluated and differential response to treatment was assessed. METHODS: Sixty-five consecutive patients with chronic pain were evaluated before and immediately after participation in an interdisciplinary pain treatment program. This heterogeneous pain-condition cohort was also differentiated on the basis of the MPI to evaluate potential differential response to treatment. RESULTS: Results revealed significant improvement among these patients with chronic pain when a comprehensive interdisciplinary pain-management program was administered. This improvement was seen across the variety of outcomes evaluated, including narcotic medication use. Most important, the MPI subgroup classification did not significantly predict the degree of positive treatment outcome; all subgroups improved. CONCLUSIONS: Although there were major differences in psychosocial functioning before treatment, the MPI was not found to significantly predict response to interdisciplinary treatment in a heterogeneous group of patients with chronic pain. Thus, a comprehensive interdisciplinary treatment program may achieve its full effectiveness across a wide array of pain/disability-related outcome variables, regardless of initial MPI profile categorization.     

A prospective one-year outcome study of interdisciplinary chronic pain management: compromising its efficacy by managed care policies

Although interdisciplinary pain management programs are both therapeutically effective as well as cost-effective, they are currently being underutilized because of managed care policies. We used this prospective comparison trial, with 1-yr follow-up of chronic pain patients, to demonstrate the short- and long-term efficacy of an interdisciplinary pain management program, and evaluate the impact of managed care's physical therapy "carve out" practices on these treatment outcomes. Consecutive chronic pain patients (n = 201) were evaluated, some of whom had their physical therapy "carved out" from this integrated program. Results revealed that successful completion of interdisciplinary pain management was therapeutically effective. Most importantly, physical therapy "carved out" practices had a negative impact on both the short-term and 1-yr follow-up outcome measures. Thus, interdisciplinary pain management is effective in treating the major health problem of chronic pain. However, insurance carrier policies of contracting treatment "carve outs" significantly compromise the efficacy of this evidence-based, best standard of medical care treatment. This raises important medico-legal and ethical issues. IMPLICATIONS: Interdisciplinary pain management is effective and cost-effective in treating the major health problem of chronic pain. The present study demonstrated its efficacy using a prospective, 1-yr posttreatment evaluation methodology. Moreover, physical therapy "carve out" practices by insurance carriers had a negative impact on the outcomes, raising important medico-legal and ethical issues.     

Work related upper limb disorders in telecommunication workers in Malaysia

A total of 323 workers from 5 different occupational groups in the telecommunication industry were studied in this cross sectional study, which sought to determine the prevalence of Work Related Upper Limb Disorders (WRULD) in 5 occupational groups; operators using the Video Display Terminals, switchboard operators, clerks, data entry processors and the supervisors. WRULD was also studied with regard to factors such as sex, race, height, age, stress and the discomfort perceived due to the work station design. The possibility of WRULD was determined from a self-administered questionnaire and confirmed by history and physical examination. Psychological stress and the discomfort due to the workstation were measured from the questionnaire. The overall prevalence was found to be 31.2% and the prevalence among the various occupations differed with it being the highest in the switchboard operators and data processors and the lowest in the supervisors. The older workers and the female workers were found to have higher prevalences of WRULD. It was also found that a higher stress score and a higher score of discomfort perceived at the work station were associated with higher prevalences of WRULD.     

Achieving high uptake of human papillomavirus vaccination in Malaysia through school-based vaccination programme

Background

In 2006, 4 years of planning was started by the Ministry of Health, Malaysia (MOH), to implement the HPV (human papillomavirus) vaccination programme. An inter-agency and multi-sectoral collaborations were developed for Malaysia’s HPV school-based immunisation programme. It was approved for nationwide school base implementation for 13-year-old girls or first year secondary students in 2010. This paper examines how the various strategies used in the implementation over the last 7?years (2010–2016) that unique to Malaysia were successful in achieving optimal coverage of the target population.

Methods

Free vaccination was offered to school girls in secondary school (year seven) in Malaysia, which is usually at the age of 13 in the index year. All recipients of the HPV vaccine were identified through school enrolments obtained from education departments from each district in Malaysia. A total of 242,638 girls aged between 12 to 13?years studying in year seven were approached during the launch of the program in 2010. Approximately 230,000 girls in secondary schools were offered HPV vaccine per year by 646 school health teams throughout the country from 2010 to 2016.

Results

Parental consent for their daughters to receive HPV vaccination at school was very high at 96–98% per year of the programme. Of those who provided consent, over 99% received the first dose each year and 98–99% completed the course per year. Estimated population coverage for the full vaccine course, considering also those not in school, is estimated at 83 to 91% per year. Rates of adverse events reports following HPV vaccination were low at around 2 per 100,000 and the majority was injection site reactions.

Conclusion

A multisectoral and integrated collaborative structure and process ensured that the Malaysia school-based HPV immunisation programme was successful and sustained through the programme design, planning, implementation and monitoring and evaluation. This is a critical factor contributing to the success and sustainability of the school-based HPV immunisation programme with very high coverage.

     

Reproducibility of Static and Dynamic 18F-FDG, 18F-FLT, and 18F-FMISO MicroPET Studies in a Murine Model of HER2+ Breast Cancer

Purpose

The objective of this study is to determine the reproducibility of static 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG), 3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F-FLT), and [¹⁸F]-fluoromisonidazole (¹⁸F-FMISO) microPET measurements, as well as kinetic parameters returned from analyses of dynamic ¹⁸F-FLT and ¹⁸F-FMISO data.

Procedures

HER2+ xenografts were established in nude mice. Dynamic data were acquired for 60 min, followed by a repeat injection and second scan 6 h later. Reproducibility was assessed for the percent-injected dose per gram (%ID/g) for each radiotracer, and with kinetic parameters (K ₁ –k ₄ , K _i ) for ¹⁸F-FLT and ¹⁸F-FMISO.

Results

The value needed to reflect a change in tumor physiology is given by the 95 % confidence interval (CI), which is ±14, ±5, and ±6 % for ¹⁸F-FDG (n?=?12), ¹⁸F-FLT (n?=?11), and ¹⁸F-FMISO (n?=?11) %ID/g, respectively. V _d (=K ₁ /k ₂), k ₃, and K _FLT are the most reproducible ¹⁸F-FLT (n?=?9) kinetic parameters, with 95 % CIs of ±18, ±10, and ±18 %, respectively. V _d and K _FMISO are the most reproducible ¹⁸F-FMISO kinetic parameters (n?=?7) with 95 % CIs of ±16 and ±14 %, respectively.

Conclusions

Percent-injected dose per gram measurements are reproducible and appropriate for detecting treatment-induced changes. Kinetic parameters have larger threshold values, but are potentially sufficiently reproducible to detect treatment response.