By V. Leon. University of Rio Grande.

Impact on quality of Somalia has been ravaged by war for over two dec- care was assessed by comparing the initial diag- ades safe persantine 100 mg, and health facilities in the country are sufer- nosis and prescription (initial management) of ing from a serious shortage of specialist doctors persantine 100mg generic. A questionnaire was also used to gather of care buy persantine 100 mg without prescription, particularly for ill children admitted to the perceptions of clinicians on the added value hospital wards, is a major concern. Consultation room and specialist the shortage of qualifed, skilled human resources paediatrician in Nairobi, Kenya, are enormous. Telemedicine means “medicine at a distance” and the rationale for introducing this in Somalia is simple – export the expertise (though not the experts) to Somalia (33). Study design A prospective observational cohort study assessed the impact of the introduction of telemedicine on the quality of paediatric care. Te added value, as perceived by local clinicians using the service, was also assessed using a questionnaire 67 Research for universal health coverage Summary of fndings of interest among those using telemedicine is Of 3920 paediatric admissions, 346 (9%) were unlikely to explain this fnding as all children referred to the telemedicine service. In 222 chil- with the described conditions were systemati- dren (64% of those referred), a signifcant change cally referred for telemedicine according to the was made to initial case management by the study protocol and cases were reviewed by the specialist paediatrician, and in 88 children (25% same specialist physician. Adverse outcomes of those referred) a life-threatening condition (deaths and losses to follow-up) on paediatric that had initially been missed was diagnosed. All seven period there was a progressive improvement in clinicians involved with telemedicine rated it as the capacity of clinicians to manage complicated having high added value in improving the rec- cases, as demonstrated by a signifcant linear ognition of risk signs and prescription practices. Loss after telemedicine consultations with a specialist in Kenya (expressed as a percentage of all Table 3. However, and enrolment to treatment is the inadequacy of the efectiveness, feasibility and acceptability of diagnostic tools. For decades, the mainstay of TB introducing such technology, and its impact on diagnosis has been sputum-smear microscopy improving access to and quality of care, in simi- for patients with suspected pulmonary TB, fol- lar and post-confict settings need to be evalu- lowed by chest radiography in those with negative ated, ideally with a more rigorous experimental sputum smears. Tis is especially true for HIV-infected TB ■ Eforts towards achieving universal health patients, among whom a signifcant proportion coverage must include people who are hard has negative sputum smears and a normal chest to reach and those who are afected by X-ray (particularly those with advanced HIV/ confict. Furthermore, smear microscopy ■ In Somalia, telemedicine technology cannot diagnose MDR-TB. USA), which uses a common platform to diag- nose mycobacterium tuberculosis (MTB) and rifampicin resistance (RIF) (Fig. Te car- Case-study 5 tridge-based system requires minimal laboratory expertise and fully automated results are avail- New diagnostics for tuberculosis: able in less than two hours. Te performance of a validity assessment of the Xpert® Xpert MTB/RIF was assessed in health facilities in Azerbaijan, India, Peru and South Africa (8). MTB/RIF assay in Azerbaijan, India, Peru and South Africa Summary of fndings Tere were 1730 patients with suspected drug-sensi- The need for research tive or multidrug resistant pulmonary tuberculosis, Despite widespread implementation of the WHO each of whom submitted three sputum specimens, Stop TB Strategy, TB remains a major public and 1462 eligible patients were included in the main health problem. In the Te overall sensitivity (% of true positives detected) same year, there were an estimated 310 000 cases for one sputum specimen in patients with smear- of multidrug-resistant TB (MDR-TB), resistant to positive tuberculosis was 97. Xpert® MTB/RIF machine being used in a health facility in South Africa TB, sensitivity increased with the number of smears procured in the public sector in 73 of the 145 tested (Fig. Te overall sensitivity and speci- countries eligible for concessional pricing (39). It may also be used as a follow-on RIF also depends on the link between diagnosis test to microscopy, especially for patients with and subsequent treatment. As of September National TB control programmes need to 2012, a total of 898 GeneXpert instruments and fnd optimal diagnostic algorithms tailored to 1 482 550 Xpert MTB/RIF cartridges had been local epidemiological conditions to make the 70 Chapter 3 How research contributes to universal health coverage ■ Following WHO recommendations in Fig. Sensitivity of Xpert MTB/RIF December 2010, approximately 900 Xpert assay with multiple smears for MTB/RIF instruments had been procured smear-negative, culture-positive for the public sector in 73 countries by the tuberculosis (commonly seen in end of September 2012. HIV-positive individuals) ■ Further research is under way to confront operational and logistic challenges in laboratory and feld areas, and to assess afordability, epidemiological impact and cost–efectiveness. Case-study 6 The “polypill” to reduce deaths from cardiovascular disease: a randomized controlled trial in India The need for research HIV, human immunodefciency virus. Tere is a growing global epidemic of noncom- Source: Boehme et al. Tese are responsible for two and related research have the potential to bring thirds of the 57 million deaths worldwide each diagnosis closer to patients. Further operational year, with 80% of deaths occurring in low- and studies are under way to investigate the cost, middle-income countries. Deaths from noncom- optimal location and use of the assay within municable diseases are projected to rise from 36 health systems and in combination with other million in 2008 to 52 million in 2030 (42). As investigations of the response to this epidemic, WHO Member States performance of Xpert MTB/RIF have prolifer- have agreed on a set of targets to reduce deaths ated, study design also appears to have improved caused by the four main noncommunicable (K Weyer, WHO, personal communication), diseases by 25% in people aged 30–70 years by indicating an instance of technological develop- 2025 (43). WHO has proposed 10 targets to reach ment boosting the quality of research (38). One of these targets is drug therapy to reduce the prevalence of risk factors for heart Main conclusions attack and stroke (42). Several dif- allowing the diagnosis of patients earlier in ferent drugs (aspirin, beta blockers, angiotensin- the course of their disease. Combining Te results of the study showed that each of the several drugs into a single polypill is appealing components of the polypill reduced the risk of because of its simplicity and acceptability, and cardiovascular disease. Several other trials have because one pill is more likely to be taken rou- since been carried out to demonstrate the efects tinely than several will be. Te gate the efcacy of the polypill in reducing the study was designated “Te Indian Polycap Study” incidence of cardiovascular disease and stroke, (TIPS) (9).

The calcu- uous infusion of ammonia and studied after 4 hours of lated VNH4 from these data was 0 persantine 100mg without prescription. Based on the stoichiometric relationship of the neuronal TCA cycle rate was not significantly increased 1 model of ⁄2 VNH4 Vana order persantine 100mg otc, a rate of anaplerotic glutamine under these conditions relative to the control condition persantine 100 mg on line, formation of 0. The rate of glutamine synthesis under hyperammo- 180 min 11. Studies that have used 14C isotope to measure the increase in V CO2 13C MRS Determination of the Rate of the with hyperammonemia found a rate of 0. As described below, both AV difference and direct isotope To determine the rate of the glutamate/glutamine cycle incorporation measurements of ammonia fixation into glu- from a [1-13C] glucose precursor under physiologic condi- 25: Glutamate and GABA Neurotransmitter Cycles 323 tions, Sibson et al. The value of Vana calculated in this manner ranged by the nerve terminal. A similar high percentage of Vcycle was calculated support of this pathway, which is referred to here as the using measurements of the net incorporation of 14CO into glutamate/ -ketoglutarate cycle, several TCA cycle interme- 2 the cerebral cortex (72). The CO2 measurement is coupled diates including malate, -ketoglutarate, and citrate are re- to total brain anaplerosis, which may be higher than an- leased from glia in cell culture and may be taken up by aplerosis used for net glutamine synthesis, and therefore synaptosomes and cultured neurons (32–34). The two pathways of glutamate trafficking shown in Fig. As described Validation of the Measurement of above, [1-13C] glucose will label both the glial and neuronal Glutamine Synthesis by Comparison of glutamate pools directly via pyruvate dehydrogenase. An RatesCalculated from 15NMRSand13C alternative strategy is to use isotopic precursors that exclu- MRS Results sively introduce label into the glia. Analysis of the flow of isotope from the glia into the neuronal glutamate pool yields To obtain an independent measurement of Vgln and Vana, 15 15 the rate of total neuronal/glial glutamate trafficking. Com- N MRS was used to measure the rate of N-labeled am- 13 parison with the rate calculated using [1- C] glucose gives monia incorporation into the N5 position of glutamine and the fraction of neuronal/glutamate trafficking due to the the unresolved resonance of N2 glutamate plus glutamine glutamate/glutamine cycle (27,36). A mathematical analysis based on the model was used The initial use with MRS of the strategy of glial selective to derive Vgln from the MRS measurement of the time 15 15 precursors to calculate the fraction of glutamate trafficking course of [5- N]glutamine and [2- N] glutamate gluta- due to the glutamate/glutamine cycle measurement was by mine. The labeling in the first hour was almost exclusively Shen et al. Under hyperammo- using N and N labeled ammonia (62,69). The low ini- 15 nemic conditions the rate of N ammonia incorporation tial rate of anaplerosis allows the rates determined from the 15 into the N5 and N2 position of glutamine is the same in N NMRstudy to be compared with the rates measured 13 the glutamate/ -ketoglutarate cycle because only the an- by C NMRunder normal physiologic conditions. The aplerotic pathway of glutamine synthesis is present. To distinguish these models, the endpoint 15N enrichment of the N2 positions Validation of the 13C MRS Measurement of glutamate and glutamine were calculated relative to the of the Glutamate/Glutamine Cycle, and glutamine N5 position for each model using the N5 gluta- Assessment of Alternate Models of mine labeling curve as an input and compared with experi- mental values. Several alternative models to the glutamate/glutamine cycle An additional test of the glutamate/glutamine cycle (Fig 25. In one alternative model model was recently performed using 2-13C] glucose as an the 13C labeling of glutamine represents an internal glial isotopic precursor (27). Label from [2-13C] glucose enters glutamate/glutamine cycle as opposed to trafficking be- the inner positions of glutamate and glutamine only tween the neuron and glia. Label enters C4-glutamine from through pyruvate incorporation into the TCA cycle by py- [1-13C] glucose in this model through exchange in the glial ruvate carboxylase, which is localized to the glia (27,74). In this pathway glu- tamate taken up by the glial cell is transaminated into - ketoglutarate and enters the TCA cycle. Reactions in the TCA cycle convert -ketoglutarate to oxaloacetate, which is then converted to pyruvate by the action of malic enzyme. The pyruvate formed from glutamate is oxidized in the TCA cycle through the action of pyruvate dehydrogenase. Calculated 15N2/15N5 fractional enrichment ratios mate lost to the brain by this pathway is then replaced by of glutamine and glutamate for three models of glial glutamine synthesis. Three models of neuronal glutamate completion were anaplerosis through pyruvate carboxylase. Evidence of this compared with experimental results in which the time course of pathway is derived primarily from isolated cell cultures. It [5-15N] glutamine and [2-15N] glutamine and glutamate were 15 has been proposed that the fraction of glutamate going measured by N nuclear magnetic resonance (NMR) in the cortex of a rat infused with 15N-labeled ammonia at 7 T (36). The mea- through this pathway increases with brain electrical activity sured ratio at the end of the infusion is in excellent agreement (64). If instead the MRS measurement of the glutamate/glutamine cycle is the cycle was internal to the astrocyte the N2/N5 glutamine rela- to cause the fraction of glutamine synthesis of net an- tive 15N enrichment would be two times higher than measured aplerosis to be overestimated and Vcycle to be consequently and no labeling would have been observed in N2 glutamate (model b). If glutamate neurotransmitter repletion took place underestimated, because the labeling of the internal posi- through the astrocytes providing the neurons with -ketogluta- tions of glutamine from the two pathways from [1-13C] rate (model c, which is diagrammed in Fig 25. The unambiguous in vivo anaplerotic and total glutamine synthesis would be similar and 13 the N5/N2 ratio of glutamine would be close to 1. A similarlabeling strategyhas recently flow from glutamate to pyruvate to be measured (10,63). Suggestive evi- dence of this pathway is the finding in several studies that the rate of anaplerosis under normal ammonia conditions tamine (27).