Ginkgo biloba modulates ET-I/NO signalling in Lead Acetate induced rat model of endothelial dysfunction: Involvement of oxido-inflammatory mediators.

This study investigated the modulatory effect of Ginkgo biloba extract on lead acetate-induced endothelial dysfunction. Animals were administered GBE (50 mg/kg and 100 mg/kg orally) after exposures to lead acetate (25 mg/kg orally) for 14 days. Aorta was harvested after euthanasia, the tissue was homogenised, and supernatants were decanted after centrifuging. Oxidative, nitrergic, inflammatory, and anti-apoptotic markers were assayed using standard biochemical procedure, ELISA, and immunohistochemistry, respectively. GBE reduced lead-induced oxidative stress by increasing SOD, GSH, and CAT as well as reducing MDA levels in endothelium. Pro-inflammatory cytokines (TNF-α and IL-6) were reduced while increasing Bcl-2 protein expression. GBE lowered endothelin-I and raised nitrite levels. Histological changes caused by lead acetate were normalised by GBE. Our findings suggest that Ginkgo biloba extract restored endothelin-I and nitric oxide functions by increasing Bcl-2 protein expression and reducing oxido-inflammatory stress in endothelium.

Total Liver Vitamin A Reserves, Determined With 13C2-Retinol Isotope Dilution, are Similar Among Tanzanian Preschool Children in Areas With Low and High Vitamin A Exposure.

BACKGROUND: In Tanzania, some districts have single vitamin A (VA) interventions and others have multiple interventions. There is limited information on total liver VA reserves (TLRs) among preschool children (PSC) in Tanzania. OBJECTIVES: We assessed total body VA stores (TBSs) and TLRs among PSC living in 2 districts with low and high exposures to VA interventions using 13C-retinol isotope dilution. METHODS: A cross-sectional, health facility-based study was conducted in 2 districts with access to VA supplementation only (low exposure to VA interventions) or multiple interventions (high exposure to VA interventions) to determine TLRs in 120 PSC aged 36-59 months. A questionnaire was used to collect data. Height and weight were measured, and the prevalence of undernutrition was based on z-scores. Blood samples were collected for measurement of TBSs, TLRs, retinol, biomarkers of infection and inflammation, and hemoglobin. 13C2-retinyl acetate (1.0 µmol) was administered to each child after blood collection, and the second sample was taken 14 days later. Serum was analyzed with HPLC and gas chromatography-combustion-isotope ratio mass spectrometry. Mann-Whitney U test was used to compare medians of nonnormally distributed variables. Pearson χ2 test was used to assess associations between 2 categorical variables. RESULTS: Median TBSs differed between PSC from low-exposure (196 µmol; IQR, 120 µmol) and high-exposure (231 µmol; IQR, 162 µmol) intervention areas (P = 0.015). Median TLRs were 0.23 µmol/g liver (IQR, 0.14 µmol/g liver) and 0.26 µmol/g liver (IQR, 0.16 µmol/g liver) from low- and high-exposure areas, respectively, which did not significantly differ (P = 0.12). Prevalences of VA deficiency (VAD; ≤0.1 µmol/g liver) were 6.3% and 1.7% for PSC from low- and high-exposure areas, respectively. There was no significant difference in VAD (P = 0.25). No child had hypervitaminosis A (≥1.0 µmol/g liver). CONCLUSIONS: TLRs in Tanzanian PSC from 2 districts did not differ between low and high exposures to VA interventions. The majority had adequate VA stores. VAD in the study area presented a mild public health problem.

Disrupted thalamic T-type Ca2+ channel expression and function during ethanol exposure and withdrawal.

Chronic ethanol exposure produces profound disruptions in both brain rhythms and diurnal behaviors. The thalamus has been identified as a neural pacemaker of both normal and abnormal rhythms with low-threshold, transient (T-type) Ca(2+) channels participating in this activity. We therefore examined T-type channel gene expression and physiology in the thalamus of C57Bl/6 mice during a 4-wk schedule of chronic intermittent ethanol exposures in a vapor chamber. We found that chronic ethanol disrupts the normal daily variations of both thalamic T-type channel mRNA levels and alters thalamic T-type channel gating properties. The changes measured in channel expression and function were associated with an increase in low-threshold bursts of action potentials during acute withdrawal periods. Additionally, the observed molecular and physiological alterations in the channel properties in wild-type mice occurred in parallel with a progressive disruption in the normal daily variations in theta (4-9 Hz) power recorded in the cortical electroencephalogram. Theta rhythms remained disrupted during a subsequent week of withdrawal but were restored with the T-type channel blocker ethosuximide. Our results demonstrate that a key ion channel underlying the generation of thalamic rhythms is altered during chronic ethanol exposure and withdrawal and may be a novel target in the management of abnormal network activity due to chronic alcoholism.

Assessing healthcare providers' knowledge and practices relating to insecticide-treated nets and the prevention of malaria in Ghana, Laos, Senegal and Tanzania.

BACKGROUND: Research evidence is not always being disseminated to healthcare providers who need it to inform their clinical practice. This can result in the provision of ineffective services and an inefficient use of resources, the implications of which might be felt particularly acutely in low- and middle-income countries. Malaria prevention is a particularly compelling domain to study evidence/practice gaps given the proven efficacy, cost-effectiveness and disappointing utilization of insecticide-treated nets (ITNs). METHODS: This study compares what is known about ITNs to the related knowledge and practices of healthcare providers in four low- and middle-income countries. A new questionnaire was developed, pilot tested, translated and administered to 497 healthcare providers in Ghana (140), Laos (136), Senegal (100) and Tanzania (121). Ten questions tested participants' knowledge and clinical practice related to malaria prevention. Additional questions addressed their individual characteristics, working context and research-related activities. Ordinal logistic regressions with knowledge and practices as the dependent variable were conducted in addition to descriptive statistics. RESULTS: The survey achieved a 75% response rate (372/497) across Ghana (107/140), Laos (136/136), Senegal (51/100) and Tanzania (78/121). Few participating healthcare providers correctly answered all five knowledge questions about ITNs (13%) or self-reported performing all five clinical practices according to established evidence (2%). Statistically significant factors associated with higher knowledge within each country included: 1) training in acquiring systematic reviews through the Cochrane Library (OR 2.48, 95% CI 1.30-4.73); and 2) ability to read and write English well or very well (OR 1.69, 95% CI 1.05-2.70). Statistically significant factors associated with better clinical practices within each country include: 1) reading scientific journals from their own country (OR 1.67, 95% CI 1.10-2.54); 2) working with researchers to improve their clinical practice or quality of working life (OR 1.44, 95% CI 1.04-1.98); 3) training on malaria prevention since their last degree (OR 1.68, 95% CI 1.17-2.39); and 4) easy access to the internet (OR 1.52, 95% CI 1.08-2.14). CONCLUSIONS: Improving healthcare providers' knowledge and practices is an untapped opportunity for expanding ITN utilization and preventing malaria. This study points to several strategies that may help bridge the gap between what is known from research evidence and the knowledge and practices of healthcare providers. Training on acquiring systematic reviews and facilitating internet access may be particularly helpful.

Bridging the gaps among research, policy and practice in ten low- and middle-income countries: development and testing of a questionnaire for researchers.

BACKGROUND: A questionnaire could assist researchers, policymakers, and healthcare providers to describe and monitor changes in efforts to bridge the gaps among research, policy and practice. No questionnaire focused on researchers' engagement in bridging activities related to high-priority topics (or the potential correlates of their engagement) has been developed and tested in a range of low- and middle-income countries (LMICs). METHODS: Country teams from ten LMICs (China, Ghana, India, Iran, Kazakhstan, Laos, Mexico, Pakistan, Senegal, and Tanzania) participated in the development and testing of a questionnaire. To assess reliability we calculated the internal consistency of items within each of the ten conceptual domains related to bridging activities (specifically Cronbach's alpha). To assess face and content validity we convened several teleconferences and a workshop. To assess construct validity we calculated the correlation between scales and counts (i.e., criterion measures) for the three countries that employed both and we calculated the correlation between different but theoretically related (i.e., convergent) measures for all countries. RESULTS: Internal consistency (Cronbach's alpha) for sets of related items was very high, ranging from 0.89 (0.86-0.91) to 0.96 (0.95-0.97), suggesting some item redundancy. Both face and content validity were determined to be high. Assessments of construct validity using criterion-related measures showed statistically significant associations for related measures (with gammas ranging from 0.36 to 0.73). Assessments using convergent measures also showed significant associations (with gammas ranging from 0.30 to 0.50). CONCLUSIONS: While no direct comparison can be made to a comparable questionnaire, our findings do suggest a number of strengths of the questionnaire but also the need to reduce item redundancy and to test its capacity to monitor changes over time.

Use of mHealth Devices to Screen for Atrial Fibrillation: Cost-Effectiveness Analysis.

BACKGROUND: With an estimated prevalence of around 3% and an about 2.5-fold increased risk of stroke, atrial fibrillation (AF) is a serious threat for patients and a high economic burden for health care systems all over the world. Patients with AF could benefit from screening through mobile health (mHealth) devices. Thus, an early diagnosis is possible with mHealth devices, and the risk for stroke can be markedly reduced by using anticoagulation therapy. OBJECTIVE: The aim of this work was to assess the cost-effectiveness of algorithm-based screening for AF with the aid of photoplethysmography wrist-worn mHealth devices. Even if prevented strokes and prevented deaths from stroke are the most relevant patient outcomes, direct costs were defined as the primary outcome. METHODS: A Monte Carlo simulation was conducted based on a developed state-transition model; 30,000 patients for each CHA2DS2-VASc (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category [female]) score from 1 to 9 were simulated. The first simulation served to estimate the economic burden of AF without the use of mHealth devices. The second simulation served to simulate the economic burden of AF with the use of mHealth devices. Afterwards, the groups were compared in terms of costs, prevented strokes, and deaths from strokes. RESULTS: The CHA2DS2-VASc score as well as the electrocardiography (ECG) confirmation rate had the biggest impact on costs as well as number of strokes. The higher the risk score, the lower were the costs per prevented stroke. Higher ECG confirmation rates intensified this effect. The effect was not seen in groups with lower risk scores. Over 10 years, the use of mHealth (assuming a 75% ECG confirmation rate) resulted in additional costs (€1=US $1.12) of €441, €567, €536, €520, €606, €625, €623, €692, and €847 per patient for a CHA2DS2-VASc score of 1 to 9, respectively. The number of prevented strokes tended to be higher in groups with high risk for stroke. Higher ECG confirmation rates led to higher numbers of prevented strokes. The use of mHealth (assuming a 75% ECG confirmation rate) resulted in 25 (7), -68 (-54), 98 (-5), 266 (182), 346 (271), 642 (440), 722 (599), 1111 (815), and 1116 (928) prevented strokes (fatal) for CHA2DS2-VASc score of 1 to 9, respectively. Higher device accuracy in terms of sensitivity led to even more prevented fatal strokes. CONCLUSIONS: The use of mHealth devices to screen for AF leads to increased costs but also a reduction in the incidence of stroke. In particular, in patients with high CHA2DS2-VASc scores, the risk for stroke and death from stroke can be markedly reduced.

Tanzania national survey on iodine deficiency: impact after twelve years of salt iodation.

BACKGROUND: In many low-income countries, children are at high risk of iodine deficiency disorders, including brain damage. In the early 1990s, Tanzania, a country that previously suffered from moderate to severe iodine deficiency, adopted universal salt iodation (USI) as an intervention strategy, but its impact remained unknown. METHODS: We report on the first national survey in mainland Tanzania, conducted in 2004 to assess the extent to which iodated salt was used and its apparent impact on the total goitre prevalence (TGP) and urinary iodine concentrations (UIC) among the schoolchildren after USI was initiated. In 2004, a cross-sectional goitre survey was conducted; covering 140,758 schoolchildren aged 6 - 18 years were graded for goitre according to new WHO goitre classification system. Comparisons were made with district surveys conducted throughout most of the country during the 1980s and 90s. 131,941 salt samples from households were tested for iodine using rapid field test kits. UIC was determined spectrophotometrically using the ammonium persulfate digestion method in 4523 sub-sampled children. RESULTS: 83.6% (95% CI: 83.4 - 83.8) of salt samples tested positive for iodine. Whereas the TGP was about 25% on average in the earlier surveys, it was 6.9% (95%CI: 6.8-7.0) in 2004. The TGP for the younger children, 6-9 years old, was 4.2% (95%CI: 4.0-4.4), n = 41,965. In the 27 goitre-endemic districts, TGP decreased from 61% (1980s) to 12.3% (2004). The median UIC was 204 (95% CF: 192-215) microg/L. Only 25% of children had UIC <100 microg/L and 35% were > or = 300 microg/L, indicating low and excess iodine intake, respectively. CONCLUSION: Our study demonstrates a marked improvement in iodine nutrition in Tanzania, twelve years after the initiation of salt iodation programme. The challenge in sustaining IDD elimination in Tanzania is now two-fold: to better reach the areas with low coverage of iodated salt, and to reduce iodine intake in areas where it is excessive. Particular attention is needed in improving quality control at production level and perhaps the national salt iodation regulations may need to be reviewed.

Optogenetically-Induced Population Discharge Threshold as a Sensitive Measure of Network Excitability.

Network excitability is governed by synaptic efficacy, intrinsic excitability, and the circuitry in which these factors are expressed. The complex interplay between these factors determines how circuits function and, at the extreme, their susceptibility to seizure. We have developed a sensitive, quantitative estimate of network excitability in freely behaving mice using a novel optogenetic intensity-response procedure. Synchronous activation of deep sublayer CA1 pyramidal cells produces abnormal network-wide epileptiform population discharges (PDs) that are nearly indistinguishable from spontaneously-occurring interictal spikes (IISs). By systematically varying light intensity, and therefore the magnitude of the optogenetically-mediated current, we generated intensity-response curves using the probability of PD as the dependent variable. Manipulations known to increase excitability, such as sub-convulsive doses (20 mg/kg) of the chemoconvulsant pentylenetetrazol (PTZ), produced a leftward shift in the curve compared to baseline. The anti-epileptic drug levetiracetam (LEV; 40 mk/kg), in combination with PTZ, produced a rightward shift. Optogenetically-induced PD threshold (oPDT) baselines were stable over time, suggesting the metric is appropriate for within-subject experimental designs with multiple pharmacological manipulations.

Evidence of the effect of rural background on rural practise in Australian dental practitioners: Does gender play a role?

BACKGROUND: People residing outside the capital cities have poorer oral health than their city counterparts. Health workforce shortages and stability issues can have negative health effects on rural populations. There has been an increasing proportion of women entering the dental practitioner workforce in Australia. This study investigated whether dental practitioners who have a rural background are more likely to work in a rural area than those who do not have a rural background; and whether the gender of dental practitioners plays a role. METHODS: A self-administered questionnaire was sent to a sample of dental practitioners via their professional dental associations. Practice location was assigned as either 'urban' or 'rural' using the Australian Standard Geographical Classification - Remoteness Area categories and measured with demographic characteristics of the respondents. Prevalence ratios (PR) were estimated using Poisson regression with robust standard errors. RESULTS: Participants with a rural background were more than twice as likely (male PR = 2.23, 95% confidence interval (CI) = 0.79-6.26; female PR = 2.82, 95% CI = 1.35-5.87) to practise in a rural area than those with an urban background. CONCLUSIONS: Dental practitioners with rural backgrounds were more than twice as likely to work in a rural practice as their urban counterparts.

Unique presynaptic and postsynaptic roles of Group II metabotropic glutamate receptors in the modulation of thalamic network activity.

The thalamic reticular nucleus (TRN) is a sheet of GABAergic neurons that project to other TRN neurons and to associated thalamocortical relay nuclei. The TRN receives glutamatergic synaptic inputs from cortex as well as reciprocal inputs from the collaterals of thalamocortical neurons. In addition to ionotropic glutamate receptors, metabotropic glutamate receptors (mGluRs) are present in the TRN circuitry. Using whole cell voltage clamp recordings, we pharmacologically characterized unique pre- and postsynaptic functions for Group II mGluRs (mGluR 2 and mGluR 3) within the TRN circuitry in ferrets. mGluR 2 was found on presynaptic cortical axon terminals in the TRN, where it reduced glutamate release, while mGluR 3 acted postsynaptically on TRN cells to increase membrane conductance. Using miniature inhibitory postsynaptic current analysis, we also found that picrotoxin-sensitive intra-TRN GABA-mediated neurotransmission was not affected by administration of a Group II mGluR agonist, indicating that neither mGluR 2 nor 3 acts on presynaptic GABA-containing terminals within the TRN. Because strong corticothalamic activation is implicated in abnormal thalamic rhythms, we used extracellular recordings in the lateral geniculate nucleus to study the effect of Group II mGluR agonists upon these slow oscillations. We induced approximately 3 Hz spike-and-wave discharge activity through corticothalamic stimulation, and found that such activity was reduced in the presence of the Group II mGluR agonist, (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268). These data indicate that Group II mGluR reduce the impact of corticothalamic excitation, and that they may be a useful target in the reduction of absence-like rhythms.

Differential response dynamics of corticothalamic glutamatergic synapses in the lateral geniculate nucleus and thalamic reticular nucleus.

The corticothalamic feedback pathway provides excitatory synaptic input to both the thalamic reticular nucleus and the lateral geniculate nucleus. We studied excitatory postsynaptic currents elicited from corticothalamic stimulation in the visual sector of the thalamic reticular nucleus and the lateral geniculate nucleus to compare the response of these neurons to stimulation of their common input pathway. Using whole cell patch clamp recordings in ferret thalamic slices, we compared single excitatory postsynaptic current decay kinetics, presynaptic glutamate release dynamics through paired pulse facilitation and responses to corticothalamic train stimulation. We found that single thalamic reticular nucleus excitatory postsynaptic currents were significantly sharper than lateral geniculate nucleus responses. The mean thalamic reticular nucleus excitatory postsynaptic current decay constant (tau) was 4.9+/-0.5 ms, while the mean lateral geniculate nucleus excitatory postsynaptic current tau value was 11.8+/-0.8 ms. Presynaptic release dynamics as measured by responses to paired stimuli were conserved between the thalamic reticular nucleus and lateral geniculate nucleus. However, facilitating responses to train stimulation were markedly different between nuclei. Lateral geniculate nucleus responses showed proportionately larger facilitation (reaching 842.9 +/- 76.4% of excitatory postsynaptic current 1 amplitude) than thalamic reticular nucleus responses (reaching 223.1 +/- 44.0% of excitatory postsynaptic current 1 amplitude). These data indicate that while the corticothalamic pathway produces excitatory postsynaptic currents in both the thalamic reticular nucleus and lateral geniculate nucleus, other factors uniquely affect the functional integration of the inputs in each nucleus.

Diurnal gene expression patterns of T-type calcium channels and their modulation by ethanol.

The transient (T-type) calcium channel participates in the generation of normal brain rhythms as well as abnormal rhythms associated with a range of neurological disorders. There are three different isoforms of T-type channels and all are particularly enriched in the thalamus, which is involved in generating many of these rhythms. We report a novel means of T-type channel regulation in the thalamus that involves diurnal regulation of gene expression. Using real time polymerase chain reaction we detected a diurnal pattern of gene expression for all T-type channel transcripts. The peak of gene expression for the CaV3.1 transcript occurred close to the transition from active to inactive (sleep) states, while expression for both CaV3.2 and CaV3.3 peaked near the transition of inactive to active phase. We assessed the effect of chronic consumption of ethanol on these gene expression patterns by examining thalamic tissues of ethanol-consuming cohorts that were housed with the controls, but which received ethanol in the form of a liquid diet. Ethanol consumption resulted in a significant shift of peak gene expression of approximately 5 h for CaV3.2 toward the normally active phase of the mice, as well as increasing the overall gene expression levels by approximately 1.7-fold. Peak gene expression was significantly increased for both CaV3.2 and CaV3.3. Measurements of CaV3.3 protein expression reflected increases in gene expression due to ethanol. Our results illustrate a novel regulatory mechanism for T-type calcium channels that is consistent with their important role in generating thalamocortical sleep rhythms, and suggests that alterations in the pattern of gene expression of these channels could contribute to the disruption of normal sleep by ethanol.

Cortical feedback to the thalamus is selectively enhanced by nitric oxide.

The brain somehow merges visual information with the behavioral context in which it is being processed, a task that is often attributed to the cerebral cortex. We have identified a new role of the gaseous neurotransmitter, nitric oxide (NO), in the early selective enhancement of corticogeniculate communication that may participate in this process at the level of the thalamus. Visual information is dynamically gated through the thalamus by brainstem neurons that release acetylcholine and NO. Using in vitro electrophysiology, we characterized NO effects on excitatory postsynaptic potentials and currents (EPSCs) elicited from retinal and cortical pathways in the lateral geniculate nucleus of the ferret. NO selectively and reversibly increased cortically-evoked postsynaptic responses, and this effect was mimicked by cyclic guanosine 3',5'-monophosphate (cGMP). Conversely, NO inhibited retinally-evoked responses independently of cGMP. We demonstrated that these differential effects were specific to postsynaptic N-methyl-d-aspartate (NMDA) receptors by studying treatment effects on pharmacologically isolated EPSCs from each pathway. We propose that when brainstem activity is increased during behavioral arousal or rapid eye movement sleep, NO may increase the relative sensitivity of relay neurons to corticogeniculate feedback. The net effect of these changes in synaptic processing may be to selectively suppress peripheral information while unifying data carried by reentrant corticogeniculate loops with the behavioral context in which the visual information is processed.

The native T-type calcium current in relay neurons of the primate thalamus.

The generation of thalamic bursts depends upon calcium currents that flow through transiently open (T)-type calcium channels. In this study, we characterized the native T-type calcium current underlying thalamic burst responses in the macaque monkey. Current clamp recordings from lateral geniculate nucleus (LGN) slices showed characteristic burst responses when relay cells were depolarized from relatively hyperpolarized membrane potentials. These bursts could also be elicited by stimulation of excitatory synaptic inputs to LGN cells. Under voltage clamp conditions, the inactivation kinetics of native currents recorded from primate LGN neurons showed consistency with T-type currents recorded in other mammals and in expression systems. Real-time reverse transcriptase PCR performed on RNA isolated from the LGN (including tissues isolated from magnocellular and parvocellular laminae) detected voltage-dependent calcium channel (Ca(v)) 3.1, Ca(v) 3.2, and Ca(v) 3.3 channel transcripts. Ca(v) 3.1 occurred at relatively higher expression than other isoforms, consistent with in situ hybridization studies in rats, indicating that the molecular basis for burst firing in thalamocortical systems is an important conserved property of primate physiology. Since thalamic bursts have been observed during visual processing as well as in a number of CNS disorders, studies of the expression and modulation of these currents at multiple levels are critical for understanding their role in vision and for the discovery of new treatments for disruptions of thalamic rhythms.

Vitamin A supplementation in Tanzania: the impact of a change in programmatic delivery strategy on coverage.

BACKGROUND: Efficient delivery strategies for health interventions are essential for high and sustainable coverage. We report impact of a change in programmatic delivery strategy from routine delivery through the Expanded Programme on Immunization (EPI+) approach to twice-yearly mass distribution campaigns on coverage of vitamin A supplementation in Tanzania METHODS: We investigated disparities in age, sex, socio-economic status, nutritional status and maternal education within vitamin A coverage in children between 1 and 2 years of age from two independent household level child health surveys conducted (1) during a continuous universal targeting scheme based on routine EPI contacts for children aged 9, 15 and 21 months (1999); and (2) three years later after the introduction of twice-yearly vitamin A supplementation campaigns for children aged 6 months to 5 years, a 6-monthly universal targeting scheme (2002). A representative cluster sample of approximately 2,400 rural households was obtained from Rufiji, Morogoro Rural, Kilombero and Ulanga districts. A modular questionnaire about the health of all children under the age of five was administered to consenting heads of households and caretakers of children. Information on the use of child health interventions including vitamin A was asked. RESULTS: Coverage of vitamin A supplementation among 1-2 year old children increased from 13% [95% CI 10-18%] in 1999 to 76% [95%CI 72-81%] in 2002. In 2002 knowledge of two or more child health danger signs was negatively associated with vitamin A supplementation coverage (80% versus 70%) (p = 0.04). Nevertheless, we did not find any disparities in coverage of vitamin A by district, gender, socio-economic status and DPT vaccinations. CONCLUSION: Change in programmatic delivery of vitamin A supplementation was associated with a major improvement in coverage in Tanzania that was been sustained by repeated campaigns for at least three years. There is a need to monitor the effect of such campaigns on the routine health system and on equity of coverage. Documentation of vitamin A supplementation campaign contacts on routine maternal and child health cards would be a simple step to facilitate this monitoring.

Intrapleural cisplatin and cytarabine in the management of malignant pleural effusions: a Lung Cancer Study Group trial.

Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. Pleurodesis with tetracycline or other sclerosing agents is the usual treatment for malignant pleural effusions. In contrast to this approach, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the effusion. Intracavitary cisplatin-based chemotherapy, which is cytotoxic rather than sclerosing, has proven safe and effective via the intraperitoneal route in ovarian cancer and malignant mesothelioma. There has been little previous experience, however, with intrapleural cisplatin-based chemotherapy. As part of a planned series of trials in malignant mesothelioma, the Lung Cancer Study Group first evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. From April 1986 to November 1987, 46 patients with cytologically proven, symptomatic, and previously untreated malignant pleural effusions were entered on study. A single dose of cisplatin 100 mg/m2 plus cytarabine 1,200 mg was instilled into the pleural space via a chest tube, which was then immediately removed. Patients were evaluated for toxicity and response at 24 hours; 1, 2, and 3 weeks; and then monthly. No recurrence of the effusion was considered a complete response (CR). Partial response (PR) was defined as a 75% or greater decrease in the amount of the effusion on serial chest radiographs. One patient experienced reversible grade 4 renal toxicity, four patients had grade 3 hematologic toxicity, and five patients had grade 3 cardiopulmonary toxicity. The overall response rate (CR plus PR) at 3 weeks was 49% (18 of 37 patients). The median length of response was 9 months for a CR and 5.1 months for a PR. The outcome of this trial was sufficiently encouraging that this regimen has been incorporated into subsequent trials for malignant pleural mesothelioma.

Ontogeny of gonadotropin, testosterone, and inhibin secretion in normal boys through puberty based on overnight serial sampling.

To investigate hormonal changes occurring in male puberty, we measured LH, FSH, testosterone, and alpha-inhibin immunoactivity in serum samples drawn every 10 min for 8 h (2100-0500 h) from each of 50 normal prepubertal and pubertal boys, aged 8.4-18.8 yr. We measured gonadotropins with ultrasensitive immunofluorometric assays, and testosterone and alpha-inhibin with RIAs. Unlike previous studies, which indexed pubertal development with Tanner stages, we used testicular volume, a more finely graduated indicator of development, to reveal patterns that were obscured when subjects were grouped by Tanner stage. The overnight mean concentration of each hormone increased with testis volume, but the rate of increase on a logarithmic scale slowed as testes grew. Log LH rose precipitously in the late prepubertal and early pubertal periods and plateaued during mid- and late puberty. Based on fitted regression curves, LH increased about 20-fold (from 0.11 IU/L) between testis volumes of 1 and 10 mL, but only an additional 1.5-fold by 30 mL. The developmental trajectory of log testosterone was like that of log LH, but rose less steeply early in puberty. From 0.14 micrograms/L at a testis volume of 1 mL, testosterone increased about 8.5-fold by 10 mL and an additional 3-fold by 30 mL. In contrast, logarithms of overnight mean FSH and alpha-inhibin concentrations rose at a more nearly constant rate throughout puberty. From 0.62 IU/L at a testis volume of 1 mL, the FSH concentration doubled by 10 mL and increased an additional 1.7-fold by 30 mL. From 270 ng/L at a testis volume of 1 mL, inhibin increased 1.5-fold by 10 mL and an additional 1.3-fold by 30 mL. Overnight pulse amplitudes exhibited developmental trajectories similar to those of the corresponding overnight mean concentrations. The number of LH and testosterone pulses during the sampling period averaged 2.2 and 2.1, respectively, at Tanner stage 1 and increased to 4.5 and 3.2, respectively, at Tanner stage 5. The number of FSH and inhibin pulses remained constant throughout puberty, averaging 3.3 and 3.5, respectively. Pairwise correlations among hormone concentrations were strong, reflecting common increasing trends through puberty; however, after accounting for developmental trends, FSH, LH, and testosterone concentrations remained correlated, whereas inhibin was uncorrelated with each of the other three hormones. Measuring gonadotropins with ultrasensitive assays and analyzing the results on a logarithmic scale as a function of testis volume made clear the dramatic hormonal changes that begin before the clinical changes of puberty.

Sequence of the OXA2 beta-lactamase: comparison with other penicillin-reactive enzymes.

The nucleotide sequence of the unusual plasmid-mediated OXA2 beta-lactamase is presented, and compared with other beta-lactamases. The OXA2 enzyme has similar features at the presumed active site, but no other significant regions of homology with other penicillin-reactive enzymes. The active site homology may therefore represent convergent evolution of otherwise dissimilar genes.

Neurotransmitters contained in the subcortical extraretinal inputs to the monkey lateral geniculate nucleus.

The lateral geniculate nucleus (LGN) is the thalamic relay of retinal information to cortex. An extensive complement of nonretinal inputs to the LGN combine to modulate the responsiveness of relay cells to their retinal inputs, and thus control the transfer of visual information to cortex. These inputs have been studied in the most detail in the cat. The goal of the present study was to determine whether the neurotransmitters used by nonretinal afferents to the monkey LGN are similar to those identified in the cat. By combining the retrograde transport of tracers injected into the monkey LGN with immunocytochemical labeling for choline acetyl transferase, brain nitric oxide synthase, glutamic acid decarboxylase, tyrosine hydroxylase, or the histochemical nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase reaction, we determined that the organization of neurotransmitter inputs to the monkey LGN is strikingly similar to the patterns occurring in the cat. In particular, we found that the monkey LGN receives a significant cholinergic/nitrergic projection from the pedunculopontine tegmentum, gamma-aminobutyric acid (GABA)ergic projections from the thalamic reticular nucleus and pretectum, and a cholinergic projection from the parabigeminal nucleus. The major difference between the innervation of the LGN in the cat and the monkey is the absence of a noradrenergic projection to the monkey LGN. The segregation of the noradrenergic cells and cholinergic cells in the monkey brainstem also differs from the intermingled arrangement found in the cat brainstem. Our findings suggest that studies of basic mechanisms underlying the control of visual information flow through the LGN of the cat may relate directly to similar issues in primates, and ultimately, humans.

Development of the cholinergic, nitrergic, and GABAergic innervation of the cat dorsal lateral geniculate nucleus.

Cholinergic projections from the brainstem have been shown to be important modulators of visual activity in the dorsal lateral geniculate nucleus (dLGN) of the adult, but little is known about the role of these modulatory inputs during development. We examined the postnatal development of the cholinergic innervation of the dLGN by using an monoclonal antibody against choline acetyl transferase (ChAT). We also investigated the development of GABAergic interneurons in the dLGN by using an antibody against glutamic acid decarboxylase (GAD), and the developmental expression of brain nitric oxide synthase (BNOS) by using an antibody against this enzyme. We found that brainstem cells surrounding the brachium conjunctivum express ChAT at birth, although axons in the dLGN do not express ChAT until the end of the first postnatal week. Cholinergic synaptic contacts were observed as early as the second postnatal week. The number of axons stained with the ChAT antibody increased slowly during the subsequent weeks in the dLGN and reached adult levels by the eighth postnatal week. GABAergic interneurons were present at birth and reached their adult soma size by the third postnatal week. GABAergic fibers are dense at birth but change during development from a diffuse pattern to clustered arrangements that can be recognized as distinct rings of GAD staining by P35. Cellular expression of BNOS was seen within all dLGN laminae during development. The BNOS-stained cells are tentatively identified as interneurons because their soma sizes were similar to those of GAD-stained cells. Although cellular BNOS staining remained robust in the C1-3 laminae through adulthood, cellular expression of BNOS in the A laminae declined during the first five postnatal weeks and remains sparse in the adult. As cellular BNOS staining declined, there was a steady increase in BNOS-stained fibers, which paralleled the increase of ChAT-stained fibers that are known to colocalize BNOS in the adult. Our results emphasize the continued transformations of intrinsic as well as extrinsic innervation patterns that occur during the development, of the dLGN.