Search PubMed⌕ Search

Biomedical subjects

J Church

Publications and source records attributed to J Church.

At least 37 records · Page 2Linked to original sources
PubMed1999

The rise and fall of the Aldabran giant tortoise population.

At the end of the 19th century, after prolonged and extensive harvesting, indigenous giant tortoises had been eliminated from all islands in the Indian Ocean, except Aldabra atoll, where only a few survived. With greatly reduced levels of exploitation during the 20th century, the population recovered to a revised estimated total of 129,000 in 1973-1974, when the first sample census was conducted. A repeat census in 1997 revealed a highly significant reduction in numbers over the past 24 years to an estimated total of 100,000. The great majority of tortoises are still found at relatively high density in south-eastern Grande Terre, where the number of animals has declined by more than one-third. In contrast, low-density subpopulations on Malabar and Picard have almost doubled in size, but they represent less than 5% of the total population. Corroborative evidence for the crash in the Grande Terre subpopulation comes from two independent observations: a significant increase in tortoise mortality; and a significant decline in tortoise counts on long-term population monitoring transects. These population changes are attributed to natural population regulatory mechanisms, exacerbated by low rainfall years in the period 1980-1997, including two consecutive years of below average rainfall in 1995-1996 and 1996-1997.

Animals↗
PubMed1999

Effects of pH changes on calcium-mediated potentials in rat hippocampal neurons in vitro.

The effects of changes in extra- and intracellular pH (pHo and pHi, respectively) on potentials mediated by the influx of Ca2+ ions were investigated in intracellular "current-clamp" recordings from CA1 pyramidal neurons in rat hippocampal slices. In neurons which exhibited a "regular-spiking" discharge in response to depolarizing current injection at pH 7.3, perfusion with pH 7.7 medium led to the development of burst firing. Conversely, neurons which were "burst-firing" at pH 7.3 became regular spiking upon exposure to pH 6.9 medium. In addition, the rebound depolarization following a current-evoked hyperpolarization to >- 60 mV, which in part reflects activation of a low-voltage-activated Ca2+ conductance, was reduced at pHo 6.9 and enhanced at pHo 7.7. Neither the burst firing pattern of discharge nor the augmented rebound depolarization observed during perfusion with pH 7.7 medium was due to the reduction in [Cl-]o consequent upon the increase in [HCO3-]o at a constant PCO2. The magnitudes of the fast afterhyperpolarization which follows a single depolarizing current-evoked action potential and the slow afterhyperpolarization which follows a train of action potentials were attenuated and enhanced, respectively, during perfusion with pH 6.9 and pH 7.7 media, compared to responses obtained at pH 7.3. Reducing pHi at a constant pHo (by exposure to pH 7.3 HCO3-/CO2-free medium buffered with 30 mM HEPES) also attenuated fast and slow afterhyperpolarizations. In tetrodotoxin- and tetraethylammonium-poisoned slices, perfusion with pH 6.9 and pH 7.7 media reduced and increased, respectively, the magnitude of current-evoked Ca2+-dependent depolarizing potentials and their associated slow afterhyperpolarizations, compared with responses obtained at pH 7.3. In contrast, reducing pHi at a constant pHo elicited only a small reduction in the magnitude of Ca2+ spikes but markedly attenuated the subsequent slow afterhyperpolarization. The results suggest that, in rat CA1 hippocampal pyramidal neurons, Ca2+-dependent depolarizing potentials mediated by the influx of Ca2+ ions through voltage-activated Ca2+ channels are sensitive to changes in pHo. These effects of changes in pHo are not dependent upon changes in pHi consequent upon the changes in pHo. Changes in pHo also affect the magnitudes of fast and slow afterhyperpolarizations mediated by Ca2+-dependent K+ conductances. In these cases, however, the effects of changes in pHo are mimicked by changes in pHi at a constant pHo, suggesting in turn that the effects of changes in pHo on fast and slow afterhyperpolarizations may be mediated both by changes in Ca2+ influx (reflecting mainly changes in pHo) and by direct effects of changes in pHi (consequent upon changes in pHo) on Ca2+-dependent K+ conductances.

Action Potentials↗
PubMed1999

Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons.

The ratiometric indicators 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein and Fura-2 were employed to examine, respectively, intracellular pH (pHi) and calcium ([Ca2+]i) changes evoked by anoxia in cultured postnatal rat hippocampal neurons at 37 degrees C. Under both HCO3-/CO2- and HEPES-buffered conditions, 3-, 5- or 10-min anoxia induced a triphasic change in pHi consisting of an initial fall in pHi, a subsequent rise in pHi in the continued absence of O2 and, finally, a further rise in pHi upon the return to normoxia, which recovered towards preanoxic steady-state pHi values if the duration of the anoxic insult was < or = 5 min. In parallel experiments performed on sister cultures, anoxia of 3, 5 or 10 min duration evoked rises in [Ca2+]i which, in all cases, commenced after the start of the fall in pHi, reached a peak at or just following the return to normoxia and then declined towards preanoxic resting levels. Removal of external Ca2+ markedly attenuated increases in [Ca2+]i, but failed to affect the pHi changes evoked by 5 min anoxia. The latency from the start of anoxia to the start of the increase in pHi observed during anoxia was increased by perfusion with media containing either 2 mM Na+, 20 mM glucose or 1 microM tetrodotoxin. Because each of these manoeuvres is known to delay the onset and/or attenuate the magnitude of anoxic depolarization, the results suggest that the rise in pHi observed during anoxia may be consequent upon membrane depolarization. This possibility was also suggested by the findings that Zn2+ and Cd2+, known blockers of voltage-dependent proton conductances, reduced the magnitude of the rise in pHi observed during anoxia. Under HCO3-/CO2-free conditions, reduction of external Na+ by substitution with N-methyl-D-glucamine (but not Li+) attenuated the magnitude of the postanoxic alkalinization, suggesting that increased Na+/H+ exchange activity contributes to the postanoxic rise in pHi. In support, rates of pHi recovery from internal acid loads imposed following anoxia were increased compared to control values established prior to anoxia in the same neurons. In contrast, rates of pHi recovery from acid loads imposed during anoxia were reduced, suggesting the possibility that Na+/H+ exchange is inhibited during anoxia. We conclude that the steady-state pHi response of cultured rat hippocampal neurons to transient anoxia is independent of changes in [Ca2+]i and is characterized by three phases which are determined, at least in part, by alterations in Na+/H- exchange activity and, possibly, by a proton conductance which is activated during membrane depolarization.

Animals↗
PubMed1998

Effects of noradrenaline on intracellular pH in acutely dissociated adult rat hippocampal CA1 neurones.

1. We examined the effects of noradrenaline on steady-state intracellular pH (pHi) and the recovery of pHi from internal acid loads imposed by the NH4+ prepulse technique in hippocampal CA1 neurones acutely dissociated from adult rats. 2. Under nominally HCO3--free conditions, acid extrusion was accomplished by a Na+-dependent mechanism, probably the amiloride-insensitive variant of the Na+-H+ exchanger previously characterized in both fetal and adult rat hippocampal neurones. In the presence of external HCO3-, acid extrusion appeared to be supplemented by a Na+-dependent HCO3--Cl- exchanger, the activity of which was dependent upon the absolute level of pHi. 3. Noradrenaline evoked a concentration-dependent and sustained rise in steady-state pHi and increased rates of pHi recovery from imposed intracellular acid loads. The effects of noradrenaline were not dependent upon the presence of external HCO3- but were blocked by substituting external Na+ with N-methyl-D-glucamine, suggesting that noradrenaline acts to increase steady-state pHi by increasing the activity of the Na+-H+ exchanger. 4. The effects of noradrenaline on steady-state pHi and on rates of pHi recovery from imposed acid loads were mimicked by beta1- and beta2-, but not alpha-, adrenoceptor agonists. The beta-adrenoceptor antagonist propranolol blocked the ability of noradrenaline to increase both steady-state pHi and rates of pHi recovery from acid loads. 5. The effects of noradrenaline on steady-state pHi and on pHi recovery rates following acid loads were not dependent on changes in [Ca2+]i. However, the effects of noradrenaline were blocked by pre-treatment with the adenylate cyclase inhibitor 2',5'-dideoxyadenosine and the cAMP-dependent protein kinase inhibitors Rp-adenosine-3',5'-cyclic monophosphorothioate (sodium salt; Rp-cAMPS) and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H-89). 6. Forskolin, an activator of endogenous adenylate cyclase, and 3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor, mimicked the ability of noradrenaline to increase both steady-state pHi and rates of pHi recovery from imposed acid loads, as did Sp-cAMPS, a selective activator of cAMP-dependent protein kinase. The effect of forskolin on steady-state pHi was blocked by pre-treatment with Rp-cAMPS whereas the effect of Sp-cAMPS was enhanced by pre-treatment with the protein phosphatase inhibitor, okadaic acid. 7. Noradrenaline also increased steady-state pHi and rates of pHi recovery from imposed acid loads in cultured postnatal rat hippocampal neurones. In this preparation, the effects of noradrenaline were occluded by 18-24 h pre-treatment with cholera toxin. 8. We conclude that noradrenaline increases the activity of the Na+-H+ exchanger in rat hippocampal neurones, probably by inducing an alkaline shift in the pHi dependence of the antiport, thereby raising steady-state pHi. The effects of noradrenaline are mediated by beta-adrenoceptors via a pathway which involves the alpha-subunit of the stimulatory G-protein Gs (Gsalpha), adenylate cyclase, cAMP and the subsequent activation of cAMP-dependent protein kinase which, in turn, may phosphorylate the exchange mechanism.

Adenylyl Cyclases↗
PubMed1998

pH modulation of Ca2+ responses and a Ca2+-dependent K+ channel in cultured rat hippocampal neurones.

1. The effects of changes in extra- and intracellular pH (pHo and pHi, respectively) on depolarization-evoked rises in intracellular free Ca2+ concentration ([Ca2+]i) and the activity of a Ca2+-dependent K+ channel were investigated in cultured fetal rat hippocampal neurones. 2. In neurones loaded with 2', 7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein (BCECF), changes in pHo evoked changes in pHi. At room temperature, the ratio DeltapHi : DeltapHo (the slope of the regression line relating pHi to pHo) was 0.37 under HCO3-/CO2-buffered conditions and 0.45 under Hepes-buffered conditions; corresponding values at 37 C were 0.71 and 0.79, respectively. The measurements of changes in pHi evoked by changes in pHo were employed in subsequent experiments to correct for the effects of changes in pHi on the Kd of fura-2 for Ca2+. 3. In fura-2-loaded neurones, rises in [Ca2+]i evoked by transient exposure to 50 mM K+ were reduced and enhanced during perfusion with acidic and alkaline media, respectively, compared with control responses at pHo 7.3. Fifty percent inhibition of high-[K+]o-evoked rises in [Ca2+]i corresponded to pHo 7.23. In the presence of 10 microM nifedipine, 50 % inhibition of high-[K+]o-evoked responses corresponded to pHo 7.20, compared with a pHo of 7.31 for 50% inhibition of [Ca2+]i transients evoked by N-methyl-D-aspartate. 4. Changes in pHi at a constant pHo were evoked by exposing neurones to weak acids or bases and quantified in BCECF-loaded cells. Following pH-dependent corrections for the Kd of fura-2 for Ca2+, rises in [Ca2+]i evoked by high-[K+]o in fura-2-loaded cells were found to be affected only marginally by changes in pHi. When changes in pHi similar to those observed during the application of weak acids or bases were elicited by changing pHo, reductions in pH inhibited rises in [Ca2+]i evoked by 50 mM K+ whereas increases in pH enhanced them. 5. The effects of changes in pH on the kinetic properties of a BK-type Ca2+-dependent K+ channel were investigated. In inside-out patches excised from neurones in sister cultures to those used in the microspectrofluorimetric studies, with internal [Ca2+] at 20 microM, channel openings at an internal pH of 6.7 were generally absent whereas at pH 7.3 (or 7.8) the open probability was high. In contrast, channel activity in outside-out patches was not affected by reducing the pH of the bath (external) solution from 7.3 to 6.7. In inside-out patches with internal [Ca2+] at 0.7 microM, a separate protocol was applied to generate transient activation of the channel at a potential of 0 mV following a step from a holding level of -80 mV. In this case open probabilities were 0.81 (at pH 7.8), 0.57 (pH 7.3), 0.19 (pH 7.0) and 0.04 (pH 6.7). Channel conductance was not affected by changes in internal pH. 6. The results indicate that, in fetal rat hippocampal neurones, depolarization-evoked rises in [Ca2+]i mediated by the influx of Ca2+ ions through dihydropyridine-sensitive and -resistant voltage-activated Ca2+ channels are modulated by changes in pHo. The effects of pHo cannot be accounted for by changes in pHi consequent upon changes in pHo. However, changes in pHi affect the unitary properties of a Ca2+-dependent K+ channel. The results support the notion that pHo and/or pHi transients may serve a modulatory role in neuronal function.

2-Amino-5-phosphonovalerate↗
PubMed1998

A comparison of two methods of securing an endotracheal tube.

While a variety of methods exist for securing an endotracheal tube (ETT), there has been little research on their safety and efficacy. This study aimed to test the equivalence of two methods in three critical care settings by randomly assigning patients to receive either the knot, which requires scissors or blade to remove the ETT tape, or the bow, which can be removed manually. These methods were evaluated by comparing ETT movement, malposition, dislodgement, inadvertent extubation, reduced skin integrity, the cutting of the pilot tube and nurse satisfaction. The 5-month study was conducted in three critical care settings in a large tertiary hospital. Of the 230 patients enrolled, 222 completed the trial. Results, based on a randomised, active control equivalence design, demonstrated the two methods to be equally effective with regard to ETT movement > 2 cm (knot = 21 per cent, bow = 19 per cent; 95 per cent confidence interval for the [2 per cent] difference-8 to 12.5 per cent). The incidence of ETT-related complications was similar for both methods. No pilot tubes were cut using either method. Nurses found that patient mouth care was easier and patient comfort and skin integrity enhanced with the bow method. On the other hand, nurses perceived the knot-tying method to be more secure and easier to apply. Given the equivalence of the two methods, the bow would seem preferable for reasons of safety and comfort.

Adult↗
PubMed1998

The anticonvulsant actions of sigma receptor ligands in the Mg2+-free model of epileptiform activity in rat hippocampal slices.

1. The anticonvulsant potency of a series of structurally-dissimilar compounds which possess nanomolar affinities for high-affinity sigma binding sites was examined in the Mg2+-free model of epileptiform activity in rat hippocampal slices. Extracellular field potential recordings in the CA1 region were employed to examine the effects of test compounds on spontaneous epileptiform activity and multiple population spikes evoked by stimulation of the Schaffer collateral-commissural pathway. 2. Applied at sigma site-selective (i.e. nanomolar) concentrations, dextromethorphan, ditolylguanidine, caramiphen and opipramol failed to modify Mg2+-free epileptiform activity; neither pro- nor anticonvulsant effects were observed. However, applied at micromolar concentrations, these and additional test compounds reversibly inhibited orthodromically-evoked epileptiform field potentials with a rank order potency (IC50 values in microM): dextrorphan (1.5) > ifenprodil (6.3) > dextromethorphan (10) > ditolylguanidine (15) > loperamide (28) > carbetapentane (38) > caramiphen (46) > opipramol (52). Micromolar concentrations of the same compounds also inhibited spontaneous epileptiform bursts recorded during perfusion with Mg2+-free medium. 3. Co-application of ropizine (10 microM), an allosteric modulator of dextromethorphan binding to high-affinity sigma receptors, failed to endow dextromethorphan 10 nM with anticonvulsant properties and did not modify the anticonvulsant potency of 10 microM dextromethorphan. 4. The effects of dextrorphan (10 microM), ifenprodil (20 microM), loperamide (50 microM) and caramiphen (100 microM) were examined in the presence of external Mg2+ on field potential input/output (I/O) relationships and paired-pulse facilitation (PPF) of field excitatory postsynaptic potentials. Only caramiphen elicited effects on these parameters, affecting synaptic transmission at the point of synaptic transfer and depressing PPF ratios to below baseline values. The effects of caramiphen on I/O relationships mimicked those of the established anticonvulsant adenosine: in contrast, adenosine evoked an increase in PPF ratios. 5. Because anticonvulsant activity was observed only at micromolar concentrations of the sigma ligands tested, the results indicate that their anticonvulsant actions should not be ascribed to their occupancy, observed at nanomolar concentrations, of high-affinity sigma binding sites. Rather, anticonvulsant activity more likely reflects functional NMDA receptor antagonism and/or blockade of high voltage-activated Ca2+ channels, effects which are associated with micromolar concentrations of the test compounds. Modulation of GABAergic inhibitory mechanisms may also contribute to the anticonvulsant properties of caramiphen.

Animals↗
PubMed1998

Regionalization of health services in Canada: a critical perspective.

Since the introduction of universal health insurance in Canada in the late 1960s, the federal and provincial governments have been concerned with cost savings, efficiency of service delivery, equity in service provision, enhanced citizen participation, and increased accountability of decision-makers. A plethora of government royal commissions and task forces have recommended a similar range of options for addressing these concerns. Central to the reforms has been a proposed regionalized health system with an intermediary body responsible for functions previously assigned to local or central structures. For its supporters, regionalization offers a means of better coordinating and integrating health care delivery and controlling expenditures, and promises a more effective provision of services and an avenue for citizen participation in health care decision-making. All provincial governments except Ontario have introduced regional structures for health care, with the hope that these changes will increase efficiency, equity, and responsiveness. However, despite the alleged benefits, regionalization presents significant challenges. It faces obstacles to integrating and coordinating services in a manner that produces economies of scale; it requires an enhanced level of information that may be difficult to achieve; it is unlikely to involve citizens in health care decision-making; and it may actually lead to increased costs.

Budgets↗
PubMed1997

Suitability of bone marrow from HIV-1-infected donors for retrovirus-mediated gene transfer.

Bone marrow samples from 21 human immunodeficiency virus type 1 (HIV-1)-infected subjects were evaluated for their suitability for retrovirus-mediated gene transduction with anti-HIV-1 genes. The percentages of CD34+ cells that could be isolated from the mononuclear fraction of bone marrow samples were determined. Fifteen of the 21 marrow samples had normal percentages of CD34+ cells isolated by immunomagnetic methods. All seven donors with CD4 counts > 100/mm3 had normal percentages of CD34+ cells; of 14 patients with low CD4 cell counts (< 100/mm3), 5 had reduced and 9 had normal percentages of CD34+ cells. Samples of the marrow were plated in a methylcellulose colony-forming unit (CFU) assay to determine the clonogenic capacity of the progenitor cells. Overall, the marrow samples from HIV-infected donors showed a 44% reduction in CFU derived from the mononuclear cell fraction and a 75% reduction in CFU derived from the isolated CD34+ cell fraction, when compared to marrow samples from uninfected donors. Isolated CD3+ cells were transduced with retroviral vectors containing various anti-HIV-1 genes to determine their susceptibility to gene transfer. Transduction of the clonogenic CD34+ cells by retroviral vectors did not differ among marrow samples from 13 HIV-1+ donors and 9 uninfected donors. Long-term bone marrow cultures established from the transduced CD34+ cells demonstrated equivalent survival of clonogenic progenitor cells from both HIV-1-infected and uninfected marrows. Toxicity from expression of the anti-HIV-1 genes was not observed; the percentages of clonogenic progenitor cells that survived in cultures transduced by vectors carrying anti-HIV-1 genes were similar to those transduced by the control LN vectors. Stromal cells cultured from marrow samples from HIV-1-infected donors showed similar growth kinetics, hematopoietic support function, and enhancement of retrovirus-mediated transduction of CD34+ cells as seen with stromal cells cultured from uninfected marrow donors. Semi-quantitative polymerase chain reaction (PCR) was performed before and after ex vivo transduction to determine the frequency of HIV-1-containing cells in the CD34+ cell preparations. Although HIV-1+ cells were present at low levels in the mononuclear cell fractions of some of the marrow samples, the CD34+ cell preparation from only one marrow sample contained detectable HIV-1 positive cells (< 1 positive cell/100,000 by PCR) prior to transduction. None of the CD34+ cell preparations contained detectable HIV-1 after transduction. These studies demonstrate that HIV-1-infected patients are candidates for retrovirus-mediated transduction of anti-HIV-1 genes in bone marrow gene therapy clinical trials.

Adolescent↗
PubMed1997

Isolated splenic metastases from colon cancer.

Metastatic tumors of the spleen are rare and usually occur in the presence of disseminated visceral metastases. The liver is the most common site of metastatic spread from colon cancer. We report a case of isolated intrasplenic metastasis from sigmoid colon cancer and review the possible reasons for the rarity of splenic metastasis. This represents the fifth reported case of isolated splenic metastasis from colon cancer. Splenectomy may be justified in presence of isolated metastatic disease, since it is an operation with a low complication rate and may provide potential long-term survival in colon cancer.

Adenocarcinoma↗
PubMed1996

Characterization of acid extrusion mechanisms in cultured fetal rat hippocampal neurones.

1. We investigated the mechanisms regulating acid extrusion in cultured fetal rat hippocampal neurones loaded with 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein. 2. In the absence of HCO3-, removal of external Na+ by substitution with N-methyl-D-glucamine caused a sustained intracellular acidification that was not observed when Na+ was replaced by Li+, but neither steady-state intracellular pH (pHi) nor the rate of pHi recovery from an imposed acid load were influenced by amiloride analogues or HOE 694, inhibitors of Na(+)-H+ exchange in other cell types. In the presence of HCO3-, removal of external Na+ or Cl- evoked an intracellular acidification and a 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid-sensitive (DIDS-sensitive) intracellular alkalinization, respectively. Applied alone, however, DIDS elicited a fall in steady-state pHi at room temperature but not at 37 degrees C. The DIDS-evoked fall in steady-state pHi and the 0 Cl(-)-evoked intracellular alkalinization observed in the presence of HCO3- at room temperature were dependent on external Na+. 3. At room temperature (18-22 degrees C), but not at 37 degrees C, the transition from HCO3(-)-free to HCO3(-)-containing medium at a constant pHo produced a net alkalinization that was dependent on external Na+ and was inhibited by DIDS or the depletion of internal Cl-. 4. Recovery of pHi from an acid load imposed in the absence of HCO3- was dependent on external Na+. Addition of HCO3- to the perfusion medium increased the rate of pHi recovery from an acid load at room temperature but not at 37 degrees C. In the presence of HCO3-, DIDS slowed the rate of recovery of pHi from an acid load at both room temperature and at 37 degrees C. 5. Recovery of pHi following an imposed intracellular acidification to pH < 6.5 could occur in the absence of external Na+, providing that HCO3- was present in the perfusate. This slow, Na(+)-independent recovery of pHi from very low levels of intracellular pH was sensitive to DIDS. 6. The results indicate that acid extrusion in cultured fetal rat hippocampal neurones involves primarily two Na(+)-dependent mechanisms, one HCO3- dependent (a HCO3(-)-Cl- exchanger) and the other HCO3- independent (possibly a Na(+)-H+ exchanger). Although both mechanisms participate in the maintenance of steady-state pHi at room temperature, only the HCO3(-)-independent mechanism does so at 37 degrees C.

Animals↗
PubMed1996

Frequent recurrence and persistence of varicella-zoster virus infections in children infected with human immunodeficiency virus type 1.

OBJECTIVE: To examine complications and treatment of varicella-zoster virus (VZV) infections in children infected with human immunodeficiency virus type 1 (HIV-1). METHODS: Cases of VZV infection were identified retrospectively by reports to the department of health services and review of medical charts. The CD4+ cell counts were correlated with severity and frequency of VZV episodes. RESULTS: We identified 117 episodes of VZV infection in 73 HIV-1-infected children between Aug. 21, 1986, and Dec. 1, 1993. The most common complications were recurrence and persistence; 38 children (53%) had 69 recurrent episodes of VZV infection. The majority of children (61%) had zoster during the first recurrent episode, and 32% had a disseminated eruption typical of varicella. There was a strong association between an increasing number of episodes of VZV infection and low CD4+ cell count (p = 0.0008). In a subgroup followed for at least 2 years after their primary varicella episode, 10 of 22 children had a recurrence. Persistence of VZV infection was documented in 10 of 73 children, whereas other complications were rare. Thirty-three children (45%) were hospitalized and received acyclovir intravenously. CONCLUSION: Primary, recurrent, and persistent VZV infections are a frequent cause of morbidity and hospitalization for HIV-1-infected children. Studies of improved preventive and therapeutic agents are urgently needed in this population.

AIDS-Related Opportunistic Infections↗
PubMed1996

Lamivudine in children with human immunodeficiency virus infection: a phase I/II study. The National Cancer Institute Pediatric Branch-Human Immunodeficiency Virus Working Group.

The safety, tolerability, pharmacokinetic profile, and preliminary activity of lamivudine (2'-deoxy-3'-thiacytidine), a novel cytidine nucleoside analogue with antiretroviral activity, in human immunodeficiency virus (HIV)-infected children beyond the neonatal period were studied. Ninety children received dosages of 1-20 mg/kg/day. Pharmacokinetic evaluation demonstrated serum and cerebrospinal fluid concentrations that increased proportionally to dose. As of January 1994, 11 children had been withdrawn from study for disease progression and 10 because of possible lamivudine-related toxicity, and 6 had died. CD4 and CD8 cell counts remained stable over 24 weeks in therapy-naive children and decrease slightly in previously treated children. Quantitative immune complex-dissociated p24 antigen and HIV RNA were decreased significantly at 12 and 24 weeks. In vitro resistance to lamivudine was documented in sequential virus isolates from some patients by 12 weeks. Lamivudine was well-tolerated and exhibited virologic activity in children, although future use in children is likely to be in combination antiretroviral regimens.

Adolescent↗
PubMed1996

Resistance to (-)-2',3'-dideoxy-3'-thiacytidine (3TC) in HIV-1 isolated from paediatric patients.

We conducted detailed virological evaluations of 16 HIV-1-infected paediatric patients treated with 3TC (lamivudine) monotherapy. High-level phenotypic resistance against this compound (up to 2,500-fold) was seen in virtually all cases, usually within 8-12 weeks of initiation of therapy. This was concomitant with the appearance of the M184V mutation in viral reverse transcriptase, previously shown to be responsiblefor such resistance. Viral burden fell in virtually all cases after commencement of therapy, and remained below baseline in each instance studied, despite a rebound effect and the appearance of drug resistance. Viral isolates from some patients underwent a switch from a non-syncytium-inducing (NSI) to a syncytium-inducing (SI) phenotype during the course of the study, although no relationship was apparent between dose of drug employed, time to development of drug resistance or time of appearance of SI phenotype.

Anti-HIV Agents↗