Parametric excitation and squeezing in a many-body spinor condensate.

Atomic spins are usually manipulated using radio frequency or microwave fields to excite Rabi oscillations between different spin states. These are single-particle quantum control techniques that perform ideally with individual particles or non-interacting ensembles. In many-body systems, inter-particle interactions are unavoidable; however, interactions can be used to realize new control schemes unique to interacting systems. Here we demonstrate a many-body control scheme to coherently excite and control the quantum spin states of an atomic Bose gas that realizes parametric excitation of many-body collective spin states by time varying the relative strength of the Zeeman and spin-dependent collisional interaction energies at multiples of the natural frequency of the system. Although parametric excitation of a classical system is ineffective from the ground state, we show that in our experiment, parametric excitation from the quantum ground state leads to the generation of quantum squeezed states.

Quantum Kibble-Zurek Mechanism in a Spin-1 Bose-Einstein Condensate.

The dynamics of a quantum phase transition are explored using slow quenches from the polar to the broken-axisymmetry phases in a small spin-1 ferromagnetic Bose-Einstein condensate. Measurements of the evolution of the spin populations reveal a power-law scaling of the temporal onset of excitations versus quench speed as predicted from quantum extensions of the Kibble-Zurek mechanism. The satisfactory agreement of the measured scaling exponent with the analytical theory and numerical simulations provides experimental confirmation of the quantum Kibble-Zurek model.

Assessment of lopinavir pharmacokinetics with respect to developmental changes in infants and the impact on weight band-based dosing.

Improved antiretroviral therapies are needed for the treatment of HIV-infected infants, given the rapid progression of the disease and drug resistance resulting from perinatal exposure to antiretrovirals. We examined longitudinal pharmacokinetics (PK) data from a clinical trial of lopinavir/ritonavir (LPV/r) in HIV-infected infants in whom therapy was initiated at less than 6 months of age. A population PK analysis was performed using NONMEM to characterize changes in lopinavir (LPV) PK relating to maturational changes in infants, and to assess dosing requirements in this population. We also investigated the relationship between LPV PK and viral dynamic response. Age and ritonavir concentrations were the only covariates found to be significant. Population PK of LPV was characterized by high apparent clearance (CL/F) in young infants, which decreased with increasing age. Although younger infants had lower LPV concentrations, the viral dynamics did not correlate with initial LPV exposure. Monte Carlo simulations demonstrated that WHO weight band-based dosing recommendations predicted therapeutic LPV concentrations and provided drug exposure levels comparable to those resulting from US Food and Drug Administration (FDA)-suggested dosing regimens.

Identification of community-residing individuals with dementia and their unmet needs for care.

BACKGROUND: Innovative approaches to the widespread delivery of evidence-based dementia care are needed. The aims of this study were to determine whether a telephone screening method could efficiently identify individuals in the community in need of care for dementia and to develop a multidimensional needs assessment tool for identifying the type and frequency of unmet needs related to memory disorders in the home setting. METHODS: This was a cross-sectional evaluation of 292 community-residing individuals aged 70 and older in Maryland. Participants were given a brief cognitive telephone screen. A subsample (n=43) received a comprehensive in-home assessment for dementia and dementia-related needs. Cognitive, functional, behavioral, and clinical factors were assessed. The Johns Hopkins Dementia Care Needs Assessment (JHDCNA) was used to identify unmet needs related to dementia. RESULTS: Telephone screening for the sample took 350 h, and 27% screened positive for dementia. Virtually all participants with dementia who received an in-home assessment had at least one unmet need, with the most frequent unmet needs being for a dementia workup, general medical care, environmental safety, assistance with ADL impairments, and access to meaningful activities. Caregivers, when present, also had a number of unmet needs, with the most common being caregiver education about dementia, knowledge of community resources, and caregiver mental health care. CONCLUSIONS: Effective and efficient means for identifying community-residing individuals with dementia are needed so that dementia care interventions can be provided to address unmet care needs of patients and their caregivers.

Abacavir pharmacokinetics during chronic therapy in HIV-1-infected adolescents and young adults.

The pharmacokinetics of abacavir and its metabolites were investigated in 30 human immunodeficiency virus (HIV)-infected adolescents and young adults 13-25 years of age, equally divided into two groups: <18 years of age and >or=18 years of age. All the subjects received the recommended adult dose of 300 mg twice daily. The area under the plasma concentration-time curve (AUC) and half-life of abacavir did not differ significantly between the age groups or by gender or race, and there were only modest associations of age with apparent abacavir clearance and with volume of distribution. There were no significant correlations of carboxylate or glucuronide metabolite levels with age or gender, although glucuronide AUC was higher in Hispanic subjects than in African-American subjects. Zidovudine and lamivudine concentration profiles were also similar in the two age groups. A novel aspect of the study included an assessment of intracellular carbovir, zidovudine, and lamivudine triphosphate levels, and these were found to be similar in the two age-based groups. Overall, these findings suggest that current recommendations relating to adult dosages are appropriate for adolescents and young adults.

Pharmacokinetics of oral zidovudine administered during labour: a preliminary study.

OBJECTIVES: The aim of this study was to determine whether oral zidovudine (ZDV) given during labour would provide a similar systemic exposure to the established intravenous regimen used to prevent mother-to-child transmission in HIV-infected pregnant women. METHODS: ZDV pharmacokinetic parameters following oral administration during labour were determined in 10 HIV-infected pregnant women in active labour. All subjects were converted to intravenous ZDV prior to delivery. RESULTS: In cohort 1 (n=6), subjects received 300 mg oral ZDV every 3 h for three doses. Oral therapy was well tolerated but plasma ZDV concentrations were substantially lower than previously reported with continuous intravenous therapy. Based on the pharmacokinetic results from cohort 1, women in cohort 2 (n=4) received an initial 600 mg dose followed by two 400 mg doses every 3 h. ZDV area under the curve and concentrations in cohort 2 increased approximately in proportion to the increase in dose but varied 6-7-fold. In both cohorts, ZDV pharmacokinetic parameters suggested erratic absorption. CONCLUSIONS: While ZDV exposure improved with the increased dosing regimen, our sample size was small and larger studies are needed to establish whether oral ZDV administration during labour can consistently provide equivalent exposure to intravenous administration.

Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared with methotrexate alone.

OBJECTIVE: To study the pharmacokinetics of methotrexate (MTX) plus cyclosporin A (CSA) in patients with rheumatoid arthritis (RA). METHODS: On day 1 of the study, patients with RA receiving stable doses of MTX had blood and urine levels of MTX and its metabolite 7-hydroxymethotrexate (7-OH-MTX) measured post oral dosing of the drug. MTX was then discontinued and CSA therapy was started on day 8. On day 20, blood levels of CSA and CSA metabolites were measured post drug dosing. On day 23, MTX therapy was restarted and levels of MTX, CSA and their metabolites were again measured as described above. RESULTS: In the 30 patients, coadministration of CSA and MTX led to a 26% increase in mean peak plasma MTX concentration (P < 0.01), an 18% increase in the mean plasma MTX concentration area under the curve (AUC, P=0.01) and an 80% decrease in plasma 7-OH-MTX AUC (P < 0.01). In 13 patients receiving a 10 mg MTX dose, CSA reduced urinary 7-OH-MTX excretion by 87% (P < 0.01) without altering MTX excretion. MTX did not alter the pharmacokinetics of CSA or its metabolites. CONCLUSION: CSA may block oxidation of MTX to its relatively inactive metabolite, 7-OH-MTX, thereby potentiating MTX efficacy.

Cellular factors for resistance against antiretroviral agents.

Substantial advancements have been made in our understanding of the complex replication cycle of, and immunopathology associated with HIV infection as well as the drugs used to treat the disease. The nucleoside reverse transcriptase inhibitors remain the cornerstones of current antiviral treatment modalities. Unfortunately, their longterm use often leads to adverse reactions and the emergence of virus mutants with decreased susceptibility to therapeutic agents. In addition to viral resistance, prolonged antiviral treatment may affect metabolic changes in the host cells that can diminish the efficacy of the treatment. Thus, both viral and cellular resistance mechanisms must be considered in the context of failing antiviral chemotherapy. This review article concerns the intracellular pharmacology of antiviral nucleoside analogues in human lymphoid cells and the possible impact of a newly identified nucleotide transporter on drug resistance.

The Psychogeriatric Assessment and Treatment in City Housing (PATCH) program for elders with mental illness in public housing: getting through the crack in the door.

Psychogeriatric Assessment and Treatment in City Housing (PATCH) is an outreach program targeting elderly public housing residents who need mental health care. The PATCH model relies on educating housing personnel to serve as case finders, providing in-home psychiatric evaluation and treatment, and addressing medical and social comorbidities through case management by psychiatric nurses. An examination of PATCH interventions suggests that the program's success is due to its emphasis on: (1) educating patients, housing personnel, and caregivers about patients' illnesses and need for treatment and support; and (2) coordinating care among housing staff members, patients' caregivers and their primary medical providers.

Under attack: devaluation and the challenge of tolerating the transference.

Devaluation presents one of the therapist's most difficult challenges: conducting therapy and managing resistance with patients who force the therapist into very aggressive and uncomfortable experiences. When these situations arise, the therapist has a twofold task. He or she must tolerate the transference so as not to engage in a countertransferential enactment. Additionally, from this vulnerable vantage point, he or she must help the patient understand both the meaning of and the consequences of devaluations of the therapist. Two cases are presented that recognize devaluation as an example of projective identification and illustrate the challenge in working with this dynamic.

Effectiveness of a nurse-based outreach program for identifying and treating psychiatric illness in the elderly.

CONTEXT: Elderly persons with psychiatric disorders are less likely than younger adults to be diagnosed as having a mental disorder and receive needed mental health treatment. Lack of access to care is 1 possible cause of this disparity. OBJECTIVE: To determine whether a nurse-based mobile outreach program to seriously mentally ill elderly persons is more effective than usual care in diminishing levels of depression, psychiatric symptoms, and undesirable moves (eg, nursing home placement, eviction, board and care placement). DESIGN: Prospective randomized trial conducted between March 1993 and April 1996 to assess the effectiveness of the Psychogeriatric Assessment and Treatment in City Housing (PATCH) program. SETTING: Six urban public housing sites for elderly persons in Baltimore, Md. PARTICIPANTS: A total of 945 (83%) of 1195 residents in the 6 sites underwent screening for psychiatric illness. Among those screened, 342 screened positive and 603 screened negative. All screen-positive subjects aged 60 years and older (n=310) and a 10% random sample of screen-negative subjects aged 60 years and older (n=61) were selected for a structured psychiatric interview. Eleven subjects moved or died; 245 (82%) of those who screened positive and 53 (88%) of those who screened negative were evaluated to determine who had a psychiatric disorder. Data were weighted to estimate the prevalence of psychiatric disorders at the 6 sites. INTERVENTION: Among the 6 sites, residents in 3 buildings were randomized to receive the PATCH model intervention, which included educating building staff to be case finders, performing assessment in residents' apartments, and providing care when indicated; and residents in the remaining 3 buildings were randomized to receive usual care (comparison group). MAIN OUTCOME MEASURES: Number of undesirable moves and scores on the Montgomery-Asberg Depression Rating Scale (MADRS), a measure of depressive symptoms, and the Brief Psychiatric Rating Scale (BPRS), a measure of psychiatric symptoms and behavioral disorder, in intervention vs comparison sites. RESULTS: Based on weighted data, at 26 months of follow-up, psychiatric cases at the intervention sites had significantly lower (F(1)=31.18; P<.001) MADRS scores (9.1 vs 15.2) and significantly lower (F(1)=17.35; P<.001) BPRS scores (27.4 vs 33.9) than those at the nontreatment comparison sites. There was no significant difference between the groups in undesirable moves (relative risk, 0.97; 95% confidence interval, 0. 44-2.17). CONCLUSIONS: These results indicate that the PATCH intervention was more effective than usual care in reducing psychiatric symptoms in persons with psychiatric disorders and those with elevated levels of psychiatric symptoms. JAMA. 2000;283:2802-2809

Cellular phosphorylation of 2',3'-dideoxyadenosine-5'-monophosphate, a key intermediate in the activation of the antiviral agent DDI, in human peripheral blood mononuclear cells.

2',3'-dideoxyadenosine 5-monophosphate (ddAMP), is a key intermediate in the metabolism of the antiviral agent 2',3'-dideoxyinosine (ddI) to its active triphosphate derivative, 2',3'-dideoxyadenosine-5'-triphosphate (ddATP). The potential role of adenylate kinase in the phosphorylation of ddAMP was studied in human peripheral blood mononuclear cells (PBMC) and a human T cell line, CEMss. Subcellular distribution, sulfhydryl inhibitor, and substrate specificity studies support the hypothesis that the mitochondrial adenylate kinase (AK2) is a major route of cellular activation of these compounds in human lymphocytes.

Systemic pharmacokinetics and cellular pharmacology of zidovudine in human immunodeficiency virus type 1-infected women and newborn infants.

Systemic and intracellular pharmacokinetics of zidovudine were determined for 28 human immunodeficiency virus type 1-infected pregnant women and their newborn infants. Plasma zidovudine and intracellular zidovudine monophosphate and triphosphate concentrations were determined in serial maternal samples and cord blood at delivery. Higher levels of cord blood zidovudine were associated with lower maternal zidovudine clearance and longer infusion times. Median levels of zidovudine monophosphate and triphosphate in maternal (1556 and 67 fmol/106 cells) and cord (1464 and 70 fmol/106 cells) blood were similar but highly variable. Intersubject pharmacokinetic variability for zidovudine is substantial, but intravenous therapy provides plasma concentrations and intracellular zidovudine triphosphate levels consistent with high antiviral activity. The substantial amount of intracellular zidovudine triphosphate in cord blood provides an explanation for the clinical success of zidovudine in reducing vertical transmission. Studies of simpler oral regimens of zidovudine can now be evaluated regarding the ability to achieve these pharmacologic end points associated with highly effective parenteral therapy.

Amitriptyline absorption in a patient with short bowel syndrome.

Oral drug therapy in patients with short bowel syndrome can be quite challenging. We report the case of a 40-yr-old woman with short bowel syndrome and depression requiring antidepressant drug therapy. After buccal administration of amitriptyline, therapeutic serum antidepressant concentrations were attained despite the patient having only 18 inches of proximal small bowel. Clinical improvement in mood was seen, with the only drug side effects being dry mouth and bitter drug taste. Buccal absorption likely is playing a major role in attaining therapeutic serum tricyclic antidepressants drug concentrations.

Pressure ulcer prevention: a randomized controlled trial of 2 risk-directed strategies for patient surface assignment.

OBJECTIVE: To compare the clinical utility, in terms of incidence of pressure ulcer (PU) development, and economic impact of 2 programs of patient surface assignment for PU prevention. DESIGN: Randomized controlled clinical trial with economic evaluation. SETTING: 30-bed multidisciplinary intensive care unit (ICU), serving as the regional trauma center. PATIENTS: 144 consecutive eligible patients at risk for the development of PUs. INTERVENTION: PU risk was assessed on admission using the Skin Ulcer Risk Evaluation (SURE) Score, and patients were randomized to either the experimental (purchase) or control group (purchase/rent). Based on their SURE Score, patients were assigned a specialty surface if needed. Patients received head-to-toe skin assessments twice weekly, new PUs were documented, a new SURE Score was calculated, and specialty surfaces were upgraded or downgraded as necessary. OUTCOMES: The incidence of PUs by site and severity, and cost. ANALYSES: Multivariate logistic regression and decision modeling. RESULTS: No significant differences were detected between groups with respect to baseline population characteristics, nor in the development of PUs. Predictors of PU development were ICU length of stay and SURE Score. The experimental (purchase) group was the less costly strategy. Under baseline assumptions, surface costs per at-risk patient were $76 CDN and $171 CDN in the experimental and control groups, respectively. The savings of $95 CDN per at-risk patient translates into conservative annual savings of $47,500 CDN. CONCLUSIONS: Using an objective, risk-based method of patient surface assignment, the authors compared the clinical and economic outcomes of 2 programs of PU prevention. In a direct comparison of alternatives, the strategy that emphasized purchased rather than rented products proved to be the more economical. Finally, this approach illustrates how by prospectively capturing data on both the costs and consequences of competing alternatives, a more objective and informed decision-making process can result.

Treatment of hairy cell leukemia-variant with cladribine.

Hairy cell leukemia-variant (HCL-V) is an extremely rare chronic B-cell lymphoproliferative disorder clinically and morphologically distinct from classic hairy cell leukemia (HCL). HCL-V is thought to represent a hybrid between prolymphocytic leukemia and HCL, the nucleus more closely resembling a prolymphocyte and the cytoplasm a hairy cell. The clinical course of HCL-V is aggressive with short survivals. Since single courses of cladribine have profound activity in HCL, inducing durable complete responses in 91% of patients, we administered cladribine to 4 patients with HCL-V over a 7-year period. During this time interval 357 patients with classic HCL received cladribine at Scripps Clinic. Each patient received cladribine at 0.1 mg/kg per day by continuous intravenous infusion for 7 days, repeated at 28-day intervals depending on response status. The 4 patients ranged in age from 28 to 70. Two presented with B-symptoms, 1 had peripheral adenopathy, and all 4 displayed massive splenomegaly. Peripheral blood counts were notable for lymphocytosis associated with mild anemia and thrombocytopenia. Only 1 of the 4 patients had received prior treatment. Peripheral blood immunophenotypic analysis revealed monoclonal B cells with expression of CD11c in 3 patients, lack of CD25 expression in 3 patients and expression of CD103 in all but 1 patient. The number of cladribine courses administered ranged from two to five. Of these 4 patients, 1 (25%) achieved a complete response and 2 (50%) partial responses, for an overall response rate of 75%. Three patients underwent splenectomy after cladribine. Cladribine is an active agent in HCL-V albeit with a lower response rate than in classic HCL. The role of other treatment modalities, such as splenectomy, interferon-alpha, and 2'-deoxycoformycin, alone or in combination with cladribine awaits further evaluation.

Development of a new cartridge radioimmunoassay for determination of intracellular levels of lamivudine triphosphate in the peripheral blood mononuclear cells of human immunodeficiency virus-infected patients.

A new sensitive method for the measurement of lamivudine triphosphate (3TC-TP), the active intracellular metabolite of lamivudine in human cells in vivo, has been established. The procedure involves rapid separation of 3TC-TP by using Sep-Pak cartridges, dephosphorylation to 3TC by using acid phosphatase, and measurement by radioimmunoassay using a newly developed anti-3TC serum. The radioimmunoassay had errors of less than 21% and a cross-reactivity of less than 0.016% with a wide variety of other nucleoside analogs. The limit of quantitation of the assay for intracellular 3TC-TP was 0.195 ng/ml (0.212 pmol/10(6) cells), and a cell sample of only 4 million cells was ample for the assay. This procedure, combined with our previously developed method for measuring zidovudine (ZDV) metabolite levels, proved capable of measuring 3TC-TP, ZDV monophosphate (ZDV-MP) and ZDV triphosphate (ZDV-TP) in human immunodeficiency virus (HIV)-infected subjects treated with combination 3TC and ZDV therapy. In seven subjects, intracellular 3TC-TP levels ranged from 2.21 to 7.29 pmol/10(6) cells, while intracellular ZDV-MP and ZDV-TP levels ranged from <0. 01 to 1.76 and 0.01 to 0.07 pmol/10(6) cells, respectively. Concentrations of 3TC in plasma determined in these subjects ranged from 0.34 to 9.40 microM, which was about fivefold higher than ZDV levels in plasma of 0.04 to 1.4 microM. This is the first study to determine the intracellular levels of the active metabolites in HIV-infected subjects treated with this combination. These methods should prove very useful for in vivo pharmacodynamic studies of combination therapy.

Connectivity and control in the year 2000 and beyond.

By now, most executives are familiar with the famous Year 2000 problem--and many believe that their companies have the situation well in hand. After all, it seems to be such a trivial problem--computer software that interprets "oo" to be the year 1900 instead of the year 2000. And yet armies of computer professionals have been working on it--updating code in payroll systems, distribution systems, actuarial systems, sales-tracking systems, and the like. The problem is pervasive. Not only is it in your systems, it's in your suppliers' systems, your bankers' systems, and your customers' systems. It's embedded in chips that control elevators, automated teller machines, process-control equipment, and power grids. Already, a dried-food manufacturer destroyed millions of dollars of perfectly good product when a computer counted inventory marked with an expiration date of "oo" as nearly a hundred years old. And when managers of a sewage-control plant turned the clock to January I, 2000 on a computer system they thought had been fixed, raw sewage pumped directly into the harbor. It has become apparent that there will not be enough time to find and fix all of the problems by January I, 2000. And what good will it do if your computers work but they're connected with systems that don't? That is one of the questions Harvard Business School professor Richard Nolan asks in his introduction to HBR's Perspectives on the Year 2000 issue. How will you prepare your organization to respond when things start to go wrong? Fourteen commentators offer their ideas on how senior managers should think about connectivity and control in the year 2000 and beyond.

Anti-human immunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA), Bis(isopropyloxymethylcarbonyl)PMPA.

Bis(isopropyloxymethylcarbonyl) 9-R-(2-phosphonomethoxypropyl)adenine [bis(POC)PMPA] has been identified as a novel prodrug of PMPA. The anti-human immunodeficiency virus activity of bis(POC)PMPA was >100-fold greater than that of PMPA in both an established T-cell line and primary peripheral blood lymphocytes. This improved efficacy was shown to be due to a rapid intracellular uptake of the prodrug resulting in an increased intracellular accumulation of PMPA diphosphate (PMPApp), the pharmacologically active metabolite. PMPApp levels in bis(POC)PMPA-treated cells exceeded by >1,000-fold the levels seen in cells treated with unmodified PMPA in both resting and activated peripheral blood lymphocytes. Significant differences in the intracellular catabolism of PMPA metabolites were noted between the resting and activated lymphocytes. The half-life for the disappearance of PMPApp, derived from either bis(POC)PMPA or PMPA, was 12 to 15 h in the activated lymphocytes and 33 to 50 h in the resting lymphocytes. This long persistence of PMPApp, particularly in resting lymphocytes, may be unique to the nucleoside phosphonate analogs and indicates that effective levels of the active metabolite can be achieved and maintained with relatively infrequent administration of the parent drug.