Loperamide-Induced Torsades de Pointes: A Case Series.

BACKGROUND: Loperamide is an over-the-counter, inexpensive, antidiarrheal opioid that can produce life-threatening toxicity at high concentrations. CASE REPORT 1: A 28-year-old man with a history of depression and substance abuse disorder (SUD) presented to the emergency department (ED) with shortness of breath and lightheadedness. He ingested large amounts of loperamide daily. The patient's initial electrocardiogram (ECG) demonstrated sinus rhythm, right axis deviation, undetectable PR interval, QRS 168 ms, and QTc 693 ms. He was administered intravenous sodium bicarbonate and magnesium sulfate and admitted to the intensive care unit, eventually developing Torsades de Pointes (TdP). He was given lidocaine and isoproterenol infusions, and an external pacemaker was placed. He was discharged in stable condition on hospital day (HD) 16. CASE REPORT 2: A 39-year-old woman with a history of hepatitis C, depression, and SUD was transported to the ED after reported seizure-like activity. The patient experienced TdP in the ED and admitted to ingesting large amount of loperamide daily. An ECG demonstrated sinus rhythm, right axis deviation, PR interval 208 ms, QRS interval 142 ms, and QTc 687 ms. She was administered intravenous magnesium, sodium bicarbonate, and isoproterenol. After intensive care unit admission, the patient experienced no further TdP and was discharged on HD 6. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should proceed with caution when treating patients with loperamide toxicity. Even in asymptomatic patients and drug discontinuance, obtain consultation with a medical toxicologist, promptly treat ECG abnormalities aggressively, and admit all patients for further monitoring.

Autonomous in situ analysis and real-time chemical detection using a backpack miniature mass spectrometer: concept, instrumentation development, and performance.

A major design objective of portable mass spectrometers is the ability to perform in situ chemical analysis on target samples in their native states in the undisturbed environment. The miniature instrument described here is fully contained in a wearable backpack (10 kg) with a geometry-independent low-temperature plasma (LTP) ion source integrated into a hand-held head unit (2 kg) to allow direct surface sampling and analysis. Detection of chemical warfare agent (CWA) simulants, illicit drugs, and explosives is demonstrated at nanogram levels directly from surfaces in near real time including those that have complex geometries, those that are heat-sensitive, and those bearing complex sample matrices. The instrument consumes an average of 65 W of power and can be operated autonomously under battery power for ca. 1.5 h, including the initial pump-down of the manifold. The maximum mass-to-charge ratio is 925 Th with mass resolution of 1-2 amu full width at half-maximun (fwhm) across the mass range. Multiple stages of tandem analysis can be performed to identify individual compounds in complex mixtures. Both positive and negative ion modes are available. A graphical user interface (GUI) is available for novice users to facilitate data acquisition and real-time spectral matching.

Principles and Considerations in the Early Identification and Prehospital Treatment of Thrombocytopenia.

Thrombocytopenia is a common condition characterized by a low platelet count, typically less than 150,000/µL. This article outlines key considerations for field medical providers to effectively identify the early signs of thrombocytopenia and treat different etiologies in the prehospital environment. Following a representative case study, we present a review of basic pathophysiology to include different manifestations of thrombocytopenia as well as diagnostic methods, treatments, and other necessary interventions in this unique setting. With an adequate understanding of typical patient histories and physical presentations leading to this diagnosis, field medics and physicians can be armed with useful information to potentially improve patient outcomes.

Bis[2-(3-carboxyphenoxy)carbonylethyl]phosphinic acid (m-BCCEP): a novel affinity cross-linking reagent for the beta-cleft modification of human hemoglobin.

The design and synthesis of bis[2-(3-carboxyphenoxy)carbonylethyl]phosphinic acid (m-BCCEP, 1) as a site-directed affinity reagent for cross-linking human hemoglobin have been reported as part of our long-term goal to generate artificial blood for emergency transfusions. Molecular modeling techniques were used to design the reagent, employing crystal coordinates of human hemoglobin A(0) imported from the Protein Data Bank. It was synthesized in four steps commencing from 3-hydroxybenzoic acid. The reagent 1 was converted to its trisodium salt to allow effective cross-linking in an aqueous medium. The reagent 1, as its trisodium salt, was found to specifically cross-link stroma-free human hemoglobin A(0) in the beta-cleft under oxygenated reaction conditions at neutral pH. The SDS-PAGE analyses of the modified hemoglobin pointed to the molecular mass range of 32 kDa as anticipated. The HPLC analyses of the product suggested that the cross-link had formed between the beta(1)-beta(2) subunits. Molecular dynamics simulation studies on the reagent-HbA(0) complex suggested that the predominant amino acid residues involved in the cross-linking are N-terminus Val-1 or Lys-82 on one of the beta-subunits and Lys-144 on the other. These predictions were borne out by MALDI-TOF MS analyses data of the peptide fragments obtained from tryptic digestion of the cross-linked product. The data also suggested the presence of a minor cross-link between Val-1 and Lys-82 on the opposing subunits. The oxygen equilibrium measurements of the m-BCCEP-modified hemoglobin product at 37 degrees C showed oxygen affinity (P(50) = 25.8 Torr) comparable to that of the natural whole blood (P(50) = 27.0 Torr) and significantly lower than that of stroma-free hemoglobin (P(50) = 14.19 Torr) assayed under identical conditions. The measured Hill coefficient value of 1.91 of the m-BCCEP-modified Hb product points to the reasonable retainment of oxygen-binding cooperativity after the cross-link formation.

Changing HIV infection-related mortality rate and causes of death among persons with HIV infection before and after the introduction of highly active antiretroviral therapy: analysis of all HIV-related deaths in Barbados, 1997-2005.

OBJECTIVES: To compare the trends in death rates and the causes of deaths before and after the introduction of highly active antiretroviral therapy. METHODS: This is a retrospective study based on chart review of all HIV-related deaths between January 1997 and December 2005. RESULTS: The HIV-specific death rate declined from 34.12 per 100,000 adult population during 1997-1999 to 17.21 per 100,000 adult population during 2003-2005 when highly active anti-retroviral therapy was available. The proportion of all HIV-related deaths among persons newly diagnosed with HIV during the terminal hospitalization decreased from 93% during 1997-1999 to 28% during 2003-2005. Opportunistic infection was at least one of the causes of death in nearly half of all cases. CONCLUSIONS: Although, the HIV-specific death rates have declined significantly since the introduction of highly active antiretroviral therapy, HIV infection continues to contribute to the premature deaths among adults, mainly because of the late presentation.

Potentially inappropriate medications (PIMs) in older hospital in-patients: Prevalence, contribution to hospital admission and documentation of rationale for continuation.

AIM: To establish prevalence, sequelae and documentation of potentially inappropriate medication (PIM) use in older hospital in-patients. METHODS: Notes of all patients ≥65 years old, admitted to our tertiary teaching hospital (January 2013), were retrospectively reviewed, and the Screening Tool of Older Persons' potentially inappropriate Prescriptions applied. RESULTS: Amongst 534 patients, 54.8% (284) were on ≥1 PIM at admission, 26.8% on multiple; 60.8% were discharged on a PIM. Six percent of all admissions were potentially attributable to a PIM; falls associated with risk therapies were commonest (23/30), and often (65.2%) associated with serious injury. Pre-specified subgroup analysis (n = 100) identified 101 PIMs-at-discharge amongst 47 patients. In 82.2%, a clinical rationale for continued prescription was documented, with this communicated to the GP by letter in 71.1%. CONCLUSION: PIMs were common, and contributed to admission and injury. Hospitalisation provides an opportunity for medication rationalisation, and documentation of rationale for any PIM use.

A novel site-directed affinity reagent for cross-linking human hemoglobin: bis[2-(4-phosphonooxyphenoxy)carbonylethyl]phosphinic acid.

Bis[2-(4-phosphonooxyphenoxy)carbonylethyl]phosphinc acid (BPPCEP) was prepared and evaluated as a site-directed affinity reagent for cross-linking human hemoglobin. It was synthesized in four steps starting from 4-benzyloxyphenol and was converted to its pentasodium salt so as to afford efficient cross-linking in an aqueous medium. The reagent was found to specifically cross-link human hemoglobin A(0) in the beta-cleft chains under oxygenated reaction conditions at neutral pH. The amino acid residues involved in the cross-linking were determined by mass spectral analyses of tryptic digest fragments of cross-linked hemoglobin, employing a MALDI-TOF mass spectrometer. The MS analyses suggested that the most likely amino acids involved in the cross-links are Val-1 or Lys-82 present on one of the beta subunits and Lys-82 or Lys-144 on the other. Molecular modeling studies performed on the reagent-HbA(0) complex corroborated the conclusions reached by MALDI-MS analyses. The oxygen equilibrium measurements of the three major BPPCEP-cross-linked Hb products, isolated and purified by preparative cation exchange chromatography, exhibited oxygen affinity (P(50)) values of 14.5, 12.1, and 15.5 Torr as compared with the P(50) of 13.1 Torr for cell-free hemoglobin. The oxygen-binding cooperativity of the modified products, as determined by the Hill coefficient generated from the Hill plots of the respective P(50) values, coupled with the absence of sigmoidal shape of the O(2) equilibrium curves, was considerably lower than that of the native hemoglobin.

The molecular epidemiology and drug resistance determination of HIV type 1 subtype B infection in Barbados.

To better understand the emergence of HIV-1 variants in Barbados and the association with transmission modes, we analyzed phylogenetic relationships and genetic variability among HIV-1 strains collected in 1996 from 36 antiretroviral therapy-naive patients. Only subtype B variants were present in this sampling, based on analysis of HIV-1 envelope (env) C2V3, protease (PR), and reverse transcriptase (RT) sequences. The genetic diversity of env sequences was broad (13.9%; range, 5.9-24.9%), suggesting multiple introductions of distinct HIV-1 strains to the island. The frequency of subtype B HIV-1 variants with similar env V3 features, including the tetrameric tips, GPGR and GPGK, the threonine deletion at position 23, and the substitution of threonine to arginine at position 22, was comparable in heterosexual, bisexual, and homosexual patients. Analyses of amino acid variations in PR sequences revealed a lack of major drug resistance-conferring mutations and a high (90%) prevalence of secondary mutations at positions 36, 63, 71, and 77. While the occurrence of 361, 63P, and 71T mutations in Barbadian strains was similar to the global prevalence for subtype B variants, the frequency (64%) of the V77I mutation was more than three times that seen worldwide. Only two RT antiretroviral resistance mutations (M41L and T215Y) were observed, both from a single patient. This comprehensive genetic analysis documents a broad diversity within HIV-1 subtype B in Barbados and suggests a lack of association between particular subtype B variants and transmission modes.

Randomized, placebo-controlled trial of product R, a peptide-nucleic acid immunomodulator, in the treatment of adults infected with HIV.

OBJECTIVE: The efficacy of Product R, a nontoxic peptide-nucleic acid, was tested in 43 HIV-infected adults naïve to antiretroviral therapy. METHOD: Patients were randomized to receive Product R (21 patients) or placebo (22 patients). Dosage was two 1 mL subcutaneous injections daily on days 1-14, followed by 1 mL daily on days 22-28, 36-42, and 50-56. The follow-up period lasted until day 120. RESULTS: Mean root CD4 count increased in the Product R group during treatment and was significantly higher (p =.013) by the end of follow-up. Four Product R-treated patients, but none of the control patients, experienced declines in viral load of >0.5 log. At the end of follow-up, the Product R group experienced a mean weight increase (p =.003), whereas the placebo group experienced a mean weight loss. The number of deaths and opportunistic infections were lower in the Product R group than in the placebo group (p =.076). No toxic effects were observed in any of the patients administered Product R. CONCLUSION: These findings suggest that Product R may have efficacy in the treatment of HIV-infected individuals.

Increased detection of HIV-specific T cell responses by combination of central sequences with comparable immunogenicity.

OBJECTIVE: To evaluate the recognition of computationally designed, centralized HIV-1 antigens derived from clade B, C and group M sequences by individuals infected with HIV-1-M clades B and C. METHODS: Three centralized sequences have been described - consensus, ancestor and center-of-tree - each of which attempts to minimize the genetic distance to circulating viruses. It is unclear whether any of these sequences affords an advantage for T cell recognition. The ability of centralized clade B and C and group M peptides to be targeted in ELISpot assays was assessed using samples from the United States, Peru, Barbados and South Africa. RESULTS: Each of the clade-specific centralized peptide sets was equally powerful in detecting cytotoxic T cell (CTL) responses. Importantly, combination of these sets detected significantly broader responses. Although broad responses were observed in populations from which few sequences informed the design of these centralized sequences, the genetic distance between local sequences and the respective test set was inversely associated with response rates. Furthermore, the CTL reactivity in clade C-infected subjects using clade B peptides was reduced relative to within-clade peptide responses, while responses to group M peptides were comparable to within-clade peptide responses in these individuals. CONCLUSIONS: All tested centralized antigens provided a similarly potent set of antigenic peptides. However, the significantly broader responses detected using the combination of sets highlight the importance of maximizing coverage of HIV-1 sequence diversity in vaccine preparations, as well as in the evaluation of CTL responses in HIV-1-infected individuals and those vaccinated.

High-throughput carbohydrate microarray profiling of 27 antibodies demonstrates widespread specificity problems.

Progress toward understanding the biological roles of carbohydrates has been remarkably slow, and efforts to exploit this class of biopolymers as diagnostic and therapeutic targets have proven extremely challenging. Both basic and clinical research rely heavily on identifying and monitoring expression levels of carbohydrates. Over the last 30 years, the majority of expression information has been derived from antibody- and lectin-binding studies. Using a carbohydrate microarray containing 80 different glycans and glycoproteins, the specificities of 27 antiglycan antibodies were evaluated, including antibodies to histo-blood group A, B, and H antigens (81FR2.2, CLCP-19B, B389, 92FR-A2, B480, B460, B376, and B393), Lewis antigens (7LE, 15C02, 28, ZC-18C, 121SLE, CA199.02, PR.5C5, 2-25LE, BR55, T174, T218, F3, A70-C/C8, FR4A5, and K21), and other tumor-associated antigens (B389, 1A4, B1.1, and 5B5). In total, evaluation of over 2000 individual carbohydrate-protein interactions was carried out. More than half of the antibodies considered to be specific for their designated antigen were found to cross-react with other glycans. The cross-reactive glycans could be mistaken for the designated antigen in biopsy samples or other biological samples, leading to inaccurate conclusions.

Control of human immunodeficiency virus replication by cytotoxic T lymphocytes targeting subdominant epitopes.

Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load.

Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection.

Stigma, discrimination, and HIV/AIDS knowledge among physicians in Barbados.

OBJECTIVE: To determine the extent of clinical knowledge of HIV/AIDS that physicians in Barbados have and their attitudes towards persons living with HIV/AIDS. METHODS: In 2000 the Barbados Association of Medical Practitioners conducted a survey in order to assess its members' views on HIV/AIDS issues. Over a two-month period 203 physicians (76% of all those practicing in the country) were interviewed. The survey included physicians working in private practice and the public sector. They were surveyed individually concerning their attitudes towards counseling as well as their clinical knowledge, perception of safe practices, fear of occupational exposure, views on ethical issues, experience treating HIV/AIDS patients, and background with HIV/AIDS continuing education. RESULTS: In comparison to physicians who had graduated in later years, physicians who had graduated in 1984 or earlier had seen fewer HIV/AIDS clients, had lower levels of knowledge about the disease, were more likely to test for HIV/AIDS without informed consent, and were less likely to have ever attended a continuing education training course on HIV/AIDS. Overall, knowledge of the clinical indications of HIV/AIDS was low, and 76% of the physicians did not think they had adequate counseling skills. Over 80% of the physicians were comfortable looking after HIV/AIDS patients. While 95% of the physicians would not release HIV test results without a patient's consent, 33% would test, without consent, a seriously ill patient, and 15% would test without consent a patient upon whom they had to perform an invasive procedure if they perceived the patient to be from a high-risk population such as gay men or commercial sex workers. Only 53% of the physicians had attended an HIV/AIDS in-service training program between 1995 and 1999. CONCLUSIONS: Physician training in Barbados should focus on all aspects of HIV/AIDS care, including clinical and emotional factors. Attendance at such training should be mandatory for public sector physicians, and medical school curricula need to be examined to ensure their HIV/AIDS content is current and comprehensive.

Stigma, discrimination, and HIV/AIDS knowledge among physicians in Barbados

OBJETIVOS: Dilucidar el alcance de los conocimientos prácticos que tienen los médicos de Barbados sobre el VIH y el sida y su actitud hacia las personas que padecen la enfermedad. MÉTODOS: En el año 2000 la Asociación de Médicos Generales de Barbados llevó a cabo una encuesta para evaluar las opiniones de los socios en torno a asuntos relacionados con el VIH y el sida. Durante un período de dos meses se entrevistó a 203 médicos (76% de los que ejercen en el país). En la encuesta se incluyeron tanto médicos del sector público como de consultorios privados. Las entrevistas fueron individuales y versaron sobre sus actitudes hacia la orientación de los pacientes, conocimientos prácticos, nociones de prácticas inocuas, temor de exponerse al contagio, modo de ver las cuestiones éticas, experiencia con el tratamiento de pacientes con VIH o sida y formación médica continua en el campo de VIH/sida. RESULTADOS: Comparados con los médicos egresados más tarde, los graduados en 1984 o antes habían tratado a menos pacientes con infección por VIH o sida, tenían menos conocimientos de la enfermedad, se inclinaban más a administrar la prueba diagnóstica sin el consentimiento válido del paciente y era menos probable que hubieran asistido a algún curso de formación continua sobre el VIH y el sida. En general, tenían poco conocimiento del tratamiento indicado y 76% no se consideraban capacitados adecuadamente para orientar a los pacientes. Más de 80% dijeron que se sentían bastante seguros atendiendo a pacientes con infección por VIH o sida. De los encuestados, 95% declararon que no entregarían los resultados diagnósticos a terceros sin el consentimiento del paciente, mientras que 33% dijeron que administrarían la prueba detectora sin consentimiento a un paciente grave y 15%, que lo harían si tuvieran que realizar una intervención invasora a un paciente de una población de alto riesgo, como las de homosexuales y trabajadores de la industria sexual. Solo 53% de los médicos habían participado en programas de adiestramiento en el servicio entre 1995 y 1999. CONCLUSIONES: Es preciso que la formación médica en Barbados comprenda la atención de pacientes con infección por VIH o sida, incluidos todos los aspectos, tanto clínicos como afectivos. Para los médicos del sector público debe ser obligatorio asistir a ese tipo de adiestramiento; además, es necesario examinar los planes de estudio de las escuelas de medicina para cerciorarse de que sean completos y actualizados.