Publications

An emotionally-distressed, elderly Caucasian woman presented with chest pain and hypertension. Electrocardiogram showed inferior ST-segment elevation, and an urgent cardiac catheterization was performed. Coronary angiography revealed normal appearing coronary arteries; however, left ventriculography showed extensive left ventricular apical akinesis. The patient had a mild rise in cardiac enzyme levels indicative of myocardial injury. She was discharged after an uncomplicated in-hospital course. One month later, the left ventricular wall motion abnormality had improved. In this report, the authors discuss this compilation of findings known as tako-tsubo-like left ventricular dysfunction.

The HIV epidemic is emerging rapidly in Vietnam. We studied the prevalence of opportunistic infections by performing clinical and microbiological investigations in 100 hospitalized HIV-infected adults in Ho Cho Minh City, Vietnam. The median CD4 count was 20 cells/mm(3) and in-hospital mortality was 28%. The most frequent diagnoses were oral candidiasis (54), tuberculosis (37), wasting syndrome (34), lower respiratory tract infection (13), cryptococcosis (9), and penicilliosis (7). Bacterial (other than tuberculosis) and parasitic infections were uncommon. Regional differences should be considered when deciding which diagnostic procedures and prophylactic measures to implement. In Vietnam, routine mycobacterial blood cultures do not provide greater yield than chest radiography and sputum and lymph node aspirate smears. Prophylactic trimethoprim/sulphamethoxazole against Pneumocystis jiroveci pneumonia may confer little benefit, and high rates of isoniazid resistance may affect the efficacy and feasibility of tuberculosis chemoprophylaxis. However, the usefulness of itraconazole prophylaxis for cryptococcosis and penicilliosis merits further consideration.

INTRODUCTION

Cardiac resynchronization therapy (CRT) improves echocardiographic measures of cardiac function and has a variable effect on QRS duration in patients with left bundle branch block (LBBB). How CRT affects these indices in patients with right ventricular (RV) pacing-induced LBBB who are "upgraded" with left ventricular (LV) leads for CRT is unknown. We studied the echocardiographic effects of RV pacing and CRT in patients with prior continuous RV pacing after LV lead placement.

METHODS AND RESULTS

Fifteen consecutive patients (age 73 +/- 11 years, LV ejection fraction 24 +/- 6%, QRS duration 190 +/- 27 msec) with New York Heart Association class IIIB-IV symptoms and continuous RV pacing underwent LV lead placement for CRT. Echocardiography and ECG were performed sequentially during RV pacing and CRT. CRT was associated with significantly reduced QRS duration (190 +/- 27 msec vs 165 +/- 18 msec, P = 0.005) and reduced LV electromechanical delay (180 +/- 33 msec vs 161+/- 43 msec). Baseline QRS duration correlated with CRT response. After CRT, patients had significant improvements in indices of systolic function, including LV ejection fraction, myocardial performance index (MPI), and LV ejection time. Abnormal baseline MPI was associated with greater improvement after CRT. LV end-diastolic and systolic volumes were similarly decreased with CRT. Mitral valve deceleration time, an index of diastolic function, was not affected by CRT.

CONCLUSION

"Upgrading" RV paced patients with advanced heart failure to CRT improves measures of electrical and LV mechanical synchrony and improves systolic function.

Platelet binding by Streptococcus gordonii strain M99 is dependent on expression of the cell wall-anchored glycoprotein GspB. This large cell surface protein is exported from the M99 cytoplasm via a dedicated transport system that includes SecA2 and SecY2. GspB is highly similar to Hsa, a protein expressed by S. gordonii Challis that has been characterized as a sialic acid binding hemagglutinin. In this study, we compared the contribution of GspB and Hsa to the adherence of S. gordonii to selected glycoproteins. Our results indicate that GspB can mediate binding to a variety of sialylated glycoproteins. GspB facilitates binding to carbohydrates bearing sialic acid in either alpha(2-3) or alpha(2-6) linkages, with a slight preference for alpha(2-3) linkages. Furthermore, GspB readily mediates binding to sialic acid residues on immobilized glycocalicin, the extracellular portion of the platelet membrane glycoprotein (GP) Ibalpha (the ligand binding subunit of the platelet von Willebrand factor receptor complex GPIb-IX-V). Although Hsa is required for the binding of S. gordonii Challis to sialic acid, most of the Hsa expressed by Challis is retained in the cytoplasm. The deficiency in export is due, at least in part, to a nonsense mutation in secA2. Hsa export can be enhanced by complementation with secA2 from M99, which also results in significantly greater binding to sialylated glycoproteins, including glycocalicin. The combined results indicate that GspB and Hsa contribute similar binding capabilities to M99 and Challis, respectively, but there may be subtle differences in the preferred epitopes to which these adhesins bind.

Platelet binding by Streptococcus gordonii strain M99 is mediated predominantly by the cell surface glycoprotein GspB. This adhesin consists of a putative N-terminal signal peptide, two serine-rich regions (SRR1 and SRR2), a basic region between SRR1 and SRR2, and a C-terminal cell wall anchoring domain. The glycosylation of GspB is mediated at least in part by Gly and Nss, which are encoded in the secY2A2 locus immediately downstream of gspB. This region also encodes two proteins (Gtf and Orf4) that are required for the expression of GspB but whose functions have not been delineated. In this study, we further characterized the roles of Gly, Nss, Gtf, and Orf4 by investigating the expression and glycosylation of a series of glutathione S-transferase-GspB fusion proteins in M99 and in gly, nss, gtf, and orf4 mutants. Compared with fusion proteins expressed in the wild-type background, fusion proteins expressed in the mutant strain backgrounds showed altered electrophoretic mobility. In addition, the fusion proteins formed insoluble aggregates in protoplasts of the gtf and orf4 mutants. Glycan detection and lectin blot analysis revealed that SRR1 and SRR2 were glycosylated but that the basic region was unmodified. When the fusion protein was expressed in Escherichia coli, glycosylation of this protein was observed only in the presence of both gtf and orf4. These results demonstrate that Gly, Nss, Gtf, and Orf4 are all involved in the intracellular glycosylation of SRRs. Moreover, Gtf and Orf4 are essential for glycosylation, which in turn is important for the solubility of GspB.

Antimalarial drug treatment policy in sub-Saharan Africa is generally guided by the results of clinical drug efficacy studies in patients with uncomplicated Plasmodium falciparum malaria. The selection criteria used to enroll these patients often vary and may have a significant impact on treatment outcomes. In Kampala, Uganda, we investigated the impact of age, baseline temperature, and pre-treatment parasite density on estimates of treatment efficacy using a statistical modeling approach in 2,138 patients enrolled in six clinical trials involving seven different treatment regimens. Decreasing age, increasing temperature, and increasing parasite density were all independent predictors of an increased risk of treatment failure across all treatment groups. Compared with an unrestrictive approach to subject selection, enrolling only patients fulfilling selection criteria recommended by the World Health Organization (age < 5 years old, documented fever, and parasite density < 200,000/microL) increased the risk of treatment failure by 25-60% for the different treatment regimens. Caution should be taken when comparing results from drug efficacy studies with different subject selection criteria.

BACKGROUND

Plasmodium falciparum resistance has rendered chloroquine monotherapy ineffective in much of Africa, but data on alternative regimens are limited. We compared chloroquine+sulfadoxine-pyrimethamine, amodiaquine+sulfadoxine-pyrimethamine, and amodiaquine+artesunate for treatment of uncomplicated malaria in Kampala, Uganda.

METHODS

Of 1017 consecutive patients aged 6 months to 10 years with uncomplicated malaria who were screened, 418 were randomised to receive: chloroquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine (25 mg/kg sulfadoxine, 1.25 mg/kg pyrimethamine, single dose); amodiaquine (25 mg/kg over 3 days) and sulfadoxine-pyrimethamine; or amodiaquine and artesunate (4 mg/kg daily for 3 days). Primary efficacy outcomes were 28-day clinical failure risks, adjusted and unadjusted by genotyping to distinguish new infection and recrudescence. The primary safety endpoint was incidence of serious adverse events during follow-up. Analysis was intention to treat and per protocol.

FINDINGS

18 patients were excluded before enrollment. Of those enrolled, 384 of 400 (96%) were assigned an efficacy outcome and 396 (99%) were assessed for safety. Risk of 28-day clinical treatment failure was significantly higher with chloroquine+sulfadoxine-pyrimethamine (44/125 [35%]) than with amodiaquine+sulfadoxine-pyrimethamine (12/129 [9%]; risk difference 26% [95% CI 16-36]; p<0.0001) or amodiaquine+artesunate (3/130 [2%]; 33% [24-42]; p<0.0001). The greater risk of clinical treatment failure with amodiaquine+sulfadoxine-pyrimethamine was balanced by a lower risk of new infection, resulting in a similar need for retreatment over 28 days for amodiaquine+sulfadoxine-pyrimethamine (17/129 [13%]) and amodiaquine+artesunate (16/130 [12%]; p=0.854). Serious adverse events were uncommon with all regimens.

INTERPRETATION

Risk of treatment failure with chloroquine+sulfadoxine-pyrimethamine was unacceptably high. Combinations of amodiaquine and sulfadoxine-pyrimethamine or artesunate were significantly more efficacious, and each regimen could be an appropriate alternative for treatment of uncomplicated malaria in Africa.

In this cross sectional descriptive study, the demographics, risk factors, and health outcomes of a volunteer, symptomatic sample of monolingual Cantonese garment workers in the Oakland, California Chinatown area are documented. Methods included a questionnaire and clinical examination and treatment at the Asian Immigrant Women Workers Clinic, a free clinic providing culturally focused occupational health consultation and treatment for painful musculoskeletal disorders. Because garment work involves highly repetitious, sustained awkward postures, focused education on stretching and ergonomics also was provided. Results from the first 100 clients revealed a highly symptomatic sample, with an average age of 48.7 years. Sixty-six percent rated their health status as fair or poor. Sixteen percent of the sample had nerve entrapments, and 99% had a diagnosed strain or sprain of the spine or upper extremities. This population did not file workers' compensation claims because of a lack of knowledge and a fear of reprisal. This study documented the barriers to seeking care for this low wage, immigrant population.

The peripheral detection of painful stimuli requires the activation of small-diameter primary afferent neurons known as nociceptors. We have exploited two features of nociceptor biology, expression of the high affinity receptor for nerve growth factor (TrkA) and sensitivity to capsaicin, to isolate novel proteins using a differential display cloning scheme. A resulting approximately 4.3-kb cDNA was isolated and sequence analysis inferred a approximately 157-kDa protein containing a signal/mitochondrial targeting peptide sequence. Due to its molecular weight and significant amino acid identity with 'human leucine-rich protein 130'[leucine-rich pentatricopeptide motif containing (LRPPRC)], we termed the cDNA candidate leucine-rich protein 157 (rLRP157). Western blot analysis of HEK293 cells over-expressing the candidate cDNA showed a single protein product of similar size to that found in rat dorsal root ganglion as well as in other neuronal tissues and cell lines. Although expressed in a wide variety of tissues, in situ hybridization and immunohistochemistry in dorsal root ganglion revealed that rLRP157 expression was restricted to the small-diameter neurons. Sequence identity with previously characterized mRNA binding proteins and its subcellular localization in sensory neurons suggest that rLRP157 is associated with mitochondrial function. Moreover, the genetic basis of French-Canadian Leigh syndrome, which confers a loss of mitochondrial cytochrome c oxidase and is characterized by neurodegeneration, was recently mapped to a mutation in the LRPPRC gene. Taken together with its expression in small-diameter sensory neurons, we hypothesize that rLRP157, the rat orthologue of the human LRPPRC, may play a role in the modulation of peripheral pain transduction and serve as a novel marker for nociceptor subtypes.