Responsiveness of the EAT-10 to Clinical Change in Head and Neck Cancer Patients with Dysphagia.

Purpose: This retrospective study evaluated the external responsiveness of the Eating Assessment Tool-10 (EAT-10) to clinical changes in a single cohort (n = 105) treated with chemoradiotherapy (CRT) or radiotherapy (RT) for head-and-neck cancer.Method: Patients completed the EAT-10 four times: (I) Within two weeks of commencing (C)RT, (II) in the final week of (C)RT, (III) two weeks post-(C)RT and (IV) following discharge from speech-language pathology services. Data was compared to their oral intake status, using the Functional Oral Intake Scale (FOIS).Result: Using Cohen's d, changes in the EAT-10 and FOIS were comparable, however, a difference was observed at data-point IV. At data-points I, II and III, the EAT-10 had a strong negative correlation with the FOIS (Spearman's ρ= -0.81, -0.80 and -0.81 resp.). At data-point IV the correlation strength decreased (Spearman's ρ= -0.69). Fisher's Z transformation found no statistically significant correlation coefficient differences between data-points I, II and III. A significant difference in correlation was found between these data-points and data-point IV (p = 0.027; p = 0.039 and p = 0.022 resp.). A very high internal consistency was found (Cronbach's α > 0.95) for all data-points.Conclusion: This study's results indicate that the EAT-10 has weaknesses in the external responsiveness and has redundancy of its question items.

Pharmacokinetic and pharmacogenomic modelling of the CYP3A activity marker 4ß-hydroxycholesterol during efavirenz treatment and efavirenz/rifampicin co-treatment.

OBJECTIVES: To assess the effect of the major efavirenz metabolizing enzyme (CYP2B6) genotype and the effects of rifampicin co-treatment on induction of CYP3A by efavirenz. PATIENTS AND METHODS: Two study arms (arm 1, n = 41 and arm 2, n = 21) were recruited into this study. In arm 1, cholesterol and 4ß-hydroxycholesterol were measured in HIV treatment-naive patients at baseline and then at 4 and 16 weeks after initiation of efavirenz-based antiretroviral therapy. In arm 2, cholesterol and 4ß-hydroxycholesterol were measured among patients taking efavirenz during rifampicin-based tuberculosis (TB) treatment (efavirenz/rifampicin) just before completion of TB treatment and then serially following completion of TB treatment (efavirenz alone). Non-linear mixed-effect modelling was performed. RESULTS: A one-compartment, enzyme turnover model described 4ß-hydroxycholesterol kinetics adequately. Efavirenz treatment in arm 1 resulted in 1.74 (relative standard error = 15%), 3.3 (relative standard error = 33.1%) and 4.0 (relative standard error = 37.1%) average fold induction of CYP3A for extensive (CYP2B6*1/*1), intermediate (CYP2B6*1/*6) and slow (CYP2B6*6/*6) efavirenz metabolizers, respectively. The rate constant of 4ß-hydroxycholesterol formation [mean (95% CI)] just before completion of TB treatment [efavirenz/rifampicin co-treatment, 7.40 × 10(-7) h(-1) (5.5 × 10(-7)-1.0 × 10(-6))] was significantly higher than that calculated 8 weeks after completion [efavirenz alone, 4.50 × 10(-7) h(-1) (4.40 × 10(-7)-4.52 × 10(-7))]. The CYP3A induction dropped to 62% of its maximum by week 8 of completion. CONCLUSIONS: Our results indicate that efavirenz induction of CYP3A is influenced by CYP2B6 genetic polymorphisms and that efavirenz/rifampicin co-treatment results in higher induction than efavirenz alone.

Amyloid vs FDG-PET in the differential diagnosis of AD and FTLD.

OBJECTIVE: To compare the diagnostic performance of PET with the amyloid ligand Pittsburgh compound B (PiB-PET) to fluorodeoxyglucose (FDG-PET) in discriminating between Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). METHODS: Patients meeting clinical criteria for AD (n = 62) and FTLD (n = 45) underwent PiB and FDG-PET. PiB scans were classified as positive or negative by 2 visual raters blinded to clinical diagnosis, and using a quantitative threshold derived from controls (n = 25). FDG scans were visually rated as consistent with AD or FTLD, and quantitatively classified based on the region of lowest metabolism relative to controls. RESULTS: PiB visual reads had a higher sensitivity for AD (89.5% average between raters) than FDG visual reads (77.5%) with similar specificity (PiB 83%, FDG 84%). When scans were classified quantitatively, PiB had higher sensitivity (89% vs 73%) while FDG had higher specificity (83% vs 98%). On receiver operating characteristic analysis, areas under the curve for PiB (0.888) and FDG (0.910) were similar. Interrater agreement was higher for PiB (κ = 0.96) than FDG (κ = 0.72), as was agreement between visual and quantitative classification (PiB κ = 0.88-0.92; FDG κ = 0.64-0.68). In patients with known histopathology, overall classification accuracy (2 visual and 1 quantitative classification per patient) was 97% for PiB (n = 12 patients) and 87% for FDG (n = 10). CONCLUSIONS: PiB and FDG showed similar accuracy in discriminating AD and FTLD. PiB was more sensitive when interpreted qualitatively or quantitatively. FDG was more specific, but only when scans were classified quantitatively. PiB slightly outperformed FDG in patients with known histopathology.

Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis.

We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8-hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*1/*1 genotypes. Ours is the first report of the CYP2B6 genotype-dependent effect of RIF on long-term EFV autoinduction.

Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution.

BACKGROUND/OBJECTIVE: Patients with posterior cortical atrophy (PCA) often have Alzheimer disease (AD) at autopsy, yet are cognitively and anatomically distinct from patients with clinical AD. We sought to compare the distribution of ß-amyloid and glucose metabolism in PCA and AD in vivo using Pittsburgh compound B (PiB) and FDG-PET. METHODS: Patients with PCA (n = 12, age 57.5 ± 7.4, Mini-Mental State Examination [MMSE] 22.2 ± 5.1), AD (n = 14, age 58.8 ± 9.6, MMSE 23.8 ± 6.7), and cognitively normal controls (NC, n = 30, age 73.6 ± 6.4) underwent PiB and FDG-PET. Group differences in PiB distribution volume ratios (DVR, cerebellar reference) and FDG uptake (pons-averaged) were assessed on a voxel-wise basis and by comparing binding in regions of interest (ROIs). RESULTS: Compared to NC, both patients with AD and patients with PCA showed diffuse PiB uptake throughout frontal, temporoparietal, and occipital cortex (p < 0.0001). There were no regional differences in PiB binding between PCA and AD even after correcting for atrophy. FDG patterns in PCA and AD were distinct: while both groups showed hypometabolism compared to NC in temporoparietal cortex and precuneus/posterior cingulate, patients with PCA further showed hypometabolism in inferior occipitotemporal cortex compared to both NC and patients with AD (p < 0.05). Patients with AD did not show areas of relative hypometabolism compared to PCA. CONCLUSIONS: Fibrillar amyloid deposition in PCA is diffuse and similar to AD, while glucose hypometabolism extends more posteriorly into occipital cortex. Further studies are needed to determine the mechanisms of selective network degeneration in focal variants of AD.

Long-term efavirenz autoinduction and its effect on plasma exposure in HIV patients.

We investigated the influence of gender and pharmacogenetic variations on long-term efavirenz autoinduction and disposition among patients with HIV in Tanzania (N = 129). Plasma concentrations (at 16 h) of efavirenz and 8-hydroxyefavirenz were quantified at weeks 4 and 16 of therapy. Genotyping was performed to identify cytochrome P450 (CYP) 2B6*6, CYP3A5*3, *6, and *7, and ABCB1-3435 C/T genotypes. There were reductions in the median efavirenz concentration (Wilcoxon matched-pair test P < 0.001) and efavirenz/8-hydroxyefavirenz ratio (P < 0.001) by 19 and 32%, respectively, at week 16 as compared with week 4. The proportion of patients with efavirenz concentration <1 µg/ml at week 16 was higher by 67, 25, and 5% in CYP2B6*1/*1, *1/*6, and *6/*6 genotypes, respectively. The defined therapeutic range based on observed plasma concentrations is affected by the time point of sampling and the CYP2B6 genotype. The effect of efavirenz autoinduction on reducing plasma exposure continues up to week 16 and predominantly affects CYP2B6 extensive metabolizers. Among CYP2B6 slow metabolizers, the presence of a CYP3A5 genotype allele is associated with greater effects of efavirenz autoinduction on plasma concentrations of the drug. The cumulative induction may influence the long-term antiretroviral therapy outcome, particularly in CYP2B6*1 carriers.

Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries; the Tanzanian experience.

OBJECTIVE: To evaluate various strategies aimed at improving adherence to antiretroviral therapy (ART). METHODS: Patients initiated on ART at Muhimbili National Hospital HIV clinic were randomly assigned to either regular adherence counseling, regular counseling plus a calendar, or regular counseling and a treatment assistant. Patients were seen monthly; during these meetings self-reported adherence to treatment was recorded. Disease progression was monitored clinically and immunologically. RESULTS: Of the 621 patients randomized, 312 received regular counseling only, 242 regular counseling and calendars, while 67 had treatment assistants in addition to regular counseling. The mean (SD) follow-up time was 14.5 (4.6) months. During follow-up 20 (3.2%) patients died, and 102 (16.4%) were lost to follow-up; this was similar in all groups. In 94.8% of all visits, patients reported to have adhered to treatment. In only 39 (0.7%) visits did patients report a < or = 95% adherence. There were no differences in adherence (P = 0.573) or differences in CD4 count and weight changes over time in the interventions. CONCLUSIONS: Good adherence to ART is possible in resource constrained countries. Persistent adherence counseling in clinic settings by itself may be effective in improving adherence to ART.

CYP3A5 genotype has an impact on the metabolism of the HIV protease inhibitor saquinavir.

CYP3A is the main enzyme subfamily involved in the metabolism of the HIV protease-inhibitor saquinavir. We hypothesized that individuals homozygous for CYP3A5*1 might have a higher oral clearance of saquinavir, compared with subjects lacking functional CYP3A5 alleles. A single-dose pharmacokinetic trial of saquinavir soft gel capsules, 1,200 mg, was performed in 16 black Tanzanian healthy volunteers with two functional CYP3A5 alleles (*1/*1) and in 18 volunteers without functional CYP3A5 alleles (both alleles being either *3, *6, or *7). The median area under the plasma concentration-time curve (AUC)0-24 reached among subjects with two functional alleles was 1,410 ng h/ml (interquartile range (IQR) 826-1,929), whereas it was 2,138 ng h/ml (IQR 1,380-3,331) in subjects without (P=0.0533, Mann-Whitney U-test). The median ratio of saquinavir over its M2 plus M3 hydroxy metabolites in urine was 64 (IQR 52-73) in subjects with two functional alleles, whereas it was 145 (IQR 89-181) in those without (P=0.000078, Mann-Whitney U-test). In conclusion, saquinavir is metabolized by CYP3A5. The median AUC0-24 for saquinavir among individuals with two functional CYP3A5 alleles was 34% lower than among those with no functional alleles. To clarify the clinical importance of the CYP3A5 polymorphism, further studies should be conducted on saquinavir, dosed to steady state, in the presence of ritonavir boosting.

Clinical and echocardiographic study of hypertrophic cardiomyopathy in Tanzania.

There are few published reports of hypertrophic cardiomyopathy (HCM) in Africans, partly due to lack of Echocardiography machines at most hospitals. Among 6680 patients referred for echocardiography at Muhimbili National Hospital between June 1998 and October 2002, 134 (0.19%) patients had HCM. Their mean age was 54.8+/-14.2 years. In total 67.9% were men and 32.1% were women. Due to the diverse clinical features only eight (5.9%) patients had a correct diagnosis of HCM prior to their ECHO. The important role of echocardiography in the diagnosis of HCM is stressed with a plea for the increasing availability of this non-invasive technique for early and accurate diagnosis.

Clinical and Echocardiographic Study of Hypertrophic Cardiomyopathy in Tanzania

There are few published reports on Hypertrophic Cardiomyopathy (HCM) in Africans. Due to lack of echocardiography machines in most hospital centers; clinical identification of HCM remains confined to those patients with a loud heart murmur associated with the outflow gradient. Between June 1998 and October 2002; 134 patients were studied at Hindu Mandal Hospital; 67.9were male and 32.1were female. Their mean age was 54.8 + 14.2 years. The presenting symptoms were Dyspnoea 62.7; Chest pain 55.9; Palpitations 50.7(Pre-syncope 21.6; Syncope 8.9) Due to the diverse clinical features; only 8(5.9) patients had a correct diagnosis of Hypertrophic Cardiomyopathy in their echocardiography request forms. Others were diagnosed as Ischaemic heart disease 31.8; Dilated Cardiomyopathy 29.9; Mitrol valve prolapse 11.2and Arrhythmias 6.7. Using Echocardiography; the pattern of LVH among these patients was found to be: Asymmetrical septal hypertrophy in 50.7and apical hypertrophy in 3.0. The important role of echocardiography in diagnosis is stressed with a plea for the increasing availability of this non-invasive technique for early and accurate diagnosis of Hypertrophic Cardiomyopathy

Stroke subtypes in Black Tanzanians: a retrospective study of computerized tomography scan diagnoses at Muhimbili National Hospital, Dar es Salaam.

Limited data are available on the stroke subtypes in Tanzania and sub-Saharan Africa. The present study was aimed at determining retrospectively the pattern of confirmed strokes in all patients in our hospital who had been given a computerized tomography (CT) brain scan during the study period (April 2001 to May 2002). Over the 12-month period 371 CT brain scans were taken, of which 148 showed stroke, 89 (60.1%) showed haemorrhage and 59 (39.9%) showed infarcts (P<0.05). Among the haemorrhagic group 48 (53.9%) were men and 41 (46.1%) women, while 31 (52.5%) men and 28 (47.5%) women had infarction. We concluded that there were relatively more cases of cerebral haemorrhage than infarction. Hypertension and diabetes mellitus were common risk factors in both subtypes of stroke.

Echocardiographic profile of endomyocardial fibrosis in Tanzania, East Africa.

OBJECTIVES: To demonstrate and evaluate the usefulness of two dimensional and Doppler echocardiography in the diagnosis of endomyocardial fibrosis (EMF) in countries with poor resources. Also to evaluate the clinical assessment as a predictor of echocardiographically proven EMF. DESIGN: Descriptive hospital based study. SETTING: Muhimbili National Hospital, Dar es Salaam, Tanzania. SUBJECTS: 39 patients (27 male and 12 female, mean age 13.5 years) attending our Cardiac Clinic were investigated to determine the extent to which specific features could be diagnosed by transthoracic echocardiography. MAIN OUTCOME MEASURES: Identifying and characterizing echocardiographic features specific for diagnosing EMF non-invasively. RESULTS: Only eight (21%) patients had a correct clinical diagnosis, leaving 79% of the patients at risk of being misdiagnosed and hence wrongly receiving expensive treatment. The majority of the patients (69.2%) presented with signs of elevated systemic venous pressure due to right ventricular EMF. CONCLUSION: We have demonstrated that echocardiography remains a fundamental investigation in the least developed countries in achieving the correct diagnosis.

Reduced adhesion of monocyte-derived macrophages from CD36-deficient patients to type I collagen.

CD36 is an 88-kDa glycoprotein expressed on platelets and monocyte/macrophages (Mphi). CD36 is a multifunctional receptor for collagen, thrombospondin, oxidized low density lipoproteins (LDL), and long-chain fatty acids. The present study was performed to investigate whether CD36 can function as an adhesion molecule which is involved in mediating human macrophages (Mphi) adhesion to type I collagen in vitro. The Mphi of human CD36-deficient as well as normal control subjects were isolated and cultured on the multi-well plates coated with type I collagen, a natural ligand for CD36. Up to 2 h of incubation, the Mphi from CD36-deficient patients showed almost a approximately 55% decrease in adhesion to type I collagen in comparison to those from controls (P < 0.01). However, there was no significant difference in the adhesion thereafter. Furthermore, the addition of antibody against CD36 into the media of control Mphi significantly inhibited the adhesion by approximately 50% (P < 0.05). The addition of oxidized LDL (OxLDL) did not alter adhesion of Mphi from both CD36-deficient and controls. These data suggest that CD36 is involved in the adhesion of Mphi to type I collagen, especially in the early stage of adhesion.

Oxidized LDL-induced NF-kappa B activation and subsequent expression of proinflammatory genes are defective in monocyte-derived macrophages from CD36-deficient patients.

-CD36 is 1 of the class B scavenger receptor expressed on monocytes, monocyte-derived macrophages (Mphi), platelets, and adipocytes. In our previous studies, we reported that the uptake of oxidized low density lipoproteins (OxLDLs) is reduced by approximately 50% in Mphi from CD36-deficient patients compared with that in control subjects. Recently, we have shown that CD36 is highly expressed in human atherosclerotic aorta. Possibilities have been raised that besides the wide distribution and multifunctional characteristics of CD36, this molecule may also be involved in the mediation of intracellular signaling. The aim of the present study was to elucidate the role of CD36 in cytokine secretion and to investigate the CD36-mediated intracellular signaling stimulated by OxLDL. On addition of OxLDL or thrombospondin-1, the Mphi from CD36-deficient patients secreted significantly less amounts of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) compared with those from controls. RNase protection assay with multiprobe template sets demonstrated that after incubation with OxLDL, the mRNAs of a variety of cytokines, including genes encoding IL-1Ra, IL-1beta, IL-6, TNF-alpha and -beta, and interferon (IFN)-gamma and -beta, were significantly lower in the Mphi of patients. The addition of antibody against CD36 attenuated this OxLDL-induced response in controls. We also observed a reduced response in nuclear factor-kappa B (NF-kappa B) activity in OxLDL-stimulated Mphi from CD36-deficient patients. Unlike OxLDL, stimulation by lipopolysaccharide induced an increase in NF-kappa B activity in Mphi from CD36-deficient patients, suggesting that lipopolysaccharide-mediated signaling was conserved. These results demonstrate that in addition to the reduced OxLDL uptake that we reported previously, CD36-deficient patients may also have an impaired response of OxLDL-induced NF-kappa B activation and subsequent cytokine expression.

Expression of macrophage (Mphi) scavenger receptor, CD36, in cultured human aortic smooth muscle cells in association with expression of peroxisome proliferator activated receptor-gamma, which regulates gain of Mphi-like phenotype in vitro, and its implication in atherogenesis.

CD36 is one of the major receptors for oxidized low density lipoproteins belonging to macrophage (Mphi) scavenger receptor (SR) class B and is thought to play an important role in the foam cell formation from monocyte-Mphi in the atherosclerotic lesions. Although it has been hypothesized that smooth muscle cells (SMCs) may be the other origin of foam cells in vivo, supporting data are still very limited. In the present study, we have tested the expression of a variety of SRs, including CD36, in 8 lots of primary human aortic SMCs (HASMCs) explanted from 8 different donors. Functional CD36 was expressed in cultured HASMCs, and the levels of expression were widely ranged between the lots. SR class A (SR-A) was expressed abundantly in CD36-negative lots. Other Mphi markers, such as CD32 and CD68, were expressed in all lots tested. These data suggest that the cultured HASMCs gained an Mphi-like phenotype. To determine the mechanism for the above-described phenotypic change, we have tested the expression of a nuclear receptor, peroxisome proliferator activated receptor-gamma, in those cells. This nuclear receptor was abundantly expressed in CD36-positive lots, whereas c-fms was expressed abundantly in CD36-negative/SR-A-positive lots. The synthetic ligand of peroxisome proliferator activated receptor-gamma, troglitazone, upregulated the expression of CD36 only in CD36-positive lots. These observations demonstrate that cultured HASMCs can gain an Mphi-like phenotype, possibly classified by the expression of CD36 or SR-A. The present study may support the possibilities of transformation of HASMCs into foam cells in vivo.

The prevalence and incidence of HIV-1 infection and syphilis in a cohort of police officers in Dar es Salaam, Tanzania: a potential population for HIV vaccine trials.

OBJECTIVES: To assess the suitability of a cohort of police officers in Dar es Salaam for HIV vaccine trials by determining the prevalence and incidence of HIV-1 infection, active syphilis and their associated factors. DESIGN AND SETTING: An open cohort study of police officers in Dar es Salaam, Tanzania. METHODS: Recruitment of police officers began in 1994. A standardized questionnaire was completed at enrolment and subsequent visits. HIV antibodies were determined using two consecutive enzyme-linked immunosorbent assays. Samples repeatedly discordant on the two tests were tested by a Western blot assay. Treponema pallidum antibodies were first determined by Venereal Disease Research Laboratory (VDRL) test and reactive sera were confirmed by Treponema pallidum hemagglutination test. RESULTS: At the end of 1996 a total of 2850 police officers had been recruited of whom 2733 (96%) consented to be tested for HIV. The overall HIV-1 seroprevalence at recruitment was 13.8% (378 of 2733). Females had a significantly higher HIV-1 seroprevalence, 18.0% (55 of 306), as compared to males, 13.3% (323 of 2427), P< 0.05. From a total of 2215 married police officers, 585 (26.4%) responded to a question on extramarital sex within the previous 3 months of whom 36.2% (212 of 585) admitted to have had at least one extramarital sexual intercourse. Condoms were not used during these encounters by 178 of 212 (84.0%). As of 31st December 1998, among the 1524 males observed for 2553 person-years (PYAR), 50 had seroconverted and among 200 females observed for 357 PYAR, eight had seroconverted. The overall crude HIV-1 incidence was thus 19.9/1000 PYAR; 19.6 and 22.4/1000 PYAR for males and females, respectively. The overall prevalence and incidence of active syphilis were 3.1% (88 of 2850) and 8.6/1000 PYAR (26 of 3149), respectively. Males had a higher prevalence of active syphilis, 84 of 2525 (3.3%) than females, five of 325 (1.5%), P = 0.09. CONCLUSIONS: There was high risk sexual practice including low condom use in this cohort of police officers. The incidence and prevalence of HIV infection were high. Police officers in Dar es Salaam are therefore a potential population group for HIV vaccine evaluation.

Case report: renal scintigraphy in the diagnosis of urinary extravasation.

Renal scintigraphy is a sensitive method for disclosing urinary extravasation. Its role following a road traffic accident is clearly presented in this case report. It is concluded that such a study can fill an important gap between the clinical and intravenous urography assessment and the more invasive studies in trauma victims.

Imaging modalities and low back pain: the role of bone scintigraphy.

The role of bone scintigraphy, both planar and single photon emission tomography (SPET), in investigating cases of chronic back pain is assessed in conjunction with other imaging modalities. A review of the literature was undertaken and an imaging strategy is suggested. It is concluded that bone scintigraphy has an important role as an imaging modality in investigating cases of chronic low back pain.

The role of bone scintigraphy and other imaging modalities in knee pain.

The role of bone scintigraphy (planar and SPET) in the investigation of chronic knee pain is assessed in conjunction with other imaging modalities. A review of the literature has been undertaken and an imaging strategy suggested. It is concluded that bone scintigraphy has an important role to play as an imaging modality when investigating cases of chronic knee pain.