Pretomanid with bedaquiline and linezolid for drug-resistant TB: a comparison of prospective cohorts.

BACKGROUND: There are no data comparing the 6-9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B-L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

A partially randomised trial of pretomanid, moxifloxacin and pyrazinamide for pulmonary TB.

BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed.METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed.RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI -2.2% to 15.4%) difference per protocol and 9.9% (95%CI -4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died.CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority.

Electroretinographic detection of human brain dopamine response to oral food stimulation.

OBJECTIVE: The activity of dopamine-dependent retinal signaling can be assessed using electroretinography. Response of this system to oral food stimulation might provide accessible insight into the brain dopamine response to oral stimuli as retinal dopamine concentration is dependent upon mid brain dopamine concentration was postulated. DESIGN AND METHODS: Nine individuals had cone ERG (b wave) response to oral food stimulation and oral methylphenidate (MPH) administration measured on separate days, and completed self reported eating behavior questionnaires. RESULTS: Significant and similar increases in b wave response to both stimuli (P = 0.012 and P = 0.042, MPH and food, respectively) and significant correlations of the food stimulated b wave amplitude with binge eating related behavior as measured by the Gormally Binge Eating Scale (r = 0.68, P = 0.044) and self-reported trait hunger as measured by the Stunkard and Messick Three Factor Eating Questionnaire (r = 0.67, P = 0.048) were found. CONCLUSION: The significant increase in food stimulated dopamine dependent b wave amplitude and correlation with methylphenidate stimulated b wave amplitude suggest that ERG may offer a relatively inexpensive and accessible methodology for potentially assess dopaminergic responses to food and other externally applied stimuli that have been implicated in the pathogenesis of a number of human diseases.

Alcohol consumption, mild cognitive impairment, and progression to dementia.

OBJECTIVE: To estimate the impact of alcohol consumption on the incidence of mild cognitive impairment and its progression to dementia. METHODS: We evaluated the incidence of mild cognitive impairment in 1,445 non-cognitively impaired individuals and its progression to dementia in 121 patients with mild cognitive impairment, aged 65 to 84 years, participating in the Italian Longitudinal Study on Aging, with a 3.5-year follow-up. The level of alcohol consumption was ascertained in the year before the survey. Dementia and mild cognitive impairment were classified using current clinical criteria. RESULTS: Patients with mild cognitive impairment who were moderate drinkers, i.e., those who consumed less than 1 drink/day (approximately 15 g of alcohol), had a lower rate of progression to dementia than abstainers (hazard ratio [HR] 0.15; 95% CI 0.03 to 0.78). Furthermore, moderate drinkers with mild cognitive impairment who consumed less than 1 drink/day of wine showed a significantly lower rate of progression to dementia than abstainers (HR 0.15; 95% CI 0.03 to 0.77). Finally, there was no significant association between higher levels of drinking (> or =1 drink/day) and rate of progression to dementia in patients with mild cognitive impairment vs abstainers. No significant associations were found between any levels of drinking and the incidence of mild cognitive impairment in non-cognitively impaired individuals vs abstainers. CONCLUSIONS: In patients with mild cognitive impairment, up to 1 drink/day of alcohol or wine may decrease the rate of progression to dementia.

Vascular risk factors, incidence of MCI, and rates of progression to dementia.

OBJECTIVE: To estimate prevalence, incidence, and rate of progression of mild cognitive impairment (MCI) to dementia and correlated vascular risk factors with incident MCI and its progression to dementia. METHODS: The authors evaluated 2,963 individuals from the population-based sample of 5,632 subjects 65 to 84 years old, at the first (1992 to 1993) and second survey (1995 to 1996) of the Italian Longitudinal Study on Aging (ILSA), with a 3.5-year follow-up. Dementia, Alzheimer disease (AD), vascular dementia (VaD), other types of dementia, and MCI were classified using current clinical criteria. RESULTS: Among the 2,963 participants, 139 MCI patients were diagnosed at the first ILSA survey. During the 3.5-year follow-up, 113 new events of MCI were diagnosed with an estimated incidence rate of 21.5 per 1,000 person-years. We found a progression rate to dementia (all causes) of 3.8/100 person-years. Specific progression rates for AD, VaD, and other types of dementia were 2.3, 1.3, and 0.3/100 person-years. Furthermore, age was a risk factor for incident MCI (RR: 5.93, 95% CI: 3.17 to 11.10), while education was protective (RR: 0.06, 95% CI: 0.03 to 0.10), and serum total cholesterol evidenced a borderline nonsignificant trend for a protective effect. There was a nonsignificant trend for stroke as a risk factor of progression of MCI to dementia. CONCLUSIONS: In this population, among those who progressed to dementia, 60% progressed to AD and 33% to VaD. Vascular risk factors influence incident mild cognitive impairment and the rate of progression to dementia.

Mediterranean diet and cognitive decline.

OBJECTIVE: To investigate the possible role of diet in age-related cognitive decline (ARCD) and cognitive impairment of both degenerative (Alzheimer's disease, AD) and vascular (vascular dementia, VaD) origin. DESIGN: Literature review. RESULTS: In an elderly population of southern Italy with a typical Mediterranean diet, high energy intake of monounsaturated fatty acids (MUFA) appeared to be associated with a high level of protection against ARCD. In addition, dietary fat and energy in the elderly seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in European and North American countries. Finally, the relative risk of dementia (AD and VaD) was lower in the subjects of a French cohort who drank three or four glasses of red wine each day compared with total abstainers. CONCLUSION: Essential components of the Mediterranean diet--MUFA, cereals and wine--seem to be protective against cognitive decline. As such, dietary antioxidants and supplements, specific macronutrients of the Mediterranean diet, oestrogens and anti-inflammatory drugs may act synergistically with other protective factors, opening up new therapeutic interventions for cognitive decline.

Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure.

BACKGROUND: Obesity results from a chronic imbalance between energy intake and energy expenditure. However, experimental evidence of the relative contribution of interindividual differences in energy intake and expenditure (resting or due to physical activity) to weight gain is limited. OBJECTIVE: To assess prospectively the association between baseline measurements of daily energy metabolism and weight changes by studying free-living adult Pima Indians, one of the most obese populations in the world. DESIGN: A study of the pathogenesis of obesity in the Pima Indians living in Southwestern Arizona. The participants were 92 nondiabetic Pima Indians (64M/28F, 35+/-12 y, 35+/-9% body fat; mean+/-s.d.). At baseline, free-living daily energy metabolism was assessed by doubly labeled water and resting metabolic rate (RMR) by indirect calorimetry. Data on changes in body weight (5.8+/-6.5 kg) over a follow-up period of 4+/-3 y were available in 74 (49M/25F) of the 92 subjects. RESULTS: The baseline calculated total energy intake (r=0.25, P=0.028) and RMR (r=-0.28, P=0.016) were significantly associated with changes in body weight. The baseline energy expenditure due to physical activity was not associated with changes in body weight. CONCLUSION: Using state-of-the-art methods to assess energy intake and expenditure in free-living conditions, we show for the first time that the baseline calculated total energy intake is a determinant of changes in body weight in Pima Indians. These data also confirm that a low RMR is a risk factor for weight gain in this population.

The Gln223Arg polymorphism of the leptin receptor in Pima Indians: influence on energy expenditure, physical activity and lipid metabolism.

Leptin regulates body weight by its receptor-mediated anorectic, thermogenic and antisteatotic effects. Recently, lower leptin binding to the soluble form of the leptin receptor (LEPR) was shown in carriers of the Arg223-encoding allele of the Gln223Arg polymorphism of the LEPR. To investigate whether this variant influences energy metabolism and adiposity in Pima Indians, we genotyped non-diabetic Pima Indians in whom we had measured body composition and 24 h energy expenditure (24 h EE), physical activity level (PAL) and 24 h respiratory quotient (24 h RQ) in a respiratory chamber (n=268) and who had undergone percutaneous fat biopsies from the periumbilical region (n=184). Genotype was not associated with percent body fat (P>0.39), but was associated with 24 h EE, PAL and mean subcutaneous abdominal adipocyte size (SAAS all P<0.05). Homozygotes for the Arg223-encoding allele had lower 24 h EE (P=0.04) and PAL (P=0.007), but larger SAAS (P=0.01) than Gln homozygotes. These findings are consistent with a role of the Gln223Arg polymorphism in reducing peripheral and central leptin binding to the LEPR in humans. However, these effects do not seem to have a major impact on adiposity in this population.

Effect of satiation on brain activity in obese and lean women.

OBJECTIVE: To investigate the response of the brains of women to the ingestion of a meal. RESEARCH METHODS AND PROCEDURES: We used measures of regional cerebral blood flow (rCBF), a marker of neuronal activity, by positron emission tomography to describe the functional anatomy of satiation, i.e., the response to a liquid meal in the context of extreme hunger (36-hour fast) in 10 lean (BMI < or = 25 kg/m(2); 32 +/- 10 years old, 61 +/- 7 kg; mean +/- SD) and 12 obese (BMI > or = 35 kg/m(2); 30 +/- 7 years old, 110 +/- 14 kg) women. RESULTS: In lean and obese women, satiation produced significant increases in rCBF in the vicinity of the prefrontal cortex (p < 0.005). Satiation also produced significant decreases in rCBF in several regions including the thalamus, insular cortex, parahippocampal gyrus, temporal cortex, and cerebellum (in lean and obese women), and hypothalamus, cingulate, nucleus accumbens, and amygdala (in obese women only; all p < 0.005). Compared with lean women, obese women had significantly greater increases in rCBF in the ventral prefrontal cortex and had significantly greater decreases in the paralimbic areas and in areas of the frontal and temporal cortex. DISCUSSION: This study indicates that satiation elicits differential brain responses in obese and lean women. It also lends additional support to the hypothesis that the paralimbic areas participate in a central orexigenic network modulated by the prefrontal cortex through feedback loops.

A Ser311Cys mutation in the human dopamine receptor D2 gene is associated with reduced energy expenditure.

Brain dopaminergic pathways play a major role in the control of movement. Absence of the murine dopamine D2 receptor gene (drd2) produces bradykinesia and hypothermia. A Ser311Cys mutation of the human DRD2 produces a marked functional impairment of the receptor and is associated with higher BMI in some populations. We hypothesized that the Ser311Cys mutation of DRD2 may inhibit energy expenditure. Here we report that total energy expenditure (doubly labeled water) measured in 89 nondiabetic Pima Indians was 244 kcal/ day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.056). The 24-h resting energy expenditure (respiratory chamber) measured in 320 nondiabetic Pimas was also 87 kcal/day lower in homozygotes for the Cys311-encoding allele when compared with those heterozygous and homozygous for the Ser311-encoding allele (P = 0.026). These findings are the first evidence that a genetic mutation is associated with reduced energy expenditure in humans. Because the impact of this mutation on human obesity is small, we suggest that either the energy deficit induced is not large enough to significantly influence body weight in this population and/or that the Cys311-encoding allele is also associated with reduced energy intake.

Apolipoprotein E in Southern Italy: protective effect of epsilon 2 allele in early- and late-onset sporadic Alzheimer's disease.

Apolipoprotein E (apoE) polymorphism was evaluated in 81 sporadic late onset Alzheimer's disease (LOAD) patients, 28 sporadic early-onset Alzheimer's disease (EOAD) and 92 sex- and age-matched healthy controls from Apulia, Southern Italy. ApoE genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. The frequency of apoE epsilon 4 allele was significantly higher in EOAD patients than in the control group, but not in LOAD patients. Furthermore, EOAD patients carrying epsilon 4 allele had lower age at onset of AD symptoms (about 4. 5 years). In the whole sample, epsilon 4 was associated to AD by an odds ratio of 2.14, while it increased up to 6.55 in < 65 years old subjects. Finally, in both < 65 and > or = 65 subgroups of subjects, epsilon 2 played a protective role against the development of AD. It is concluded that the geographic decreasing trend of epsilon 4 allele and the age at onset may influence the association of apoE polymorphism with sporadic AD in a Southern Italian sample.

[Age-related cognitive decline: evaluation and prevention strategy]. / Declino cognitivo età-correlato: valutazione e strategie per la prevenzione.

The age-related decline of cognitive functions generally refers to a mild deterioration in memory performance, executive functions, and speed of cognitive processing. The terms "age-related cognitive decline" (ARCD) and "aging-associated cognitive decline" have been proposed recently to indicate an objective decline in cognitive functioning associated to the ageing process but within normal limits given the person's age. Whether ARCD is expression of a normal ageing process or represents a distinct clinical entity or, eventually, is a continuum with dementia is, at present, difficult to establish. The causes of ARCD are unknown, but some studies have suggested that it may be prevented. Avoidance of cardiovascular and other chronic diseases, high educational level, and maintenance of vision and hearing have been identified as protective factors from ARCD. On the contrary, hypertension, effects of altered metabolism of steroid hormones, smoking, low-complexity occupation, higher density of persons/bedroom in home, and low level of physical activity have been identified as risk factors for ARCD. Recent findings suggest a possible role of diet in the ARCD. In fact, in an elderly population of Southern Italy with a typical Mediterranean diet, high monounsaturated fatty acids energy intake appeared to be associated with a high protection against cognitive decline. Dietary antioxidants, specific macronutrients, estrogens, and anti-inflammatory drugs, may act synergistically with other protective factors, opening new therapeutic interventions for cognitive decline.

Increased bile acid excretion and reduction of serum cholesterol after crenotherapy with salt-rich mineral water.

The effect of a spring mineral water from Montecatini (Italy) on bile acid excretion, and lipid and apolipoprotein serum levels was evaluated. The study was conducted in subjects with serum total cholesterol (TC) level > 240 mg/dL and LDL cholesterol (LDL-C) > 170 mg/dL, over a 9-week period, with 3 weeks of dietary stabilization, 3 weeks of active treatment, and 3 weeks of tap-water treatment as a control period. Serum lipids and apolipoproteins, total and fractionated bile acid excretion, gallbladder motility, and safety parameters were evaluated. Active treatment with mineral water significantly reduced serum TC by 7.5%, LDL-C by 12.5%, TC/HDL-cholesterol ratio by 6.3%, and apolipoprotein B by 6.3%; total fecal bile acid excretion was increased by 98.9%, and gallbladder volume was reduced by 40%. The reduction in serum and LDL-cholesterol levels observed during the active treatment period ran parallel to the increased excretion of bile acids in the stools. We suggest that salt-rich spring water treatment reduces serum and LDL-cholesterol levels in subjects with mild hypercholesterolemia through a mechanism of increased excretion of fecal bile acid sterols.

High monounsaturated fatty acids intake protects against age-related cognitive decline.

OBJECTIVE: To study the relationships between dietary macronutrient intakes and age-related changes in cognitive functions. METHODS: We investigated these associations in the prevalence survey (1992 through 1993) of the Italian Longitudinal Study on Aging (ILSA). The population-based sample of 5,632 subjects of the ILSA, age 65 to 84 years, was identified from the electoral rolls of eight Italian municipalities. In this study, standardized test batteries assessing global cognitive functions (Mini-Mental State Examination [MMSE]), selective attention (Digit Cancellation Test [DCT]), and episodic memory (Babcock Story Recall Test), and a semi-quantitative food frequency questionnaire evaluating macronutrient energy intakes, were performed on 278 nondemented elderly subjects from the randomized cohort of Casamassima, Bari (n = 704). RESULTS: There was an inverse relationship between monounsaturated fatty acids (MUFAs) energy intake and cognitive decline (MMSE < 24). The effect of education on the odds of having a MMSE score <24 decreased exponentially with the increase of MUFA intakes (over 2,400 kJ; odds ratio, 0.69). Moreover, a significant inverse association was observed between MUFA intakes and DCT score (odds ratio, 0.99). No association was found between nutritional variables and episodic memory. CONCLUSIONS: In an elderly population of Southern Italy with a typical Mediterranean diet, high MUFA intakes appeared to be protective against age-related cognitive decline. Prospective clinical trials are needed to evaluate the impact of specific dietary macronutrient intakes on the age-related changes of cognitive functions.

Decreased frequency of apolipoprotein E epsilon4 allele from Northern to Southern Europe in Alzheimer's disease patients and centenarians.

Apolipoprotein E (apoE) polymorphism was studied in 79 sporadic late onset Alzheimer's disease (LOAD) patients, 125 unrelated caregivers or volunteers (19-80 years), and 67 centenarians from Apulia, Southern Italy. The frequency of apoE epsilon2 allele was higher in centenarians than in LOAD patients, while epsilon4 was lower. In middle-aged adults, the epsilon4 allele frequency was higher than in centenarians. The epsilon4 allele frequency was lower in healthy adults than in LOAD patients, while epsilon2 was higher. Compared with the allele frequencies of Northern and Central European countries, a geographic trend for epsilon3 and epsilon4 alleles in LOAD and middle-aged adults was observed. The frequency of epsilon3 increased from Northern to Southern Europe, while epsilon4 decreased significantly. In centenarians, epsilon2 showed a North-South increasing pattern, while epsilon4 was in opposite trend.