Comparative analysis of exit interviews and direct clinical observations in pediatric ambulatory care services in Afghanistan.

OBJECTIVE: To assess the receiver operating curves (ROCs) for counseling in the management of common childhood diseases comparing direct observations with exit interviews. DESIGN: Eight thousand six hundred and fifty-nine randomly selected new outpatient consultations of sick children under 5 years were assessed by observation using a standardized checklist and an exit interview with their parent/guardian, taken between 2005 and 2007 from 948 health facilities in Afghanistan. The observation checklist was used as a 'gold standard' for counseling provided. MAIN MEASURE: Sensitivity, specificity and ROCs were estimated for five counseling items, including explanations of: a working diagnosis; what to do at home; possible adverse reactions to medicine; signs that require a return to the health facility; and a time to return. RESULTS: The prevalence of counseling items was relatively low (ranging from 8 to 80%), but generally increasing each year. Exit interviews had relatively low levels of sensitivity for the counseling items, ranging from 33 to 88%, with higher levels of specificity (ranging from 63 to 91%), whereas the ROCs ranged from 61 to 77%. Although ROCs varied significantly from year to year (P < 0.002 for each item), there was little difference based on the sex or type of the health provider. CONCLUSIONS: Exit interviews did not provide reliable measurements of provider performance compared with direct observations. Observations identified low prevalence of counseling tasks though increasing over time. The differences between observation and exit interviews identified significant gaps in communication, suggesting that exit interviews are of low accuracy and should not be used alone.

Can Dietary Fatty Acids Affect the COVID-19 Infection Outcome in Vulnerable Populations?

There is high mortality in coronavirus disease 2019 (COVID-19)-infected individuals with chronic inflammatory diseases, like obesity, diabetes, and hypertension. A cytokine storm in some patients after infection contributes to this mortality. In addition to lungs, the intestine is targeted during COVID-19 infection. The intestinal membrane serves as a barrier to prevent leakage of microorganisms and their products into the bloodstream; however, dietary fats can affect the gut microbiome and may increase intestinal permeability. In obese or diabetic individuals, there is an increase in the abundance of either Gram-negative bacteria in the gut or their product, endotoxin, in systemic circulation. We speculate that when the COVID-19 infection localizes in the intestine and when the permeability properties of the intestinal membrane are compromised, an inflammatory response is generated when proinflammatory endotoxin, produced by resident Gram-negative bacteria, leaks into the systemic circulation. This review discusses conditions contributing to inflammation that are triggered by microbially derived factors from the gut.

Psychotherapy for depression among incurable cancer patients.

BACKGROUND: The most common psychiatric diagnosis among cancer patients is depression; this diagnosis is even more common among patients with advanced cancer. Psychotherapy is a patient-preferred and promising strategy for treating depression among cancer patients. Several systematic reviews have investigated the effectiveness of psychological treatment for depression among cancer patients. However, the findings are conflicting, and no review has focused on depression among patients with incurable cancer. OBJECTIVES: To investigate the effects of psychotherapy for treating depression among patients with advanced cancer by conducting a systematic review of randomized controlled trials (RCTs). SEARCH STRATEGY: We searched the Cochrane Pain, Palliative and Supportive Care Group Register, The Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, and PsycINFO databases in September 2005. SELECTION CRITERIA: All relevant RCTs comparing any kind of psychotherapy with conventional treatment for adult patients with advanced cancer were eligible for inclusion. Two independent review authors identified relevant studies. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the original reports using standardized data extraction forms. Two independent review authors also assessed the methodological quality of the selected studies according to the recommendations of a previous systematic review of psychological therapies for cancer patients that utilized ten internal validity indicators. The primary outcome was the standardized mean difference (SMD) of change between the baseline and immediate post-treatment scores. MAIN RESULTS: We identified a total of ten RCTs (total of 780 participants); data from six studies were used for meta-analyses (292 patients in the psychotherapy arm and 225 patients in the control arm). Among these six studies, four studies used supportive psychotherapy, one adopted cognitive behavioural therapy, and one adopted problem-solving therapy. When compared with treatment as usual, psychotherapy was associated with a significant decrease in depression score (SMD = -0.44, 95% confidence interval [CI] = -0.08 to -0.80). None of the studies focused on patients with clinically diagnosed depression. AUTHORS' CONCLUSIONS: Evidence from RCTs of moderate quality suggest that psychotherapy is useful for treating depressive states in advanced cancer patients. However, no evidence supports the effectiveness of psychotherapy for patients with clinically diagnosed depression.

Oral administration of propentofylline, a stimulator of nerve growth factor (NGF) synthesis, recovers cholinergic neuronal dysfunction induced by the infusion of anti-NGF antibody into the rat septum.

We have reported that the continuous infusion of anti-nerve growth factor (NGF) monoclonal antibody into the septum of rats produces an impairment of memory and a decrease in choline acetyltransferase (ChAT) and cholinesterase (ChE) activities in the hippocampus. Propentofylline, a xanthine derivative, has potent stimulatory effects on NGF synthesis/secretion in mouse astrocytes in vitro. To investigate the pharmacological effects of propentofylline in vivo, we induced amnesia in rats by infusing anti-NGF antibody into the septum for 16 days. One group of rats was given no further treatment, while the other group was treated with propentofylline orally once a day for 19 days, commencing 3 days before the implantation of the mini-osmotic pump, and continuing throughout the period during which the animals performed the behavioral tasks. In the treated amnesic rats, learning and memory in the 3 tasks and ChAT and ChE activity were reduced compared to values in control rats. The administration of propentofylline recovered the decreased learning capacity and the deficit in cholinergic marker enzyme activity. These results suggest that the use of NGF stimulators may provide a new approach to the treatment of dementia.

Propentofylline prevents neuronal dysfunction induced by infusion of anti-nerve growth factor antibody into the rat septum.

We have reported that the continuous infusion of anti-nerve growth factor (NGF) monoclonal antibody into the septum of rats produces neuronal dysfunction in the cholinergic system. Propentofylline has potent stimulatory effects on NGF synthesis/secretion in mouse astrocytes in vitro. To investigate the pharmacological effects of propentofylline, we used an animal model of dementia in which anti-NGF antibody was infused into the septum for 16 days via a mini-osmotic pump. The rats were treated with propentofylline orally once a day throughout the period during which performance in learning and memory tasks was observed. In the vehicle-treated dementia rats, learning and memory ability and choline acetyltransferase and cholinesterase activity were reduced compared to values in the control rats. The administration of propentofylline prevented the decreased learning capacity and the deficit in cholinergic marker enzyme activities. These results suggest that the use of NGF stimulators may provide a new approach to the treatment of dementia.

The lack of antifungal activity by avermectin B1a.

Streptomyces avermitilis produces avermectin, oligomycin and a polyene antifungal. The latter two compounds account for the antifungal activity in the methanol extracts of the fermentation broth. Pure avermectin does not inhibit fungi or affect fungal chitin metabolism.

L-657,398, a novel antifungal agent: fermentation, isolation, structural elucidation and biological properties.

L-657,398 is a broad spectrum antifungal agent isolated from solid fermentation or from the mycelium of the liquid fermentation of Aspergillus ochraceus. Structurally, the compound is a novel pyrollidine related to anisomycin.

Restricticin, a novel glycine-containing antifungal agent.

Restricticin (1) is a naturally-occurring antifungal agent which contains triene, pyran and glycine ester functionalities and is unrelated to any previously known family of natural products. This unstable compound, as well as its corresponding N,N-dimethyl derivative (2), have been produced and isolated from both solid and liquid fermentations of Penicillium restrictum. The desglycyl hydrolysis product, restrictinol (3), was produced via the hydrolysis of pure restricticin and as an artifact of the isolation of restricticin.

Antimicrobial activity of viridiofungins.

A family of aminoacyl alkyl citrate compounds called viridiofungins, are novel squalene synthase inhibitors. The compounds have broad spectrum fungicidal activity but lack antibacterial activity. Although the compounds inhibit squalene synthase, the first committed step in ergosterol biosynthesis, results presented in this paper show that inhibition of fungal growth is not related to inhibition of ergosterol synthesis.

Development of a Portable Acceleration Monitor Device and its clinical application for the Quantitative Gait Assessment of the Elderly.

In this study, a handy gait assessment system with a tri-axial accelerometer has been developed and its application for a quantitative assessment of gait in the elderly was examined. This assessment system consists of a portable acceleration monitor device and PC analysis software. This portable device was fixed to the lower front of the subject, and the subject was asked to walk around a test course at a voluntary speed. The activities performed on the test course include standing up, normal walking, fast walking, and walking over a barrier. Gaits in 402 elderly people were measured three times every three months. These subjects were under nursing health services, such as expert place nursing, walking training, power rehabilitation, fall prevention training, and pool training. The measured acceleration was converted into relative velocity and relative displacement of the center of gravity of the subject. Four evaluation indices, i.e., physical activity, stability, symmetry, and average speed were calculated. The results reveal that both the physical activity and average speed decreased after six months under nursing services.

Rhodopseudomonas sphaeroides membranes: alterations in phospholipid composition in aerobically and phototrophically grown cells.

The effects of growth conditions on phospholipid composition in Rhodopseudomonas sphaeroides have been reexamined. The levels of phosphatidylethanolamine (27 to 28%), phosphatidylglycerol (23 to 24%), and phosphatidylcholine (11 to 18%) were very similar in cells grown aerobically or phototrophically at a high light intensity, consistent with findings for another member of Rhodospirillaceae. In addition, an unknown phospholipid species was detected which comprised 20 to 30% of the total phospholipid in these cells. In cells growing phototrophically at low-intensity illumination, the level of phosphatidylethanolamine increased by about 1.6-fold and that of the unknown phospholipid markedly decreased. Although the synthesis of photosynthetic pigments, light-harvesting protein, and intracytoplasmic photosynthetic membranes also increased markedly, the ratios of individual phospholipid species were essentially identical in photosynthetic membrane and cell wall fractions purified from these cells. Since a significant exchange of lipids apparently did not occur during the isolation of these fractions, it was suggested that the changes in cellular phospholipid accumulation were not due to a unique composition within the photosynthetic membrane. Instead, these phosphoglyceride changes were found to be related to overall phospholipid metabolism and could be accounted for principally by differences in biosynthetic rates. These results, together with studies in nutrient-restricted aerobic cells, suggested that the mechanism by which phospholipid levels are regulated may be related to radiant energy flux rather than cellular energy limitation.

Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase.

The lipopeptide antifungal agents, echinocandins, papulacandins, and pneumocandins, kill Candida albicans by inhibiting glucan synthesis. For this fungus, there is a good correlation of in vitro enzyme inhibition with in vitro assays of MICs. Semisynthetic lipopeptides such as cilofungin, LY303366, L-693,989, and L-733,560 have activity in vivo against Aspergillus infections but appear to be inactive in broth dilution in vitro tests (MICs, > 128 micrograms/ml). To understand how compounds which lack activity in vitro can have good in vivo activity, we monitored the effect of pneumocandins on the morphology of Aspergillus fumigatus and A, flavus strains by light microscopy and electron microscopy and related the changes in growth to inhibition of glucan synthesis. Pneumocandin B0 caused profound changes in hyphal growth; light micrographs showed abnormally swollen germ tubes, highly branched hyphal tips, and many cells with distended balloon shapes. Aspergillus electron micrographs confirmed that lipopeptides produce changes in cell walls; drug-treated germlings showed very stubby growth with thick walls and a conspicuous dark outer layer which was much thicker in the subapical regions. The rest of the hyphal tip ultrastructure was unaffected by the drug, indicating considerable specificity for the primary target. The drug-induced growth alteration produced very compact clumps in broth dilution wells, making it possible to score the morphological effect macroscopically. The morphological changes could be assayed quantitatively by using conventional broth microdilution susceptibility assay conditions. We defined the endpoint as the lowest concentration required to produce the morphological effect and called it the minimum effective concentration to distinguish it from the no-growth endpoints used in MIC determinations. The minimum effective concentration assay was related to inhibition of glucan synthase activity in vitro and may provide a starting point for development of susceptibility testing methods for lipopeptides.

Smell identification test as an indicator for cognitive impairment in Alzheimer's disease.

OBJECTIVES: The aim of the present study was to assess olfactory dysfunction in patients with Alzheimer's disease (AD) and to compare utility of the olfactory tests as possible clinical markers. METHODS: Two olfactory identification tests (The Cross-Cultural Smell Identification Test [CC-SIT] and the Picture-based Smell Identification Test [P-SIT]) and the Mini Mental State Examination (MMSE) were administered to patients with AD and age-matched controls. Apolipoprotein E (Apo E) genotypes of patients with AD were identified. RESULTS: Patients with AD had significantly lower olfactory identification scores than age-matched non-demented elderly subjects in both olfactory assessments. In the AD group, the coefficient of correlation between the MMSE scores and the P-SIT scores was higher than that between the MMSE scores and the CC-SIT scores. Receiver operating curve (ROC) analyses for both tests indicated that the P-SIT discriminated AD patients from controls more reliably than did the CC-SIT. Within AD patients, those who were carrying one or two ApoE epsilon4 alleles had a higher coefficient of correlation between the MMSE scores and the P-SIT scores than patients without the ApoE epsilon4 allele. CONCLUSIONS: The results suggest that a short and simple non-lexical olfactory identification test can be useful as a clinical marker of AD appropriate for Japanese elderly population.

Pharmacokinetics of L-671,329 in rhesus monkeys and DBA/2 mice.

The time course of plasma drug levels and urinary recovery for two lipopeptide antifungal antibiotics, L-671,329 and cilofungin, were measured in male rhesus monkeys (Macaca mulatta) and in female DBA/2 mice. The antibiotics were administered intravenously at 10 mg/kg of body weight in phosphate-buffered saline-26% polyethylene glycol for the rhesus monkeys and in 5% dimethyl sulfoxide for the mice. Plasma and urine drug concentrations were determined by high-pressure liquid chromatography and/or a microbiological assay versus Aspergillus niger, and pharmacokinetic parameters were determined for both species. In each of the two rhesus crossover tests as well as in the mouse studies, the pharmacokinetics of the two compounds were similar; however, a marked difference was evident between species. The half-lives of L-671,329 and cilofungin in plasma were 39 and 34 min in the mice and averaged 1.8 and 2 h in the rhesus monkeys, respectively. In mice and rhesus monkeys, urinary recovery was less than 4% for both compounds.

Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis.

The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-beta-D-glucan in susceptible fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections. Substitution by an aminoethyl ether at the hemiaminal and dehydration and reduction of the glutamine of pneumocandin B0 produced a semisynthetic compound (L-733,560) with intrinsic water solubility, significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we determined that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphological alterations as pneumocandin B0. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase. All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action.

Geranylgeranyltransferase I of Candida albicans: null mutants or enzyme inhibitors produce unexpected phenotypes.

Geranylgeranyltransferase I (GGTase I) catalyzes the transfer of a prenyl group from geranylgeranyl diphosphate to the carboxy-terminal cysteine of proteins with a motif referred to as a CaaX box (C, cysteine; a, usually aliphatic amino acid; X, usually L). The alpha and beta subunits of GGTase I from Saccharomyces cerevisiae are encoded by RAM2 and CDC43, respectively, and each is essential for viability. We are evaluating GGTase I as a potential target for antimycotic therapy of the related yeast, Candida albicans, which is the major human pathogen for disseminated fungal infections. Recently we cloned CaCDC43, the C. albicans homolog of S. cerevisiae CDC43. To study its role in C. albicans, both alleles were sequentially disrupted in strain CAI4. Null Cacdc43 mutants were viable despite the lack of detectable GGTase I activity but were morphologically abnormal. The subcellular distribution of two GGTase I substrates, Rho1p and Cdc42p, was shifted from the membranous fraction to the cytosolic fraction in the cdc43 mutants, and levels of these two proteins were elevated compared to those in the parent strain. Two compounds that are potent GGTase I inhibitors in vitro but that have poor antifungal activity, J-109,390 and L-269,289, caused similar changes in the distribution and quantity of the substrate. The lethality of an S. cerevisiae cdc43 mutant can be suppressed by simultaneous overexpression of RHO1 and CDC42 on high-copy-number plasmids (Y. Ohya et al., Mol. Biol. Cell 4:1017, 1991; C. A. Trueblood, Y. Ohya, and J. Rine, Mol. Cell. Biol. 13:4260, 1993). Prenylation presumably occurs by farnesyltransferase (FTase). We hypothesize that Cdc42p and Rho1p of C. albicans can be prenylated by FTase when GGTase I is absent or limiting and that elevation of these two substrates enables them to compete with FTase substrates for prenylation and thus allows sustained growth.

Hyalodendrosides A and B, antifungal triterpenoid glycosides from a lignicolous hyphomycete, Hyalodendron species.

Two antifungal triterpenoid glycosides, hyalodendrosides A and B (1 and 2), were isolated from a solid matrix fermentation of a lignicolous hyphomycete, Hyalodendron sp. Their structures were determined based upon extensive examination of spectral parameters, particularly NMR and MS data. Both compounds have beta-linked glucose moieties. Compounds 1 and 2 show weak to moderate antifungal activity against some clinically relevant fungi.