Protein-Energy Supplementation in Early-Life Decreases the Odds of Mental Distress in Later Adulthood in Guatemala

The prevalence of mental health concerns is growing worldwide, along with lack of access to and receipt of needed treatment. Current gaps in treatment provision have led to exploring alternative methods of prevention, with research linking nutrition and mental health, of particular relevance in low- and middle-income countries, with a high prevalence of undernutrition. To examine whether exposure to a protein-energy nutritional supplement during the first 1000 d of life decreased odds of mental distress in adulthood among men and women in Guatemala compared with receiving a low energy-no protein supplement or supplementation outside the 1000-d window. Data from participants (n = 1249) in a longitudinal cohort protein-energy supplementation trial (early-life, supplementation data from 1969 to 1977, ages 0­7 y; life course, outcome data from 2017­2018 follow-up, ages 40­57 y) were analyzed for associations between nutrition in the first 1000 d and mental distress in adulthood (WHO Self- Reporting Questionnaire 20 [SRQ-20]), controlling for early-life variables and current life stress; life course variables (e.g. education) were examined as potential mediators of this relation. Generalized linear mixed models and zero-inflated Poisson generalized linear mixed models were utilized. Both partial and full supplementation with Atole during the first 1000 d were associated with 63% (95% CI: 0.16, 0.87) and 56% (95% CI: 0.19, 1.03) lower odds, respectively, of experiencing mental distress in adulthood. Did not differ by sex. These inverse relations remained relatively unchanged (partial OR = 0.34 [95% CI: 0.14, 0.83]; full OR = 0.38 [95% CI: 0.16, 0.92]) after controlling for early-life and life course variables, including life stress. Protein-energy supplementation during the first 1000 d of life in Guatemala, where undernutrition is prevalent, may reduce the prevalence of later mental distress in adulthood. This effect appears to occur directly, rather than indirectly, through pathways of life course variables such as education, wealth, and marital status. Keywords: early childhood nutrition, protein-energy

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

Inhibition-induced plasticity in tinnitus patients after repetitive exposure to tailor-made notched music.

OBJECTIVE: Notch-filtered music has been shown to induce frequency-specific inhibition. Here, we investigated which cortical structures are affected by tailor-made notched music (TMNM) in tinnitus patients and how this inhibition-induced plasticity develops over time. METHODS: Nine subjects suffering from chronic tonal tinnitus listened to music passing through a notch-filter centered at the patient's individual tinnitus frequency (TMNM) for three hours on three consecutive days. Before and after each listening session, a tone at the tinnitus frequency and a control tone of 500 Hz were presented in the magnetoencephalograph. Subjective tinnitus loudness was measured via visual analog scales. RESULTS: TMNM exposure reduced subjective tinnitus loudness and neural activity evoked by the tinnitus tone in temporal, parietal and frontal regions within the N1m time interval. Reduction of temporal and frontal activation correlated significantly with tinnitus loudness decline. Reduction of tinnitus related neural activity persisted and accumulated over three days. CONCLUSIONS: Inhibition-induced plasticity occurs in a cortical network, known to be crucial for tinnitus perception. This cortical reorganization evolves fast and accumulates across sessions. SIGNIFICANCE: This study extends previous work on inhibition-induced plasticity, as it demonstrates the involvement of parietal and frontal areas and discovers a cumulative effect of cortical reorganization in tinnitus patients.

Establishment of a family-centred care programme with follow-up home visits: implications for clinical care and economic characteristics.

BACKGROUND: Elternberatung Frühstart is a family-centred care programme for very preterm infants and seriously ill neonates and their parents. The uniqueness of this programme is in its consistency and continuity in parental counselling from pregnancy at risk to follow-up home visits. PATIENTS AND METHODS: Family-centred care is provided by specialised nurses, a social education worker, a case manager, a psychologist and neonatologists. They give support and information to parents and facilitate transition to home including co-ordination of health care services and support networks. The programme starts with information for parents at risk of preterm delivery to lessen their anxieties and worries. After birth, parental bonding is encouraged and parents are involved in daily care procedures. The following weeks focus on communication, information and education in order to enhance parental competence. Discharge planning and coordinated follow-up visits involve the family doctor and several members of the welfare and health care system. One of the key objectives is to prevent re-hospitalisation. Over a 4 year period 330 families participated. Funding is provided by: 1) the hospital, from admission to discharge equivalent to one full-time nursing staff, 2) charity donations for follow-up visits and 3) health care insurance for social medical aftercare (Bunter Kreis) following §43, 2 SGB V in severe cases. RESULTS: As a result of this programme, the median length of stay was reduced by 24 days; the number of patients that stayed longer than average were reduced by 64% in the group of patients born < 1 500 g. At the same time the patient throughput increased from 243 to 413. CONCLUSION: To conclude, a family-centred care programme with coordinated follow-up increases parental satisfaction, reduces the length of the hospital stay and is therefore profitable.

Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation with fludarabine and melphalan is associated with durable disease control in myelodysplastic syndrome.

We retrospectively evaluated the outcome of reduced-intensity conditioning (RIC) followed by allogeneic hematopoietic stem cell transplantation (HCT) in 43 patients with myelodysplastic syndrome (MDS) or AML arising from MDS. All patients received fludarabine plus melphalan followed by an allogeneic HCT from an HLA-identical sibling (SIB: n=19) or unrelated donor (MUD: n=24). Median age was 58 years (range: 30-71). Diagnoses at transplantation were RA (n=8), RARS (n=1), RAEB (n=13), RAEB-T (n=6), or AML arising from MDS (n=15). Of 28 patients with MDS, two patients had low, 10 had intermediate-1, nine had intermediate-2 and seven had high-risk MDS by IPSS criteria. All patients initially engrafted with the median neutrophil recovery of 15 days (range: 9-27). The 2-year overall survival, disease-free survival, relapse and transplant-related mortality were 53.5% (CI 45.2-61.1), 51.2% (CI 43.3-58.5), 16.3% (CI 7.9-30.7) and 35.2% (26.4-45.7), respectively. Grade II-IV acute graft-versus-host disease occurred in 27 (63%) patients. There was no significant survival difference between SIB and MUD-HCT, but the relapse rate was higher among SIB donor recipients when compared to MUD (38.5 versus 7%, P=0.02). RIC with fludarabine plus melphalan was associated with durable disease control and acceptable toxicity in this high-risk cohort.

Thalamocortical theta coherence in neurological patients at rest and during a working memory task.

We simultaneously recorded the local field potential (LFP) in the thalamus and the electroencephalogram (EEG) on the scalp of 5 patients suffering from neurogenic pain, epilepsy and movement disorders. In an earlier study [], we have investigated the slowing of EEG and the high thalamocortical coherence in the framework of thalamocortical dysrhythmia, the common underlying pathophysiology. The current study focuses on the effects of different cognitive conditions. When patients rested with eyes closed, a theta peak dominated the EEG spectra. The peak height was reduced upon opening the eyes, reminiscent of the classical alpha blocking. This peak reduction also appeared in the thalamic LFP recording. When patients activated their working memory by counting backwards, the theta peak increased in scalp EEG or in the LFP recorded in thalamic nuclei VA/VL. The coherence estimates between EEG and LFP ranged between 21% and 76% for different patients and cognitive conditions (mean: 50%). The involvement of both cortex and thalamus in working memory and the high thalamocortical coherence underline, in addition to cortico-cortical interactions, the importance of thalamocortical modules in the generation of higher cognitive functions.

Low-level laser irradiation promotes proliferation and differentiation of human osteoblasts in vitro.

OBJECTIVES: The aim of the present study was to investigate the effect of low-level laser irradiation on proliferation and differentiation of a human osteoblast cell line. BACKGROUND DATA: It was previously found that low-level laser therapy (LLLT) enhances bone repair in experimental models. MATERIALS AND METHODS: Cultured osteoblast cells were irradiated using He-Ne laser irradiation (632 nm; 10 mW power output). On the second and third day after seeding the osteoblasts were exposed to laser irradiation. The effect of irradiation on osteoblast proliferation was quantified by cell count and colorimetric MTT (dimethylthiazol tetrazolium bromide) assay 24 and 48 h after second irradiation. RESULTS: A significant 31-58% increase in cell survival (MTT assay) and higher cell count in the once-irradiated as compared to nonirradiated cells was monitored. Differentiation and maturation of the cells was followed by osteogenic markers: alkaline phosphatase (ALP), osteopontin (OP), and bone sialoprotein (BSP). A two-fold enhancement of ALP activity and expression of OP and BSP was much higher in the irradiated cells as compared to non-irradiated osteoblasts. CONCLUSION: We conclude that LLLT promotes proliferation and maturation of human osteoblasts in vitro. These results may have clinical implications.

Learning and change among leaders of a professional nursing association.

This is a report of the results of a qualitative research study that investigated the informal learning and changes experienced by 20 members of an exemplary chapter of critical care nurses as they advanced from being new members to becoming officers and board members. Qualitative research methods were used that included analysis of critical incidents, documents, and individual interviews. Methods used, results of the study, and conclusions and recommendations are discussed.

Different frequencies for different scales of cortical integration: from local gamma to long range alpha/theta synchronization.

Cortical activity and perception are not driven by the external stimulus alone; rather sensory information has to be integrated with various other internal constraints such as expectations, recent memories, planned actions, etc. The question is how large scale integration over many remote and size-varying processes might be performed by the brain. We have conducted a series of EEG recordings during processes thought to involve neuronal assemblies of varying complexity. While local synchronization during visual processing evolved in the gamma frequency range, synchronization between neighboring temporal and parietal cortex during multimodal semantic processing evolved in a lower, the beta1 (12-18 Hz) frequency range, and long range fronto-parietal interactions during working memory retention and mental imagery evolved in the theta and alpha (4-8 Hz, 8-12 Hz) frequency range. Thus, a relationship seems to exist between the extent of functional integration and the synchronization-frequency. In particular, long-range interactions in the alpha and theta ranges seem specifically involved in processing of internal mental context, i.e. for top-down processing. We propose that large scale integration is performed by synchronization among neurons and neuronal assemblies evolving in different frequency ranges.

Using the Baldrige management system framework in health care: the Veterans Health Administration experience.

BACKGROUND: In 1998 the Veterans Health Administration (VHA) developed the Quality Achievement Recognition Grant, a competitive grant application open to all Veterans Integrated Service Networks (VISNs) within the VHA system and based on the Baldrige management framework. Eight of the 22 VISNs attended the educational programs and initiated the grant application process; 7 completed applications. Team award experts from VHA and external sources reviewed, scored, and wrote feedback reports to all applicants and conducted four site visits. IDENTIFICATION OF BEST PRACTICES AND RECOMMENDATIONS FOR FUTURE APPLICANTS: Each application was compared to examples of ideal applications to identify areas of excellence and areas for improvement. In general, the best applicants identified and described key processes and articulated the methods used to evaluate and improve processes. For example, they were able to identify the process used to incorporate key constituents into the strategy development process. One applicant developed a series of management advisory committees, the membership of which includes veterans' service organizations, academic affiliates, community members, and congressional delegates, which were tapped to develop a strategic plan. Leading applicants in the future are likely to be able to demonstrate evidence of deployment and constant review of the strategy and to emphasize the human resources plan into the strategic planning and deployment. CONCLUSIONS: The Baldrige management framework is a useful tool for identification of areas of achievement and areas for improvement within the VHA. Potential applicants for the award could benefit from ensuring coherence across the application, placing a greater emphasis on work systems, and incorporating more extensive analysis of market conditions.

Early childhood nutrition, education and fertility milestones in Guatemala.

Data on fertility milestones were collected in 1994 and linked to information collected in a trial conducted in eastern Guatemala between 1969 and 1977, to examine whether early childhood nutrition was associated with the timing of fertility milestones. In the original trial, two pairs of villages were randomly allocated to receive either a high energy, high protein supplement (Atole) or a low energy, no-protein supplement (Fresco). Mean age at follow-up was 23.47 y (n = 240). About 62% of women had experienced first birth (median age at first birth = 19.83 y). The median intervals from menarche to first intercourse and from first intercourse to first birth were 5.67 and 0.95 y; they were 1.68 and 0.06 y shorter, respectively, for the Atole group than for the Fresco group. Women who had received Atole in utero and/or during early childhood experienced earlier milestones even after adjusting for socioeconomic status (SES), education and age at the prior event. Median age at first birth was 1.17 y earlier for the Atole group. Better growth during early childhood (not severely stunted) led to earlier milestones (median age at first birth was 1.04 y earlier), primarily among women with illiterate fathers. Completion of primary school significantly delayed fertility milestones; the median age at first birth was 4.27 y later for those who completed primary school compared with those who did not (P < 0.05). In sum, improved nutrition during early childhood results in earlier fertility milestones, but the effects of schooling in delaying fertility milestones are greater in magnitude. Intervention programs that improve early childhood nutrition should be accompanied by investments in education that ensure that girls complete primary school.

Extracorporeal photochemotherapy for treatment of drug-resistant graft-vs.-host disease.

Extracorporeal photochemotherapy (EP) is a therapeutic approach to the treatment of drug-resistant graft-vs.-host disease (GVHD) that uses the known immunosuppressive and immunomodulatory effects of ultraviolet light. In 1990, we initiated a pilot study to evaluate the efficacy and safety of EP in patients with refractory GVHD. Between 1991 and 1996, six patients with acute grade IV liver GVHD, 12 patients with chronic following acute GVHD, and six patients with de novo chronic GVHD were treated with EP. All patients had failed to respond to conventional GVHD immunosuppressive drug therapy of cyclosporine and prednisone. The six patients with acute liver GVHD had also received antithymocyte globulin (ATG); therapy for chronic GVHD included thalidomide in eight patients, psoralen plus ultraviolet A in five patients, and ATG in two patients. All patients with acute liver GVHD had progressive liver failure with short survival despite frequent EP. The response rate with EP treatment was 3 of 6 for patients with de novo chronic GVHD and 3 of 12 for patients with chronic following acute GVHD. Three patients with bronchiolitis obliterans had either no response or no documented disease progression while undergoing EP. Side effects of EP were minor and included gastrointestinal upset frequently, catheter-related sepsis in four patients, increased red blood cell and platelet transfusion requirements in one patient, and leukopenia in two patients. EP was discontinued in three patients because of side effects, including GI upset in one patient and bone marrow suppression in two patients. Side effects were reversible with the discontinuation of EP. We were unable to correlate response to EP with the level of methoxypsoralen, number of lymphocytes treated, or pattern of pre- and posttreatment CD4/CD8 ratio. We concluded that EP has some efficacy in the treatment of drug-resistant chronic GVHD, with minor overall toxicity.

The possible meaning of the upper and lower alpha frequency ranges for cognitive and creative tasks.

This study is aimed at verifying the functional independence of two frequency bands within the alpha range. It is based on experiments that examined the role of these two hands with regard to the amount of local electrogenesis (amplitude) and the cooperation of brain areas (coherence) in mental tasks concerning: (1) visual perception and imagery; (2) listening to and composing music; (3) verbal and visual creativity; and (4) aspects of mood. In all experiments EEG were recorded for at least 1 min during each task, separated one from another by at rest periods of at least equal lengths. EEG electrodes were pasted according to the 10/20 system (averaged ear lobes as reference). After FFT power was calculated for all 19 electrodes, coherence was estimated for all possible electrode pairs (i.e. 171). This was done for six frequency ranges between 1.5 and 31.5 Hz, the alpha range having been divided into two (7.5-9 Hz and 9.5-12.5 Hz). The spectral parameters obtained during each task were compared with those of the merged EEG at rest, significant changes (P < or = 0.01-P < or = 0.05) were entered into schematic maps of the brain. Generally, fewer differences were found for amplitude than for coherence. In all four tasks concerning visual perception the clearest differences were found in single person studies. But also in group studies more or less distinct differences were found between alpha 1 and 2. Also in the series with music the two alpha bands did not behave uniformly, nor were uniform features found in the two series of musically trained and untrained subjects. Distinct discrepancies were also found in a verbal and visual imagery task. With respect to mood, only elevated mood was correlated with a decrease of coherence in alpha 2 and an increase of amplitude in alpha 1. This study though hinting at a different functional significance of these two alpha bands, however, does not allow to draw any conclusions as to their distinct functional meanings. Generally, the long-term coherence changes observed under these different mental tasks support the idea that part of information processing in the brain is reflected by the EEG. Structural peculiarities and microelectrode recordings of the cortex support this conclusion.

Protective effects of garlic and related organosulfur compounds on acetaminophen-induced hepatotoxicity in mice.

In previous studies, we have demonstrated that diallyl sulfide, a flavor component of garlic, protects against chemically induced hepatotoxicity. The present study examined the activities of fresh garlic homogenates (FGH) and related organosulfur compounds in the protection against acetaminophen (APAP)-induced hepatotoxicity and the possible mechanisms involved in this protection. When FGH (5 g/kg) was administered to Swiss-Webster mice 2 hr prior to, or immediately after, an APAP treatment (0.2 g/kg), APAP-induced hepatotoxicity was essentially prevented as indicated by serum levels of alanine aminotransferase and lactate dehydrogenase and by liver histopathology. Partial protection was observed with a lower dose of FGH (0.5 g/kg). FGH also prevented APAP-induced hepatic glutathione depletion in a dose-dependent manner. FGH significantly inhibited the formation of APAP-oxidized metabolites, as indicated by decreased plasma levels of oxidized APAP metabolites. The amount of APAP excreted as oxidized metabolites in the 24 hr urine samples was also significantly lower in the mice pretreated with FGH. FGH supernatant inhibited cytochrome P450-dependent APAP oxidation in microsomal incubations. The results suggest that the protection against APAP-induced hepatotoxicity by FGH is mainly due to its inhibition of P450-mediated APAP bioactivation. Several garlic-derived organosulfur compounds and structurally related compounds were examined for their abilities to protect against APAP-induced hepatotoxicity. An S-allyl structure appears to be a common feature for most sulfides to inhibit P450 2E1-dependent activity and to display good protective activities.

Treatment of Pseudomonas aeruginosa-infected orthopedic prostheses with ceftazidime-ciprofloxacin antibiotic combination.

Indwelling device infections are associated with considerable morbidity and extremely high cost. Pseudomonas aeruginosa is the most frequent gram-negative etiologic agent associated with infections of indwelling catheters and foreign body implants. It is generally agreed that eradication of infection in the presence of a foreign body requires removal of the foreign body. Using a combination of ceftazidime and ciprofloxacin, we cured nine of nine patients with P. aeruginosa-infected osteosynthetic material and four of five patients with hip and knee prostheses without removing the foreign material. Follow-up was for a mean of 21 months (range, 6 to 60 months). Some patients experienced minor side effects (arthralgia in one patient and rash in another patient). We conclude that this combination is effective and safe and should be useful in the treatment of P. aeruginosa-infected orthopedic implants.