Effect of 25-hydroxycholecalciferol supplementation with different dietary available phosphorus levels for broilers.

1. Based on the hypothesis that 25-hydroxycholecalciferol (25-OH-D3) inclusion would optimise dietary mineral digestibility and ameliorate growth performance and bone mineralisation in available phosphorus (AvP) deficient-fed broilers, a trial was conducted to evaluate its effect on diets with different levels of AvP.2. Broilers aged 1-21 d were randomly assigned one of the eight treatments, consisting of four dietary levels of AvP (0.45%, 0.42%, 0.39%, and 0.36%) and with or without supplementation with 25-OH-D3 at 69 µg/kg of feed. All diets contained 100 µg/kg of vitamin D3 (cholecalciferol).3. The addition of 25-OH-D3 resulted in higher feed intake and body weight gain, and lower FCR (P < 0.05) compared to non-supplemented diets, whereas AvP levels had a quadratic effect only on feed intake. There were no interactions between treatment factors.4. Increasing AvP levels linearly reduced the ileal digestibility of Ca and P (P < 0.01) and supplementing 25-OH-D3 increased both Ca and P ileal digestibility (P < 0.05), without any interactions observed for ileal digestibility.5. There was an interaction, whereby 25-OH-D3 inclusion increased serum metabolites in broilers fed 0.36% to 0.42% AvP compared to the non-supplemented diets (P < 0.001), whereas, at 0.45% AvP, diets with or without 25-OH-D3 had similar results.6. The P content in bone linearly increased in line with AvP levels (P < 0.05) and supplementation of 25-OH-D3 increased ash bone content (P < 0.001).7. Broilers can benefit from 25-OH-D3 supplementation combined with cholecalciferol with regard to Ca and P utilisation and vitamin D status, allowing for a reduction of dietary AvP levels down to 0.36% without impairing growth performance or bone status.

Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution

PurposeWe retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution.Methods and patientsElectronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan–Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models.ResultsForty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2–NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death.ConclusionOverall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

Exploratory analysis of clinical benefit of ipilimumab and nivolumab treatment in patients with metastatic melanoma from a single institution.

PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

Productividad energética y financiera en fincas campesinas del departamento de caldas: tres estudios de caso / Enegetic and finnancial productivity in peasants' frms in the depaartment o f caldas: three case studies

Con el objetivo de estimar la productividad energética y financiera, se estudiaron tres fincas campesinas en los municipios de Filadelfia y Manizales en el departamento de Caldas (Colombia). Las fincas estudiadas se seleccionaron de los clústeres resultantes en la investigación: "Flujo de masas y energía en fincas campesinas de la zona cafetera: vínculos entre la racionalidad campesina y el flujo de materiales"5. Para realizar los análisis, se recabó información con base en entrevistas semiestructuradas aplicadas a cada una de las familias de dichas fincas. Con la información, se elaboraron modelos analógicos, que muestran las entradas y salidas del sistema café, componente principal de la unidad familiar. Se estimó la productividad energética y financiera de cada unidad. Se concluyó que la Finca 1 es la que presenta la mayor eficiencia energética y financiera, debido a su diversidad, reciclaje de materiales y uso de mano de obra familiar. En consecuencia, es la más sustentable.

Three peasants' farms in the municipalities of Filadelfia and Manizales, Caldas (Colombia) were studied with the purpose of estimating energetic and financial productivity. The studied farms were selected from the resulting clusters in the research project "Mass and energy flow in peasants' farms in the coffee triangle: links between peasants' rationality and materials flow"5. In order to perform the analysis, information was gathered through semi-structured interviews applied to each family from the above mentioned farms. With this information, analogical models were developed which show the coffee system income and expenditure, a main component in family unit. It was concluded that Farm 1 presents the highest energetic and financial efficiency because of its diversity, materials recycling process and use of family work force. Consequently it is the most sustainable one.

Association between a serotonin transporter promoter region polymorphism and mood response during tryptophan depletion.

This study investigated the relationship between depressive symptom response during tryptophan (TRP) depletion and a functional polymorphism of the promoter region of the serotonin (5-HT) transporter gene (SLC6A4).(1) Forty-three subjects in remission from a major depressive episode who underwent TRP depletion were genotyped. DNA was extracted from blood lymphocytes or from cheek cells.(2) The two common alleles are designated long (l) and short (s). Depressive symptoms were measured with the 25-item Hamilton Depression Rating Scale (HDRS).(3) There was a significant association between the l homozygous genotype and the depressive response to TRP depletion, with a significant main effect of time (F = 8.763, df = 3, 38, P = <0.001), and time x l homozygous allele interaction (F = 3.676, df = 3, 38, P = 0.02). Individuals whose genotype predicted increased 5-HT transporter activity may be more susceptible to depressive changes in response to transient 5-HT perturbations. The use of endophenotypic markers for affective disorders such as the mood response to TRP depletion may facilitate studies of complex genetic traits such as depression by decreasing its heterogeneity.

Living with anxiety disorders: as good as it gets...?

The high prevalence of anxiety disorders, along with the high rate of associated comorbidity, leads to significant financial burden and human suffering, making early detection and proper intervention a clinical priority for these conditions. Despite advances in the understanding and treatment of anxiety disorders, a number of factors diminish the likelihood that people with anxiety will benefit from these advances. The authors discuss current issues relating to the treatment of anxiety disorders. This review highlights the need for recognition of comorbid conditions, the importance of reducing the high rates of partial treatment response, the importance of being aware of the common utilization of alternative treatment interventions, and the need to recognize and treat medication-induced sexual dysfunction.

Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes.

BACKGROUND: This study investigated the relationship between depressive symptom response during tryptophan depletion and future depressive episodes. METHODS: Twelve subjects with prior major depressive episodes in remission and medication-free for > or =3 months (patients), and 12 matched healthy (control) subjects received two tryptophan depletion tests 1 week apart. During follow-up the Hamilton Depression Rating Scale was administered weekly for 1 month, monthly for 3 months, and once at 6 and 12 months. RESULTS: With results from both tests, tryptophan depletion has a sensitivity of 78%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 86% to identify future depressive episodes. Survival analysis shows that mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year (r =.2725, p =.014). CONCLUSIONS: Tryptophan depletion may be clinically useful in identifying individuals at risk for future major depressive episodes.

Role of norepinephrine in depression.

This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and the therapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletion studies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved in antidepressant action, but the specific impairment that underlies depression is unclear and is likely to vary among patients. Results from neurotransmitter depletion studies in depressed patients who have responded to treatment suggest that, while interactions between NE and 5-HT are likely, neither of these 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressant drugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability of NE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent on the availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic and serotonergic systems-such as mirtazapine-may be dependent on the availability of both neurotransmitters for their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjects or worsened depression in unmedicated symptomatic patients with major depression. This finding suggests that the cause of depression is more complex than just an alteration in the levels of 5-HT and/or NE. For some patients, depression may be more directly caused by dysfunction in brain areas or neuronal systems modulated by monoamine systems. We propose that antidepressant drugs may enhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependent but as yet undiscovered process, restore function to brain areas modulated by monoamine neurons. Future research should focus on understanding the adaptive changes that follow enhancement of synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus. Research investigating the neurobiology of depression may be more informed if the focus is shifted to investigating areas of the brain modulated by monoamine systems rather than the monoamine systems themselves.

The Arizona Sexual Experience Scale (ASEX): reliability and validity.

Although sexual dysfunction is common in psychiatric patients, quantification of sexual dysfunction is limited by the paucity of validated, user-friendly scales. In order to address this problem, the authors have developed the Arizona Sexual Experiences Scale (ASEX), a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Possible total scores range from 5 to 30, with the higher scores indicating more sexual dysfunction. This study assesses the internal consistency, test-retest reliability, and convergent and discriminant validity of the ASEX.

Tryptophan depletion and depressive vulnerability.

BACKGROUND: Rapid and transient depletion of tryptophan (TRP) causes a brief depressive relapse in most patients successfully treated with and taking selective serotonin reuptake inhibitors, but little change in drug-free, symptomatic depressed patients. This study investigates the effects of TRP depletion in drug-free subjects in clinical remission from a prior major depressive episode (MDE). METHODS: Twelve subjects with a prior MDE, currently in clinical remission and drug-free for at least 3 months (patients), and 12 healthy subjects without personal or family history of Axis I disorder (controls), received TRP depletion. The study was conducted in a double-blind, controlled [full (102-g) and quarter-strength (25 g) 15-amino acid drinks], crossover fashion. Behavioral ratings and plasma TRP levels were obtained prior to, during, and after testing. RESULTS: All subjects experienced significant depletion of plasma TRP on both test-drinks, showing a significant dose-response relation. Healthy control subjects had minimal mood changes, but patients had a depressive response of greater magnitude. CONCLUSIONS: In the context of prior TRP depletion studies with antidepressant-treated, and drug-free symptomatic depressed patients, these results suggest that depression may be caused not by an abnormality of 5-HT function, but by dysfunction of other systems or brain regions modulated by 5-HT.

Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action.

BACKGROUND: Brain serotonin (5-HT) content is dependent on plasma levels of the essential amino acid, tryptophan (TRP). We have previously reported that rapid TRP depletion more frequently reversed the antidepressant response to monoamine oxidase inhibitors and 5-HT reuptake inhibitors than to desipramine (DMI). This study further investigates the relationship of relapse during TRP depletion to antidepressant type in nonrefractory, depressed patients randomly assigned to treatment with either DMI or fluoxetine (FLU). METHODS: Fifty-five drug-free depressed (DSM-III-R) patients were randomly assigned to antidepressant treatment with either DMI or FLU. All patients were either treatment naive (n = 34) or had previously received successful antidepressant treatment (n = 21). During the treatment phase, 35 patients had therapeutic responses by predetermined criteria (DMI 18/25; FLU 17/23) and 30 of these (15 DMI responders and 15 FLU responders) went on to TRP depletion testing. Patients received two 2-day test sessions involving administration of similar amino acid drinks. One session led to rapid TRP depletion and the other did not. Behavioral ratings [Hamilton Depression Scale (HDRS)] and plasma for TRP levels were obtained prior to, during, and after testing. Relapse was defined as a 50% increase in HDRS with total < or = 17. RESULTS: Total and free TRP decreased 70% to 80% 5 hours after the TRP-free drink. While 8/15 FLU responders relapsed, only 1/15 of the DMI responders relapsed. No patient experienced significant depressive symptoms during control testing. CONCLUSIONS: Rapid depletion of plasma TRP transiently reverses the antidepressant response in many patients on FLU but not DMI. Depressive relapse during TRP depletion appears to be more related to antidepressant type than to patient variables since patients were randomly assigned to the two treatments. Antidepressant response to FLU appears to be more dependent on 5-HT availability than that of DMI, suggesting that antidepressants mediate their therapeutic effects through different mechanisms.

Different roles for serotonin in anti-obsessional drug action and the pathophysiology of obsessive-compulsive disorder.

BACKGROUND: There is a major role for serotonin in the mechanism of anti-obsessional drug action. Drugs that block uptake of noradrenaline are not effective in the treatment of obsessive-compulsive disorder (OCD), while drugs that potently bock serotonin reuptake are effective. While enhancement of serotonin neurotransmission is clearly involved in the treatment of OCD, the role of serotonin in the pathophysiology of OCD is less clear. METHOD: This paper provides a brief, focused review of the literature regarding treatment of OCD, the effects of drugs with selective action at various serotonin receptors and results of neurotransmitter depletion studies in patients with OCD. RESULTS: Some patients with OCD may experience remission of OCD symptoms during intoxication with psychedelic drugs that have potent 5-HT2A/2C agonist activity. These findings, coupled with results from serotonin depletion studies in depressed and OCD patients, suggest that enhancement of serotonin neurotransmission may underlie both antidepressant and anti-obsessional drug action, although the targeted brain areas may differ. CONCLUSIONS: OCD may not involve a dysfunction of the serotonin system. Rather, it is more likely to involve a dysfunction of specific brain circuits, particularly in the frontal cortex. Modulation of these circuits by serotonin neurons may underlie the specific action of anti-obsessional drugs.

Hallucinogens, serotonin and obsessive-compulsive disorder.

The serotonin (5-HT) neurotransmitter system has been implicated in the pathophysiology of several neuropsychiatric disorders, especially obsessive-compulsive disorder (OCD). Blockade of 5-HT reuptake appears to be an important initial neurobiological event in the therapeutic mechanism of action of antiobsessional drugs. However, for reasons that continue to be poorly understood, clinical improvement following initiation of treatment with 5-HT reuptake inhibitors can take up to eight to 12 weeks, and most patients do not fully improve. Recent data suggest that activation of 5-HT2A and/or 5-HT2C receptors may be important for the improvement of OCD symptoms. Most psychedelic drugs are potent agonists at 5-HT2A and 5-HT2C receptors and their binding potency to these receptors is strongly correlated with their human potency as hallucinogens. This article will briefly review the relevant clinical and preclinical studies relating to the effects of hallucinogens on OCD. These data suggest that activation of 5-HT2 receptors by hallucinogens may lead to acute reduction of, as well as possible longer-lasting beneficial effects on, the symptoms of OCD. Evidence for and against involvement of 5-HT2A and/or 5-HT2C receptors in the therapeutic effects of drug therapies for OCD are reviewed. Issues related to the pharmacological properties and safety of psychedelic drugs, when considered as potential treatments for patients with OCD, are summarized. The authors suggest that controlled trials of potent 5-HT2 agonists in people suffering from OCD are warranted.

Pindolol augmentation of treatment-resistant depressed patients.

BACKGROUND: Recent uncontrolled reports describe a dramatic and rapid improvement of depressive symptoms in patients treated with the combination of pindolol and serotonin selective reuptake inhibitors or monoamine oxidase inhibitors. The present study attempts to replicate those findings. METHOD: Ten outpatients with current DSM-III-R major depressive disorder who had failed to obtain or maintain an appropriate response to an adequate trial of antidepressant drug were included in a randomized double-blind, placebo-controlled, crossover study. Subjects received pindolol 2.5 mg p.o. t.i.d. or placebo for 2 weeks in addition to their current antidepressant. Clinical monitoring, vital signs, and behavioral ratings were performed weekly for the duration of the study. RESULTS: Pindolol was well tolerated by all patients. None of the subjects experienced significant symptom worsening during the addition of either placebo or active drug. At the end of the 2-week trial, there was no statistically significant difference between pindolol augmentation and placebo. Two patients had a categorical response during placebo treatment. No categorical responses were observed during pindolol augmentation. CONCLUSION: This study failed to replicate the rapid and dramatic response to pindolol augmentation in treatment-resistant depressed patients.