Ketogenic diet for epilepsy and obesity: Is it the same?

The term "ketogenic diet" (KD) is used for a wide variety of diets with diverse indications ranging from obesity to neurological diseases, as if it was the same diet. This terminology is confusing for patients and the medical and scientific community. The term "ketogenic" diet implies a dietary regimen characterized by increased levels of circulating ketone bodies that should be measured in blood (beta-hydroxybutyrate), urine (acetoacetate) or breath (acetone) to verify the "ketogenic metabolic condition". Our viewpoint highlights that KDs used for epilepsy and obesity are not the same; the protocols aimed at weight loss characterized by low-fat, low-CHO and moderate/high protein content are not ketogenic by themselves but may become mildly ketogenic when high calorie restriction is applied. In contrast, there are standardized protocols for neurological diseases treatment for which ketosis has been established to be part of the mechanism of action. Therefore, in our opinion, the term ketogenic dietary therapy (KDT) should be reserved to the protocols considered for epilepsy and other neurological diseases, as suggested by the International Study Group in 2018. We propose to adjust the abbreviations in VLCHKD for Very Low CarboHydrate Ketogenic Diet and VLEKD for Very Low Energy Ketogenic Diet, to clarify the differences in dietary composition. We recommend that investigators describe the researchers describing efficacy or side effects of KDs, to clearly specify the dietary protocol used with its unique acronym and level of ketosis, when ketosis is considered as a component of the diet's mechanism of action.

Fremanezumab for the prevention of chronic and episodic migraine.

On September 15, 2018, the U.S. Food and Drug Administration (FDA) approved subcutaneous fremanezumab, a calcitonin gene-related peptide (CGRP) monoclonal antibody, for the treatment of episodic and chronic migraine in adults, with two recommended dosages: 225 mg monthly or 675 mg every 3 months. On March 28, 2019, the European Commission granted fremanezumab Marketing Authorization in the E.U. for the same indication. In this monograph we review data on the pharmacokinetics, metabolism and safety of fremanezumab as reported in the scientific literature from phase I to phase III studies. Fremanezumab demonstrated a very low incidence of adverse events. Primary and secondary endpoints in randomized, controlled trials on the efficacy of fremanezumab were achieved. Fremanezumab was demonstrated to be able to reduce the number of migraine days, headache hours and number of days with use of acute treatment agents. No data on drug-drug interactions with fremanezumab are available. However, it is worth mentioning that fremanezumab showed a very low incidence of development of adverse drug antibodies compared with other CGRP antibodies.

The potential impact of biomarker-guided triage decisions for patients with urinary tract infections.

OBJECTIVES: Current guidelines provide limited evidence as to which patients with urinary tract infection (UTI) require hospitalisation. We evaluated the currently used triage routine and tested whether a set of criteria including biomarkers like proadrenomedullin (proADM) and urea have the potential to improve triage decisions. METHODS: Consecutive adults with UTI presenting to our emergency department (ED) were recruited and followed for 30 days. We defined three virtual triage algorithms, which included either guideline-based clinical criteria, optimised admission proADM or urea levels in addition to a set of clinical criteria. We compared actual treatment sites and observed adverse events based on the physician judgment with the proportion of patients assigned to treatment sites according to the three virtual algorithms. Adverse outcome was defined as transfer to the intensive care unit (ICU), death, recurrence of UTI or rehospitalisation for any reason. RESULTS: We recruited 127 patients (age 61.8 ± 20.8 years; 73.2 % females) and analysed the data of 123 patients with a final diagnosis of UTI. Of these 123 patients, 27 (22.0 %) were treated as outpatients. Virtual triage based only on clinical signs would have treated only 22 (17.9 %) patients as outpatients, with higher proportions of outpatients equally in both biomarker groups (29.3 %; p = 0.02). There were no significant differences in adverse events between outpatients according to the clinical (4.5 %), proADM (2.8 %) or urea groups (2.8 %). The mean length of stay was 6.6 days, including 2.2 days after reaching medical stability. CONCLUSIONS: Adding biomarkers to clinical criteria has the potential to improve risk-based triage without impairing safety. Current rates of admission and length of stay could be shortened in patients with UTI.

TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study).

This study evaluated the effect of physiological, TSH-guided, L-thyroxine treatment on serum lipids and clinical symptoms in patients with subclinical hypothyroidism. Sixty-six women with proven subclinical hypothyroidism (TSH, 11.7 +/- 0.8 mIU/liter) were randomly assigned to receive L-thyroxine or placebo for 48 wk. Individual L-thyroxine replacement (mean dose, 85.5 +/- 4.3 microg/d) was performed based on blinded TSH monitoring, resulting in euthyroid TSH levels (3.1 +/- 0.3 mIU/liter). Lipid concentrations and clinical scores were measured before and after treatment. Sixty-three of 66 patients completed the study. In the L-thyroxine group (n = 31) total cholesterol and low density lipoprotein cholesterol were significantly reduced [-0.24 mmol/liter, 3.8% (P = 0.015) and -0.33 mmol/liter, 8.2% (P = 0.004), respectively]. Low density lipoprotein cholesterol decrease was more pronounced in patients with TSH levels greater than 12 mIU/liter or elevated low density lipoprotein cholesterol levels at baseline. A significant decrease in apolipoprotein B-100 concentrations was observed (P = 0.037), whereas high density lipoprotein cholesterol, triglycerides, apolipoprotein AI, and lipoprotein(a) levels remained unchanged. Two clinical scores assessing symptoms and signs of hypothyroidism (Billewicz and Zulewski scores) improved significantly (P = 0.02). This is the first double blind study to show that physiological L-thyroxine replacement in patients with subclinical hypothyroidism has a beneficial effect on low density lipoprotein cholesterol levels and clinical symptoms of hypothyroidism. An important risk reduction of cardiovascular mortality of 9-31% can be estimated from the observed improvement in low density lipoprotein cholesterol.

Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease.

The influence of thyroid failure on haemostasis is controversial, both hypocoagulable and hypercoagulable states have been reported. Since both subclinical and overt hypothyroidism have been associated with atherosclerosis, a hypercoagulable state in addition might represent a risk factor for thromboembolic disease. We investigated various haemostatic variables in 42 women with subclinical hypothyroidism and compared them to 66 euthyroid controls. Prothrombin time, activated partial thromboplastin time, fibrinogen, factor VII activity (FVII:C), factor VII antigen (FVII:Ag), factor VIII activity, von Willebrand factor (vWF), antithrombin III, heparin cofactor II, protein C, protein S, plasminogen, antiplasmin, plasminogen activator inhibitor and tissue plasminogen activator, as well as common lipid variables, were measured. Factor VII:C (P < 0.02) and the ratio FVII:C/FVII:Ag (P < 0.01) were significantly increased in subclinical hypothyroid patients compared to the control group. Both parameters remained higher in hypothyroid patients after exclusion of 18 women on oestrogen replacement therapy. No differences were found between the groups with respect to vWF or the other haemostatic and lipid variables tested. Patients with subclinical hypothyroidism had significantly higher levels of FVII:C. The greater increase in FVII:C compared to that of FVII:Ag, as shown by the increase in their ratio, might reflect the presence of activated FVIIa. This might mean a hypercoagulable state, which could contribute to the increased prevalence of coronary heart disease reported in such patients. A hypercoagulable state might be another argument in favour of thyroxine replacement treatment in subclinical hypothyroidism, especially in patients with additional risk factors for vascular disease.

[Functional dynamics of impending overt hypothyroidism: spontaneous evolution in patients in the years before the beginning of treatment]. / Funktionsdynamik in der Frühphase der manifesten Hypothyreose: Spontanverlauf bei Patientinnen in den Jahren vor Therapiebeginn.

The syndrome of subclinical hypothyroidism, with its clinical and metabolic consequences, is frequent. Only a minority of these patients will eventually become overtly hypothyroid. It was the aim of the present study to analyse the spontaneous evolution over 10 years of 27 patients with subclinical hypothyroidism who became overtly hypothyroid (group A). For comparison, 27 patients remaining subclinically hypothyroid and matched for their TSH concentrations were characterised (group B). In group A, continuous increase of TSH concentrations was observed over the whole observation period (p = 0.002; ANOVA). The concentrations of fT4 remained initially stable, and only fell at a late stage in the three years before overt hypothyroidism (p = 0.0001; ANOVA). The concentrations of total T3 remained normal throughout the observation period. Thyroid reserve was already impaired at the beginning and during the whole study period. In contrast, these thyroid parameters of patients of group B remained unchanged over 10 years, and thyroid reserve remained normal. The pathogenesis of overt hypothyroidism is a graded process. Increasing concentrations of TSH, a decrease of fT4 and impaired thyroid reserve are predictors of overt thyroid failure.

[Ultrasensitive TSH screening for detection of thyroid gland dysfunctions in women of a medical ambulatory care patient group]. / Ultrasensitives TSH-Screening zur Erfassung von Schilddrüsendysfunktionen bei Frauen eines ambulanten medizinischen Krankenguts.

This aim of the study was to identify the prevalence of unsuspected thyroid dysfunction in a female population attending a medical primary care unit (case-finding study). A TSH assay of the third generation was used as a screening test. The overall prevalence of unsuspected thyroid dysfunction in 1061 female patients was 2.5% (0.5% overt hyperthyroidism, 0.3% overt hypothyroidism, 0.5% subclinical hyperthyroidism, and 1.2% subclinical hypothyroidism). The prevalence of thyroid disease is clearly age dependent with 4.3% over the age of 40 and 5.9% for 50-60 year-olds. The ratio for females below 40 and over 40 was 10.75 (Odds ratio, p < 0.0001). We conclude from our study and from the literature that TSH screening as a case-finding strategy is indicated, and also seems cost-effective, in women over 40 years of age.

[Long-term study of subclinical hypothyroidism: spontaneous course and predictors of manifest hypothyroidism]. / Langzeitstudie bei subklinischer Hypothyreose: Spontanverlauf und Prädiktoren der manifesten Hypothyreose.

The syndrome of subclinical hypothyroidism is frequent and predominantly affects females over 40. Only limited data on its natural course is available. It was the aim of our prospective trial to analyze the spontaneous evolution of this syndrome, to identify risk factors of the development of overt hypothyroidism and to develop guidelines for the management of such patients. 154 female patients were followed over a mean observation period of 10 years. After 10 years, 34% had developed overt hypothyroidism, 57% remained in the subclinical stage, and in 9% thyroid function had normalized. The initial grading of TSH-concentration (< 6 mU/l, 6-12 mU/l, > 12 mU/l) was highly predictive for thyroid failure: 7.3%, 25% and 78%, respectively, overt hypothyroidism occurred. Further risk factors for thyroid failure included an impaired thyroid reserve (T3-stimulation after TRH) and elevated titers of microsomal antibodies. We therefore recommend to controlling patients with a TSH-concentration < 6 mU/l, start thyroxine hormone replacement therapy in patients with a TSH-concentration > 12 mU/l and, depending on the additional risk factors, either controlling or treating patients with a TSH-concentration of 6-12 mU/l.

Relationship of blood transfusion, post-operative infections and immunoreactivity in patients undergoing surgery for gastrointestinal cancer.

BACKGROUND AND OBJECTIVE: The immunosuppression induced by perioperative blood transfusion (BT) and its effect on the incidence of post-surgical infectious complications remains controversial. In this study, the relationship between BT and postoperative infections was investigated in 136 gastrointestinal cancer patients submitted to curative surgery. METHODS: Clinical and laboratory variables, data on postoperative infections, infection risk factors and types of transfusion were analyzed. Immune function was evaluated in 76 patients and compared before and after surgery. RESULTS: The overall postoperative infection rate was 28% for the transfused and 4.6% for the untransfused patients. The univariate analysis of investigated variables indicated that BT, progressive cancer stage, duration of surgery, drains, all had significant association with infection. The multiple logistic regression analysis confirmed BT (p = 0.0028) and advanced cancer stage (p < 0.001) as significant risk factors for the postoperative infections. The results of immunological tests showed no significant differences between transfused and untransfused patient groups, after surgery. Comparing pre- and postoperative data from individual patients, an impairment of natural killer (NK) activity was observed in all patients regardless of their transfusional status; the synthesis of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) was also decreased respectively in the untransfused and in the transfused patients. INTERPRETATION AND CONCLUSIONS: These results indicate that other factors, beside BT, can induce immunosuppressive effects in these patients and thus increase their susceptibility to postoperative infections.

Plasma viremia titration and RNA quantitation in ICD-p24 negative HIV type-1-infected patients.

Quantitative culture of human immunodeficiency virus (HIV) was performed on 202 plasma samples obtained from asymptomatic and early symptomatic HIV-1 infected patients (mean CD4+ count: 186/mm3) before antiretroviral therapy was started. HIV could be isolated from 84% of the plasma samples (titers ranging from 10(0) to 10(2.75) TCID50/ml). Immune complex dissociated p24 antigen (ICD-p24) was detected in 66% of the samples. Only 23 samples (11%) were negative for both ICD-p24 as well as HIV culture. Discordant results were obtained in 55 samples, and 45 samples negative for ICD-p24 were positive for HIV culture. A significant proportion (42%) of patients that were negative for ICD-p24 belonged to a very advanced group with very low CD4+ cell count. However, almost 90% of these ICD-p24 negative samples were positive for HIV plasma viremia, stressing the value of this virological marker in patients with low CD4+ cell count and without any detectable ICD-p24 antigenemia. HIV-1 RNA was detected in all ICD-p24 negative plasma samples tested by the branched DNA (bDNA) assay. A very good correlation was found between high RNA copy number and HIV plasma isolation in samples obtained from patients with low CD4+ cell count, suggesting that HIV-1 RNA quantitation may also reflect viral infectivity of plasma.

Recombinant interleukin-2 treatment before and after autologous stem cell transplantation in hematologic malignancies: clinical and immunologic effects.

Autologous bone marrow transplantation (ABMT) for hematologic malignancies is associated with a high relapse rate. Interleukin-2 (IL-2) administration is a therapy that may prevent relapse if used when the tumor burden is minimal. In this study we administered recombinant IL-2 (rIL-2) therapy to 12 patients affected by hematologic malignancies either before or after autologous stem cell transplantation (ASCT). rIL-2 was given by a 6 day continuous intravenous infusion with escalating doses, up to 18 x 10(6)/m2/day, depending on patient tolerance. The functional immune responses of the patients were assessed as natural killer (NK) and lymphokine-activated killer (LAK) cytotoxic activities and in vitro interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synthesis. During rIL-2 treatment, the expected side effects occurred; only 3 patients, who showed severe cardiovascular toxicity, required suspension of the treatment. All toxicities reversed after the end of the therapy. Immunologic monitoring was carried out the day before starting rIL-2 infusion and then repeated on days 3, 7, and 14 after rIL-2 was discontinued. Following every rIL-2 course, a pronounced increase in CD3+, CD8+, CD56+ cells was found, with a peak value on day 3. The NK and LAK activities showed a significant increase on day 3 (p < 0.001) over pretherapy values; the increase lasted until day 14, although the difference at later time points was not significant. Before transplant the synthesis of both IFN-gamma and TNF-alpha decreased following rIL-2 therapy, whereas higher levels of these lymphokines were found after posttransplant rIL-2 courses.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoresponsiveness of cancer patients: effect of blood transfusion and immune reactivity of tumor infiltrating lymphocytes.

The immunoreactivity of cancer patients submitted to surgery and perioperatively transfused was investigated. Peripheral blood mononuclear cells (PBMC) and tumor infiltrating lymphocytes (TIL) were tested for the natural killer (NK) cytotoxic activity, for the in vitro synthesis of interleukin-2 (IL-2), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2). The serum levels and the production of PGE2 by PBMC were significantly higher in patients than in controls, whereas no significant differences in the tested immunological variables emerged between the two groups of subjects. Instead, TIL produced significant larger amounts of spontaneous PGE2 (p < 0.001) and significant lower amounts of IFN-gamma (p < 0.001) and TNF-alpha (p < 0.001) than autologous PBMC, suggesting an involvement of PGE2 in the impairment of the host immunoreactivity at the tumor site. To evaluate the immunomodulating effect of blood transfusion, the patients were reexamined 8 to 20 days after surgery. No differences were found in the NK cytotoxic activity, lymphokine synthesis, serum levels, and production of PGE2 between transfused and untransfused patients. These results do not support the hypothesis that blood transfusions negatively affect the immune response of neoplastic patients.

[Combined endocrine autoimmune syndrome--incidence, forms of manifestation and clinical significance]. / Das kombinierte endokrine Autoimmunsyndrom--Häufigkeit, Manifestationsformen und klinische Bedeutung.

UNLABELLED: In a retrospective case finding study we collected data from patients with polyglandular autoimmune syndrome type II (PGAS Type II) who had been treated in our endocrine outpatient clinic between 1975 and 1989. 31 adult patients (25 females and 6 males) fulfilled the criteria for PGAS Type II (association of autoimmune endocrine disease with at least one other--usually endocrine--autoimmune disease or autoantibodies against another organ). Among these patients, 18 had hypothyroidism due to autoimmune thyroiditis, 8 were hyperthyroid (Graves' disease), and 4 had silent autoimmune thyroiditis (without thyroid dysfunction). Insulin dependent (type I) diabetes mellitus (IDDM) was seen in 11, Addison's disease in 7, primary hypogonadism in 5, vitiligo in 6 and pernicious anemia in 5 cases. The presence of antiparietal cell antibodies was demonstrated in 21 of 30 investigated patients. These patients also showed other evidence of autoimmune gastritis, such as increased gastrin (in 10 out of 13), diminished vitamin B12 levels (6 out of 13), atrophic gastritis (9 out of 9), pernicious anemia (6 out of 30) and funicular myelosis (2 out of 30). CONCLUSION: The most common endocrine diseases in our patient group were autoimmune thyroid diseases (97%) followed by IDDM (35%) and Addison's disease (23%). A high percentage (70%) of our subjects had elevated titers of antiparietal cell antibodies. Polyglandular autoimmune syndrome must be suspected in all patients with autoimmune endocrine disease, especially in the presence of relatives suffering from PGAS. Patients at risk should be screened regularly by measuring thyrotropin (ultrasensitive assay), fasting blood glucose levels, and by checking red blood count and antiparietal cell antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of blood transfusion on the immune responsiveness and survival of cancer patients: a prospective study.

To evaluate whether blood transfusion exerts an adverse influence on cancer evolution, a prospective clinical and immunologic investigation was carried out on 58 surgical patients with gastric or colorectal adenocarcinoma. None had had previous transfusion; 35 received perioperative transfusion. Among preoperative variables, only red cell count and hemoglobin concentration were significantly reduced in the patients transfused at operation. Other clinical characteristics and immunologic functions (except interferon-gamma release) did not differ significantly from those of untransfused patients. The survival rate of transfused patients, although shorter, was not significantly different from that of untransfused patients. Immunologic tests done after surgery on 30 patients (17 transfused and 13 untransfused) did not show significant differences in the two groups. Significant increases in interleukin-2-stimulated production and immunoglobulin M synthesis were observed in transfused patients after surgery. Patients transfused perioperatively with more than 3 units of blood had some evidence of decreased immune function, but differences were not significant. While shorter survival and some immunologic changes may correlate with the number of transfusions, more patients must be studied to determine whether this relationship will be confirmed.

Investigation on the humoral immune response in patients with gastro-intestinal cancer.

The humoral immune reactivity was studied in patients affected by gastro-intestinal cancer. The number of peripheral B lymphocytes, the concentration of serum immunoglobulins (Ig) and of C3 complement factor and the frequency of circulating immuno complexes (CIC) did not significantly differ between patients and age-matched controls, while the C4 factor level was significantly increased. The frequency of serum monoclonal components (M-components) was higher in the patients than in the elderly subjects. Moreover the results concerning the "in vitro" functional response of patient B lymphocytes showed a significant decrease of the proliferative responses to Staphylococcus Aureus Cowan I (SAC) and a significant increase of the IgG and IgM synthesis by peripheral blood mononuclear cells (PBMC) in unstimulated and pokeweed mitogen (PWM) stimulated cultures. The meaning of these results, taken together with those reported by others, is discussed.

Functional analysis of lymphocytes from two patients affected by common variable immunodeficiency (CVI).

Two patients affected by severe hypogammaglobulinemia classified as CVI were studied. Both patients showed an increase in peripheral T cells and a normal or elevated number of surface immunoglobulin-bearing cells (sIg+); the T cell subsets showed a decrease of CD4 and an increment of CD8 cells with an inversion of the CD4/CD8 ratio. Patient peripheral blood mononuclear cells (PBMC) did not proliferate after Staphylococcus aureus Cowan I (SAC) activation. Moreover, patient PBMC were not able to differentiate into plaque - forming cells (PFC) either spontaneously or after pokeweed mitogen (PWM) stimulation. The immunoglobulin synthesis from patient PBMC stimulated in vitro by PWM was very little as compared to controls. When isolated patient B cells were cultured in the presence of exogenous B cell growth factor (BCGF) and BCGF plus anti-mu and anti-delta antibodies, no proliferation was observed. Taken together the results concerning B cell function of our CVI patients indicate the presence of an intrinsic defect of B cells. These cells are normal in number, but they are not able to leave the resting state, enter the activation state, proliferate and differentiate into Ig secreting cells. Moreover the alteration of the T cell subset proportions seems to suggest an impaired cooperation between B and T cells.

Effects of the allogeneic stimulation on B cell function in thalassaemic polytransfused patients.

The immunological abnormalities of polytransfused patients affected by beta-thalassaemia major have been investigated in relation to B cell function. The spontaneous in vitro production of Ig by patient peripheral mononuclear cells was not modified, while the pokeweed mitogen induced IgM synthesis was significantly reduced. However, by comparing the splenectomized and non-splenectomized patients, this alteration proved to be present only in the splenectomized group. The proliferation of patient peripheral B cells in vitro stimulated with B cell growth factor alone was not significantly enhanced in respect to the controls. These results indicate that in vivo activation state of patient B cells is not different from that of the controls. The stimulation of peripheral B cell with anti-mu or anti-alpha antibodies and anti-mu and anti-alpha antibodies plus B cells growth factor induced a significant increase in proliferative responses of B cells from the splenectomized patients. Taken together, these findings suggest that circulating B cells of thalassaemic polytransfused patients are not hyperactivated. The splenectomy can account for the immunological changes observed in our thalassaemic sample as compared to control group.

Immunoenzymatic determination of immunoglobulins secreted by human peripheral blood lymphocytes in pokeweed mitogen and lipo-polysaccharide stimulated cultures.

Immunoglobulins (Ig) production by peripheral blood mononuclear cells (PBMC) from 27 healthy subjects at the 6th and 12th day of in vitro stimulation by pokeweed mitogen (PWM) or bacterial lipo-polysaccharide (LPS) was investigated. Total IgG, IgA, IgM in the culture supernatants were measured by an enzyme linked immunosorbent assay (ELISA). The average values of Ig production (in ng per ml of culture supernatants) under PWM and LPS stimulation after 12 days of culture are respectively: 3397 and 2557 for IgG, 512 and 374 for IgA, 3172 and 1439 for IgM. The use of PWM and LPS mitogens for stimulating Ig secreting cells may provide insights into the nature of the interacting cells on immune responses and into the pathogenesis of different diseases.

Immune profile alterations in thalassaemic patients.

Aspects of the humoral and cellular immune response have been studied in polytransfused patients with beta-thalassaemia major. Serum immunoglobulins (G, A, M) levels were significantly higher than in controls; reduced C4 serum level and high incidence of circulating immune complexes and anti-nuclear autoantibodies were found in the majority of patients. Marked increases were also observed in absolute and relative numbers of lymphocytes and their subpopulations. Such results suggested that the allogenic stimulation, by frequent transfusion, is the mainly responsible of the immunological alterations observed in these patients.