Combinatorial immune checkpoint blockade increases myocardial expression of NLRP-3 and secretion of H-FABP, NT-Pro-BNP, interleukin-1ß and interleukin-6: biochemical implications in cardio-immuno-oncology.

Background: Immune checkpoint blockade in monotherapy or combinatorial regimens with chemotherapy or radiotherapy have become an integral part of oncology in recent years. Monoclonal antibodies against CTLA-4 or PD-1 or PDL-1 are the most studied ICIs in randomized clinical trials, however, more recently, an anti-LAG3 (Lymphocyte activation gene-3) antibody, Relatlimab, has been approved by FDA in combination with Nivolumab for metastatic melanoma therapy. Moreover, Atezolizumab is actually under study in association with Ipilimumab for therapy of metastatic lung cancer. Myocarditis, vasculitis and endothelitis are rarely observed in these patients on monotherapy, however new combination therapies could expose patients to more adverse cardiovascular events. Methods: Human cardiomyocytes co-cultured with human peripheral blood lymphocytes (hPBMCs) were exposed to monotherapy and combinatorial ICIs (PD-L1 and CTLA-4 or PD-1 and LAG-3 blocking agents, at 100 nM) for 48 h. After treatments, cardiac cell lysis and secretion of biomarkers of cardiotoxicity (H-FABP, troponin-T, BNP, NT-Pro-BNP), NLRP3-inflammasome and Interleukin 1 and 6 were determined through colorimetric and enzymatic assays. Mitochondrial functions were studied in cardiomyocyte cell lysates through quantification of intracellular Ca++, ATP content and NADH:ubiquinone oxidoreductase core subunit S1 (Ndufs1) levels. Histone deacetylases type 4 (HDAC-4) protein levels were also determined in cardiomyocyte cell lysates to study potential epigenetic changes induced by immunotherapy regimens. Results: Both combinations of immune checkpoint inhibitors exert more potent cardiotoxic side effects compared to monotherapies against human cardiac cells co-cultured with human lymphocytes. LDH release from cardiac cells was 43% higher in PD-L1/CTLA-4 blocking agents, and 35.7% higher in PD-1/LAG-3 blocking agents compared to monotherapies. HDAC4 and intracellular Ca++ levels were increased, instead ATP content and Ndufs1 were reduced in myocardial cell lysates (p < 0.001 vs. untreated cells). Troponin-T, BNP, NT-Pro-BNP and H-FABP, were also strongly increased in combination therapy compared to monotherapy regimen. NLRP3 expression, IL-6 and IL-1ß levels were also increased by PDL-1/CTLA-4 and PD-1/LAG-3 combined blocking agents compared to untreated cells and monotherapies. Conclusions: Data of the present study, although in vitro, indicate that combinatorial immune checkpoint blockade, induce a pro- inflammatory phenotype, thus indicating that these therapies should be closely monitored by the multidisciplinary team consisting of oncologists, cardiologists and immunologists.

Virome of crab-eating (Cerdocyon thous) and pampas foxes (Lycalopex gymnocercus) from southern Brazil and Uruguay.

Crab-eating (Cerdocyon thous) and Pampas foxes (Lycalopex gymnocercus) are wild canids distributed in South America. Domestic dogs (Canis lupus familiaris) and wild canids may share viral pathogens, including rabies virus (RABV), canine distemper virus (CDV), and canine parvovirus 2 (CPV-2). To characterize the virome of these wild canid species, the present work evaluated the spleen and mesenteric lymph node virome of 17 crab-eating and five Pampas foxes using high-throughput sequencing (HTS). Organ samples were pooled and sequenced using an Illumina MiSeq platform. Additional PCR analyses were performed to identify the frequencies and host origin for each virus detected by HTS. Sequences more closely related to the Paramyxoviridae, Parvoviridae and Anelloviridae families were detected, as well as circular Rep-encoding single-stranded (CRESS) DNA viruses. CDV was found only in crab-eating foxes, whereas CPV-2 was found in both canid species; both viruses were closely related to sequences reported in domestic dogs from southern Brazil. Moreover, the present work reported the detection of canine bocavirus (CBoV) strains that were genetically divergent from CBoV-1 and 2 lineages. Finally, we also characterized CRESS DNA viruses and anelloviruses with marked diversity. The results of this study contribute to the body of knowledge regarding wild canid viruses that can potentially be shared with domestic canids or other species.

Epidemiological and Pathological Characterization of Feline Injection Site Sarcomas in Southern Brazil.

Feline injection site sarcoma (FISS) is a mesenchymal neoplasm with highly malignant characteristics. These tumours originate in anatomical sites where there has been previous parenteral administration of medicinal substances or implantation of medical devices. The aim of this study was to investigate the epidemiological and pathological features associated with FISS in the southern region of Brazil. The database of the Department of Veterinary Pathology of the Federal University of Rio Grande do Sul was searched for excisional and incisional biopsy samples compatible with FISS submitted between 2007 and 2017. Biopsy reports were reviewed and epidemiological information, including breed, age and sex of affected cats, as well as gross findings including anatomical location and size of the tumour and the presence of tissue invasion, were extracted. Eighty-nine samples were selected based on the established criteria. Most animals were of undefined breed and were female cats with a median age of 10 years. Grossly, 84.8% of the tumours were >2 cm in diameter. Regarding anatomical location, 34.9% of the tumours were located in the subcutaneous tissue of the thoracic wall, 29.2% in the flank, 21.3% in the interscapular region and 14.6% in the limbs. Histologically, the tumours originated in the subcutaneous tissue and were diagnosed as malignant mesenchymal neoplasms. Most were compatible with fibrosarcomas, but variants with features of pleomorphic sarcoma or chondrosarcoma were recognized. All tumours exhibited areas of necrosis and peripheral inflammatory infiltrate, composed predominantly of lymphocytes, plasma cells and macrophages. The results of this study suggest the need for dissemination of information on FISS epidemiology and guidelines for management of this tumour to veterinarians in the region.

Cardiotoxicity and pro-inflammatory effects of the immune checkpoint inhibitor Pembrolizumab associated to Trastuzumab.

BACKGROUND: The immunotherapy has revolutionized the world of oncology in the last decades with considerable advantages in terms of overall survival in cancer patients. The association of Pembrolizumab and Trastuzumab was recently proposed in clinical trials for the treatment of Trastuzumab-resistant advanced HER2-positive breast cancer. Although immunotherapies are frequently associated with a wide spectrum of immune-related adverse events, the cardiac toxicity has not been properly studied. PURPOSE: We studied, for the first time, the putative cardiotoxic and pro-inflammatory effects of Pembrolizumab associated to Trastuzumab. METHODS: Cell viability, intracellular calcium quantification and pro-inflammatory studies (analyses of the production of Interleukin 1ß, 6 and 8, the expression of NF-kB and Leukotriene B4) were performed in human fetal cardiomyocytes. Preclinical studies were also performed in C57BL6 mice by analyzing fibrosis and inflammation in heart tissues. RESULTS: The combination of Pembrolizumab and Trastuzumab leads to an increase of the intracellular calcium overload (of 3 times compared to untreated cells) and to a reduction of the cardiomyocytes viability (of 65 and 20-25%, compared to untreated and Pembrolizumab or Trastuzumab treated cells, respectively) indicating cardiotoxic effects. Notably, combination therapy increases the inflammation of cardiomyocytes by enhancing the expression of NF-kB and Interleukins. Moreover, in preclinical models, the association of Pembrolizumab and Trastuzumab increases the Interleukins expression of 40-50% compared to the single treatments; the expression of NF-kB and Leukotriene B4 was also increased. CONCLUSION: Pembrolizumab associated to Trastuzumab leads to strong cardiac pro-inflammatory effects mediated by overexpression of NF-kB and Leukotriene B4 related pathways.

Histiocytic Ulcerative Colitis in an American Staffordshire Terrier.

A 9-year-old female American Staffordshire terrier was presented to a veterinary hospital with diarrhoea, severe prostration, hypothermia, dehydration and anaemia. The dog died 6 days after the first consultation. At necropsy examination the serosa of the large intestine showed a granular appearance and the mucosa was thickened, ulcerated and red, with prominent folding. Histological examination revealed marked inflammatory infiltration of macrophages into the mucosa and submucosa of the large intestine. These cells stained positively by the periodic acid-Schiff reaction. Immunohistochemistry showed marked presence of intracytoplasmic Escherichia coli in the macrophages. Bacteriological examination of intestinal sections yielded E. coli growth and the isolate displayed atypical characteristics when compared with strains associated with previously published cases of histiocytic ulcerative colitis (HUC). The molecular characterization showed that the isolate harboured none of the genes associated with enterotoxigenic E. coli strains and harboured only a limited number of genes associated with extra-intestinal pathotypes. Adherent and invasive E. coli are unlikely to have been involved in the pathogenesis of HUC in the present case. HUC is a rare disease with a predisposition for boxer dogs; however, sporadic occurrence in other breeds may occur. This is the first reported case of HUC in an American Staffordshire terrier.

Effects of the acupoints PC 6 Neiguan and LR 3 Taichong on cerebral blood flow in normal subjects and in migraine patients.

Acupuncture has been proven to be effective in the treatment of various cardiovascular disorders; it acts both on the peripheral flow and on the cerebral flow. Our study aimed to evaluate the effects of the insertion of PC 6 Neiguan and LR 3 Taichong acupoints on the cerebral blood flow (CBF) in the middle cerebral artery (MCA). These effects were measured in a group of patients suffering from migraine without aura (Group M) and in a healthy control group (Group C). In the study, we included 16 patients suffering from migraine without aura, classified according to the criteria of the International Headache Society, and 14 healthy subjects as a control group. The subjects took part in the study on two different days, and on each day, the effect of a single acupoint was evaluated. Transcranial Doppler was used to measure the blood flow velocity (BFV) in the MCA. Our study showed that the stimulation of PC 6 Neiguan in both groups results in a significant and longlasting reduction in the average BFV in the MCA. After pricking LR 3 Taichong, instead, the average BFV undergoes a very sudden and marked increase; subsequently, it decreases and tends to stabilize at a slightly higher level compared with the baseline, recorded before needle insertion. Our data seem to suggest that these two acupoints have very different effects on CBF. The insertion of PC 6 Neiguan probably triggers a vasodilation in MCA, while the pricking of LR 3 Taichong determines a rapid and marked vasoconstriction.

A novel fully human antitumour immunoRNase targeting ErbB2-positive tumours.

BACKGROUND: ErbB2 is an attractive target for immunotherapy, as it is a tyrosine kinase receptor overexpressed on tumour cells of different origin, with a key role in the development of malignancy. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer with success, can engender cardiotoxicity and a high fraction of patients is resistant to Trastuzumab treatment. METHODS: A novel human immunoRNase, called anti-ErbB2 human compact antibody-RNase (Erb-hcAb-RNase), made up of the compact anti-ErbB2 antibody Erbicin-human-compact Antibody (Erb-hcAb) and human pancreatic RNase (HP-RNase), has been designed, expressed in mammalian cell cultures and purified. The immunoRNase was then characterised as an enzymatic protein, and tested for its biological actions in vitro and in vivo on ErbB2-positive tumour cells. RESULTS: Erb-hcAb-RNase retains the enzymatic activity of HP-RNase and specifically binds to ErbB2-positive cells with an affinity comparable with that of the parental Erb-hcAb. Moreover, this novel immunoRNase is endowed with an effective and selective antiproliferative action for ErbB2-positive tumour cells both in vitro and in vivo. Its antitumour activity is more potent than that of the parental Erb-hcAb as the novel immunoconjugate has acquired RNase-based cytotoxicity in addition to the inhibitory growth effects, antibody-dependent and complement-dependent cytotoxicity of Erb-hcAb. CONCLUSION: Erb-hcAb-RNase could be a promising candidate for the immunotherapy of ErbB2-positive tumours.

Two novel human anti-ErbB2 immunoagents are active on trastuzumab-resistant tumours.

BACKGROUND: Overexpression of ErbB2 receptor in breast cancer is associated with disease progression and poor prognosis. Trastuzumab, the only humanised anti-ErbB2 antibody currently used in breast cancer, has proven to be effective; however, a relevant problem for clinical practice is that a high fraction of breast cancer patients shows primary or acquired resistance to trastuzumab treatment. METHODS: We tested on trastuzumab-resistant cells two novel human anti-tumour immunoconjugates engineered in our laboratory by fusion of a human anti-ErbB2 scFv, termed Erbicin, with either a human RNase or the Fc region of a human IgG1. Both Erbicin-derived immunoagents (EDIAs) are selectively cytotoxic for ErbB2-positive cancer cells in vitro and vivo, target an ErbB2 epitope different from that recognised by trastuzumab and do not show cardiotoxic effects. RESULTS: We report that EDIAs are active also on trastuzumab-resistant tumour cells both in vitro and in vivo, most likely because of the different epitope recognised, as EDIAs, unlike trastuzumab, were found to be able to inhibit the signalling pathway downstream of ErbB2. CONCLUSION: These results suggest that EDIAs are immunoagents that could not only fulfil the therapeutic need of patients ineligible to trastuzumab treatment due to cardiac dysfunction but also prove to be useful for breast cancer patients unresponsive to trastuzumab treatment.

Development of a structured sensory honey analysis: application to artisanal Madrid honeys.

In this work a methodology to evaluate the sensory properties of honeys has been developed. The sensory analysis was carried out by means of a quantitative descriptive analysis (QDA) method, based on several reference scales, for the coverage of the designed range for each descriptor. The peculiarity of this sensory analysis is that the reference scales have been constituted by common foodstuffs agreed upon by consensus of the panel. The main sensory attributes evaluated in the analyses were: adhesiveness, viscosity, bitterness, aroma, sweetness, acidity, color and granularity. Both the intensity and persistence of honey aromas have also been estimated, together with the classification of the identified aromatic attributes into different groups. The method was applied to 55 artisanal honeys from Madrid (Spain) with the following results: (i) the developed sensory profile sheet allowed a satisfactory description of Madrid honeys; (ii) correlations between sensory attributes of three broad groups of Madrid honeys were obtained and (iii) aroma persistence, sweetness, bitterness, color and granularity appeared as the main sensorial characteristics of honey with discrimination power between floral and honeydew honeys.

Combinatorial experimental protocols for Erbicin-derived immunoagents and Herceptin.

Erbicin is a human anti-ErbB2 single-chain antibody fragment with high affinity and selectivity for ErbB2-positive cancer cells. Two anti-ErbB2 immunoconjugates, called Erb-hRNase and Erb-hcAb, have been prepared and found to be selectively cytotoxic on ErbB2-positive cancer cells in vitro and vivo. In Erb-hRNase, Erbicin is linked to a human RNase and in Erb-hcAb it is linked to the key structural and functional regions of a human IgG. Herceptin is an anti-ErbB2 humanised antibody successfully used in the immunotherapy of breast cancer. We report here that the Erbicin-derived immunoagents target on breast cancer cells an ErbB2 epitope different than that of Herceptin. This finding led us to verify the effects of Herceptin on breast cancer cells when it was used in combination with the Erbicin-derived immunoagents. The results indicated that in combination experiments the antitumour action of Herceptin and that of the novel agents were significantly increased in an additive fashion. An inspection of the mechanism of action of Erb-hRNase or Erb-hcAb combined with Herceptin provided evidence that the antibody combinations engendered an increased downregulation of the ErbB2 receptor, and led to an enhanced apoptotic cell death.

Naproxen sodium in short-term prophylaxis of pure menstrual migraine: pathophysiological and clinical considerations.

We investigated the biological and clinical effects of naproxen sodium (NxS) in the short-term prophylaxis of pure menstrual migraine (PMM) in 25 women suffering from migraine without aura, occurring exclusively from 2 days before to 5 days after menstruation onset. Daily oral NxS (550 mg) from 7 days before menstruation to 7 days after menstruation onset was given for 3 menstrual cycles, and 5 days before menstruation to 5 days after menstruation onset over the next 3 menstrual cycles. In the month before initiation of treatment and in the third month of treatment, 6-keto-PGF1(alpha), TXB(2) and PGE(2) were measured in plasma before menstruation (day -2) and on the second day (day +2) after bleeding onset. In the 20 women analysed, 6-keto-PGF1(alpha) was 17% lower (p<0.0001) and TXB(2) was 30% lower (p<0.0001) on day -2 during treatment than the same day pretreatment; TXB(2) was also lower (p<0.02) on day +2 during treatment than day +2 pretreatment. The 6-keto-PGF1(alpha)/TXB(2) ratio was higher (p<0.01) on day -2 treatment than day -2 pretreatment. PGE(2) levels were significantly lower (p<0.002) on day +2 than pre-treatment values on the same day. The number of attacks reduced from 1.7+/-0.11 pretreatment to 1.2+/-0.10 at the 3rd month (p<0.001), to 1.1+/-0.06 at the 6th month (p<0.0001). The duration reduced from 25.6+/-4.42 h pretreatment to 15.5+/-4.43 h in the 3rd month (p<0.02), to 13.35+/-4.26 h in the 6th month (p<0.001). The intensity reduced from 2.4+/-0.11 pretreatment, to 1.2+/-0.10 in the 3rd month of treatment (p<0.0001), and 1.1+/-0.07 in the 6th month (p<0.0001).

Advanced strategies of short-term prophylaxis in menstrual migraine: state of the art and prospects.

Patients suffering from menstrual migraine (MM) may be ideal candidates for an intermittent prophylaxis, usually termed short-term or mini-prophylaxis. It covers the whole period of vulnerability, e. g., the perimenstrual period, starting some days before the expected onset of MM attack. Theoretically MM attacks are an optimal target for drugs specifically developed for acute head pain. Unfortunately, due to their particular tendency to be longer, more intense and less responsive to analgesics, symptomatic approaches alone are not often able to completely control pain and its correlates. Many drugs have been proposed for short-term prophylaxis of MM. In this paper we analyse only non-steroidal anti-inflammatory drugs, coxibs and triptans (especially those with longer half-life, naratriptan and frovatriptan). Moreover, MM can be prevented by a variety of hormonal manipulations, including oral contraceptives, which may be administered with an extended-dosing strategy; oestrogen replacement therapy; antioestrogen agents (danazol, tamoxifen); gonadotropin-releasing hormone agonists followed by oestrogen add-back therapy. Finally, the use of some products, such as magnesium and phytoestrogens, that probably meet the requirements of those patients that appreciate a more "natural" approach, is discussed.

Oral contraceptives in women with migraine: balancing risks and benefits.

Oral contraceptives (OCs) are a safe and highly effective method of birth control, but can also be associated with some risks, mainly a potential thrombotic risk. OCs may condition the course of headache and sometimes start it, but their influence on the clinical evolution of migraine is not easily assessable. The last Classification of Headache Disorders of the International Headache Society clearly identifies an "exogenous hormone-induced headache" that could be triggered by intake of OCs. Old high-dose OCs could effectively worsen headache in a significant proportion of patients, but the newest formulations influence headache course to a lesser extent. In any case, while an increase in migraine frequency or intensity do not oblige the cessation of OCs, experiencing a migraine aura for the first time, or even a clear worsening of a preexistent aura suggest discontinuation of OCs. Even if both migraine and OCs intake are associated with an increased risk of ischaemic stroke, migraine per se is not a contraindication for OCs use; however, patients suffering from migraine with aura generally show a greater thrombotic risk than women with migraine without aura. Other risk factors (patient's age, tobacco use, hypertension, hyperlipidaemia, obesity and diabetes) must be carefully considered when prescribing OCs in migraine patients. Furthermore, all OCs, even those with low oestrogen content, are a major risk for venous thrombosis, particularly in women with hereditary thrombophilia. A thorough laboratory control of the genetics of prothrombotic factors and coagulative parameters should precede any decision of OCs prescription in migraine patients.

Picotamide in migraine aura prevention: a pilot study.

In an open, preliminary trial we evaluated the use of picotamide, an antiplatelet drug, in the prophylactic treatment of migraine aura (MA). Twenty-two women suffering from migraine with typical aura or MA without headache, diagnosed according to International Headache Society criteria, entered a nine-month study. They underwent a three-month run-in period free of prophylactic drugs, followed by a six-month treatment period (subdivided in two trimesters, TI and TII) with 300 mg of picotamide administered twice daily. A detailed diary reporting neurological symptoms, duration and frequency of MA was compiled by patients along the trial time. The number of MA significantly decreased during treatment (from 6.85+/-3.82 in the run-in trimester to 2.85+/-2.72 during TI and to 2.55+/-2.89 during TII). Also, MA duration was decreased significantly, being 36.75+/-20.28 min during run-in, 20.00+/-16.94 during TI and 17.75+/-16.26 during TII. In 25% of patients MA totally disappeared. The number and the features of aura neurological symptoms were also positively modified by the use of picotamide. No serious adverse event was provoked by picotamide administration. Picotamide is effective in reducing MA frequency, duration and symptomatology. The effect is clearly evident in the first trimester of treatment and is maintained with no further modifications during the second trimester.

A human, compact, fully functional anti-ErbB2 antibody as a novel antitumour agent.

A new human, compact antibody was engineered by fusion of a human, antitumour ErbB2-directed scFv with a human IgG1 Fc domain. Overexpression of the ErbB2 receptor is related to tumour aggressiveness and poor prognosis. This new immunoagent meets all criteria for a potential anticancer drug: it is human, hence poorly or not immunogenic; it binds selectively and with high affinity to target cells, on which it exerts an effective and selective antiproliferative action, including both antibody-dependent and complement-dependent cytotoxicity; it effectively inhibits tumour growth in vivo. Its compact molecular size should provide for an efficient tissue penetration, yet suitable to a prolonged serum half-life.

[Low-dose spiral CT of the lung in the follow-up of non-malignant lung disease]. / Niedrigdosis-Spiral-CT des Thorax in der Verlaufskontrolle nichtmaligner Lungenerkrankungen.

PURPOSE: To assess image quality of chest CT with an 80 to 90 percent dose reduction in follow-up studies of patients with lung disease, dose and image quality of a low-dose protocol was investigated. MATERIALS AND METHODS: A follow-up low-dose CT (ND-CT, 120 kV, 10 mAs/slice, 3 mm slice thickness) was performed on 35 patients with non-malignant lung disease and compared with the initial standard dose CT (= SD-CT, 100 mAs/slice, 3 or 5 mm slice thickness). The dose was measured by thermo-luminescence in an Alderson phantom. Image quality was assessed by four independent radiologists in six perihilar, central and peripheral lung regions using a 4-point-scale ("very good", "good", "moderate", and "poor"). RESULTS: Effective dose was 0.5 mSv for ND-CT and 4.0 - 5.0 mSv for SD-CT. The ratings "very good"/"good" were given in the perihilar regions in ND-CT 97.5 % versus SD-CT 99.3 % (n. s.), in the central regions in ND-CT 96.4 % versus SD-CT 94.6 % (n. s.), and in the peripheral regions in ND-CT 70.0 % versus SD-CT 88.2 % (p < 0.01). CONCLUSION: Follow-up CT of pulmonary structures in patients with chronic lung disease can be performed with substantial dose reduction. A decrease of image quality may result in peripheral lung regions.

SPME analysis of volatile compounds from unfermented olives subjected to thermal treatment.

The effect of different types of thermal treatment, designed to increase the product's shelf-life, on the volatile composition of "Campo Real" unfermented table olives, has been studied by headspace solid-phase microextraction (HS-SPME) and GC-MS analysis. Different SPME fibres were evaluated to determine their selectivity for a mixture of the main components of the different spices used in "Campo Real" olive dressing. Of the different fibres investigated, the polydimethylsiloxane/divinylbenzene (PDMS/DVB) fibre was selected for analysis of the olive brines, which contained nine main aroma components. The types of thermal treatment were sterilisation (121 degrees C, 15 min) and four pasteurisation conditions (60 degrees C or 80 degrees C each for 5 or 9 min). Pasteurisation did not lead to significant changes in the amounts of these nine volatile compounds; the 2-butanol signal was reduced by treatment at 80 degrees C. On the other hand, sterilisation of the brine resulted in an decrease in the signals from these compounds and the appearance of a new, high signal for benzaldehyde; the origin of this has not yet been determined. Results suggest that the selected pasteurisation conditions do not significantly modify the typical, and valued, aroma characteristics of "Campo Real".

Crystal structure of the dimeric unswapped form of bovine seminal ribonuclease.

Bovine seminal ribonuclease is a unique case of protein dimorphism, since it exists in two dimeric forms, with different biological and kinetic behavior, which interconvert into one another through three-dimensional swapping. Here we report the crystal structure, at 2.2 A resolution, of the unswapped form of bovine seminal ribonuclease. Besides completing the structural definition of bovine seminal ribonuclease conformational dimorphism, this study provides the structural basis to explain the dependence of the enzyme cooperative effects on its swapping state.

Non-pharmacological approaches to chronic headaches: transcutaneous electrical nerve stimulation, lasertherapy and acupuncture in transformed migraine treatment.

In an open, randomized trial, we evaluated transcutaneous electrical nerve stimulation (TENS), infrared lasertherapy and acupuncture in the treatment of transformed migraine, over a 4-month period free of prophylactic drugs. Sixty women suffering from transformed migraine were assigned, after a one month run-in period, to three different treatments: TENS (Group T; n=20), infrared lasertherapy (Group L; n=20) or acupuncture (Group A; n=20). In each group the patients underwent ten sessions of treatment and monthly control visits. In Group T patients were treated for two weeks (5 days/week) simultaneously with three TENS units with different stimulation parameters (I: pulse rate = 80 Hz, pulse width = 120 micros; II: 120 Hz, 90 micros; III: 4 Hz, 200 micros). In Group L an infrared diode laser (27 mW, 904 nm) was applied every other day on tender scalp spots. In Group A acupuncture was carried out twice a week in the first two weeks and weekly in the next 6 weeks. A basic formula (LR3, SP6, LI4, GB20, GV20 and Ex-HN5) was always employed; additional points were selected according to each patient's symptomatology. The number of days with headache per month significantly decreased during treatment in all groups. The response in the groups differed over time, probably due to the different timing of applications of the three methods. TENS, lasertherapy and acupuncture proved to be effective in reducing the frequency of headache attacks. Acupuncture showed the best effectiveness over time.

[Migraine during pregnancy and lactation: treatment of the acute attack and non-pharmacological prophylactic strategies]. / L'emicrania in corso di gravidanza e allattamento: trattamento dell'attacco acuto e strategie non farmacologiche di profilassi.

Migraine is a typical "women's disease": the fluctuations of sex hormones, in particular estrogens, during woman's reproductive life show a direct and major influence on migraine course. Even if during pregnancy a high percentage of migraineurs report an improvement of symptomatology, it is still controversial how to manage migraine crises occurring during pregnancy, considering that almost all drugs are partially or totally contraindicated during gestation. The most important drugs employed in acute attack management (triptans, non steroidal anti-inflammatory drugs, analgesics, antiemetics, ergot derivatives and combination products) are reviewed and the indications and contraindications of their use during the 3 trimesters of pregnancy and during lactation, taking into consideration the indications of the Food and Drug Administration and of the American Academy of Pediatrics, are analysed. Furthermore, the therapeutic effects of the 2 most important non pharmacological therapies used for migraine prophylaxis, biofeedback and acupuncture, are discussed. For this latter therapy, the personal preliminary positive experience using a predetermined formula of acupoints for the combined treatment of migraine and hyperemesis gravidarum is reported.