Is controlled ovarian stimulation safe in patients with hormone receptor-positive breast cancer receiving neoadjuvant chemotherapy?

INTRODUCTION: Controlled ovarian stimulation (COS) for oocyte/embryo cryopreservation is the method of choice for fertility preservation (FP) in young patients diagnosed with early-stage breast cancer (eBC). Nevertheless, some challenges still question its role, particularly in the neoadjuvant setting, where concerns arise about potential delay in the onset of anticancer treatment, and in hormone receptor-positive (HR+) disease, as cancer cells may proliferate under the estrogenic peak associated with stimulation. Therefore, this review aims to examine the available evidence on the safety of COS in eBC patients eligible for neoadjuvant treatment (NAT), particularly in HR+ disease. METHODS: A comprehensive literature search was conducted to identify studies evaluating the feasibility and safety of COS in eBC and including patients referred to NAT and/or with HR+ disease. Time to NAT and survival outcomes were assessed. RESULTS: Of the three matched cohort studies assessing the impact of COS on time to start NAT, only one reported a significant small delay in the cohort undergoing COS compared with the control group, whereas the other studies found no difference. Regarding survival outcomes, overall, no increased risk of recurrence or death was found, either in patients undergoing COS in the neoadjuvant setting regardless of HR expression or in HR+ disease regardless of the timing of COS relative to surgery. However, there are no data on the safety of COS in the specific combined scenario of HR+ disease undergoing NAT. CONCLUSION: Neither the indication to NAT nor the HR positivity constitutes per se an a priori contraindication to COS. Shared decision making between clinicians and patients is essential to carefully weigh the risks and benefits in each individual case. Prospective studies designed to specifically investigate this issue are warranted.

Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer.

PURPOSE: HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2-zero, obtained by immunohistochemistry (IHC). METHODS: Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1-10%). HER2 gene expression by ODX was negative if lower 10.7. RESULTS: The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70-9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p < 0.001] compared to the HER2-zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups. CONCLUSION: Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2-zero IHC whose accurate identification is critical in the context of HER2-negative BC.

Access Challenge Index: A Novel Disparity Measure Predictive of Language Outcomes in Children Who Are Deaf/Hard of Hearing.

OBJECTIVE: To evaluate the effect of demographic disparities on language outcomes in a diverse group of children who are deaf or hard of hearing. STUDY DESIGN: Retrospective cohort study. SETTING: UCSF Benioff Children's Hospital (a tertiary care center). METHODS: Forty-four patients aged <18 years were identified with sensorineural hearing loss managed with a behind-the-ear hearing aid or cochlear implant. Demographic and clinical data were extracted from the medical record. The primary outcome measure was the Preschool Language Scales-5 at least 6 months after intervention. Predictors of language outcome were assessed: hearing level at the time of hearing intervention, cochlear implant status, age of identification and intervention, travel time to site of hearing care, home language, race/ethnicity, insurance type, and Access Challenge Index-a novel measure of educational environment and family support based on the Child Cochlear Implant Profile. Multivariate and univariate analysis assessed predictors for association with intervention and receptive, expressive, and total language scores. RESULTS: Overall 82% of patients had cochlear implants. The median age at hearing intervention was 12 months. The sample was 59% female, 52% non-White, and 61% publicly insured, and 20% had a non-English primary home language. Accounting for multiple demographic and clinical predictors, a high Access Challenge Index score was independently associated with longer time to intervention (P = .01) and poorer language outcomes (P < .001). CONCLUSION: Access Challenge Index-a novel comprehensive measure of educational and family environment-is a strong independent predictor of language outcomes in children who are deaf or hard of hearing.

Evaluation of Levothyroxine Bioavailability after Oral Administration of a Fixed Combination of Soy Isoflavones in Post-menopausal Female Volunteers.

BACKGROUND: Post-menopausal women under treatment with levothyroxine for their medical conditions may take concomitantly dietary supplements containing soy isoflavones in combination to treat their post-menopausal symptoms. The aim of this study was to investigate the effect of a fixed combination of soy isoflavones on the oral bioavailability of levothyroxine in post-menopausal female volunteers. METHODS: 12 healthy post-menopausal female, who were on stable oral levothyroxine as replacement/supplementation therapy for hypothyroidism, received a single recommended oral dose of a food supplement containing 60 mg of soy isoflavones (>19% genistin and daidzin) concomitantly with (test) and 6 h later (reference) the administration of levothyroxine in a randomized, open label, crossover fashion. Plasma concentrations of levothyroxine and soy isoflavones (daidzin, daidzein, genistin, genistein, S-equol) were determined by LC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analysis. No effect of soy isoflavones was assumed if the 90% confidence intervals (CIs) for the estimated ratio test/reference was included in the acceptance limits 0.80-1.25 for PK parameters Cmax and AUCt. RESULTS: The test/reference ratios Cmax and AUCt of levothyroxine were very close to unity (1.02 and 0.99, respectively) and the corresponding 90% CIs (0.99-1.04 and 0.88-1.12, respectively) fell entirely within the acceptance bioequivalence limits. CONCLUSION: The combination of soy isoflavones used in the present investigation does not affect the rate and extent of levothyroxine absorption when administered concomitantly in post-menopausal women.

Single nucleotide polymorphisms in candidate genes associated with gastrointestinal nematode infection in goats.

Cytokines are small cell-signaling proteins that play an important role in the immune system, participating in intracellular communication. Four candidate genes of the cytokine family (IL2, IL4, IL13, and IFNG) were selected to identify Single Nucleotide Polymorphisms (SNPs) that might be associated with resistance to gastrointestinal endoparasites in goats. A population of 229 goats, F2 offspring from an F1 intercross was produced by crossing pure Saanen goats, considered as susceptible to gastrointestinal endoparasites, with pure Anglo-Nubian goats, considered resistant. Blood was collected for DNA extraction and fecal samples were also collected for parasite egg count. Polymorphisms were prospected by sequencing animals with extreme phenotype for fecal egg count (FEC) distribution. The association between SNPs and phenotype was determined by using the Fisher exact test with correction for multiple tests. Three of the 10 SNPs were identified as significant (P ≤ 0.03). They were found in intron 1 of IL2 (ENSBTA00000020883), intron 3 of IL13 (ENSBTA00000015953) and exon 3 of IFNG (ENSBTA00000012529), suggesting an association between them and gastrointestinal endoparasite resistance. Further studies will help describe the effects of these markers accurately before implementing them in marker assisted selection. This study is the pioneer in describing such associations in goats.

Response of resistant and susceptible Brazilian Somalis crossbreed sheep naturally infected by Haemonchus contortus.

This study was carried out to evaluate the performance of Brazilian Somalis sheep to natural infections by gastrointestinal nematodes. During 98 days, 75 weaned sheep, initially 3-4 months old, were kept on the same pasture and evaluated. Fecal and blood samples were collected for parasitological and hematological exams. After this period, the eight most resistant and the eight most susceptible animals were selected based on their individual averages of nematode fecal egg counts and were slaughtered for worm burden determination and nematodes identification. Abomasum and abomasum lymph nodes were also recovered for gene expression analysis. The animals selected as resistant had lower fecal egg counts during experimental period and smaller worm burdens than the susceptible ones (P < 0.05). The genus Haemonchus, followed by Trischostrongylus and Oesophagostomum, were identified in composite cultures. Haemonchus contortus was the specie identified in the abomasum. Packed cell volume and total plasma protein means were higher in the resistant group (27.2% and 6.1 g/dL) than in the susceptible one (22.5% and 5.3 g/dL), respectively. Regarding cytokine gene expression, IL-4 (P < 0.05) was up-regulated in the abomasum of resistant animals and TNF-α (P < 0.03) and IFN-γ (P < 0.03) in susceptible ones. In abomasum lymph nodes, IL-4 (P < 0.04) and IL-13 (P < 0.05) were up-regulated in the resistant animals and IFN-γ in the susceptible one (P < 0.01). This work provides further evidence that, within a given animal breed, individuals have different responses when infected by gastrointestinal nematodes. Resistant animals who responded more quickly and efficiently to these infections activated a TH2-type response.

Use of a lipid-lowering food supplement in patients on hormone therapy following breast cancer.

AIM: The aim of this paper was to determine the activity of a natural nutraceuticals combination (AP=Berberine+Red Yeast Rice) on dyslipidemia which frequently persists after life style changes in patients on hormone-therapy following breast cancer (HT-BC). METHODS: Twenty-one HT-BC patients, free of tumor, mean age 59.9 years, BMI 28,9 kg/m2, waist circumference 95.9 cm, with altered lipid profile (total cholesterol 269.0 mg/dL, high-density lipoprotein (HDL) cholesterol 54.9 mg/dL, low-density lipoprotein (LDL) cholesterol 184.0 mg/dL, and triglycerides 263.3 mg/dL) were recruited. They were recommended a 3-month period of diet followed by a 3-month period of treatment with AP 1 tablet/day. AP tablets contain berberine 500 mg, red yeast rice extract 200 mg (equivalent to 3 mg monacolins), policosanol 10 mg, folic acid 0.2 mg, coenzyme Q10 2 mg, and asthaxantin 0.5 mg. RESULTS: The lipid profile was significantly improved by AP vs. diet: 1.8% decrease in total cholesterol on diet and a further 15.3% decrease with AP vs. diet (P<0.001); a 3.1% decrease in LDL cholesterol after diet and an 18.9% decrease after AP treatment vs diet alone (P<0.01); a 2.3% decrease in triglycerides after diet alone and a 36.5% decrease after AP vs. diet (P<0.05). CONCLUSION: Adequate life style therapy is effective in reducing, but not in normalizing, the lipid profile in patients on hormone-therapy following breast cancer. The use of natural nutraceuticals as AP, combined with diet, leads to a good therapeutic response and optimal acceptance by the patients.

Randomized controlled study on clinical efficacy of isoflavones plus Lactobacillus sporogenes, associated or not with a natural anxiolytic agent in menopause.

AIM: The aim of this paper was to evaluate the activity of magnolia bark extract added to isoflavones and lactobacilli in menopausal women with typical menopausal symptoms and concomitant borderline psychoaffective and/or sleep alterations, of severity not requiring a psychopharmacological therapy. METHODS: Menopausal women were enrolled in a multicenter, controlled, parallel-group study and randomized to E (isoflavones 60 mg + Lactobacillus sporogenes + calcium and vitamin D3 - Estromineral, Rottapharm Madaus) versus ES (magnolia bark extract + E - Estromineral serena) 1 tablet/night for 12 weeks. RESULTS: In 91 gynecological centers, 634 women were treated (300 with E and 334 with ES), mean age 53.1 years and Body Mass Index (BMI) 25.2 kg/m2; 28% were past hormone replacement therapy HRT users and 3.3% had had a previous breast cancer. Both treatments significantly reduced versus baseline the symptoms tested at 0, 4, 8 and 12 weeks. E and ES showed a similar efficacy on hot flushing, nocturnal sweating with awakenings, palpitations and vaginal dryness. ES was more active on insomnia, irritability, anxiety, depressed mood, asthenia and loss of libido. Woman's well-being and physician's final judgment were positive in >70% in both groups. The rate of adverse events was 1% with E (metrorrhagia, cramps and constipation) and 1.2% with ES (gastralgia, blood loss, constipation and breast tension). CONCLUSION: Isoflavones are effective in improving the classical menopause symptoms. The clinical activity of magnolia bark extract on the relevant psycho-affective symptoms, particularly anxiety, irritability and insomnia, was evident. ES in the mild psychical alterations that can occur in climacterium avoids to run the known dependence risks linked to psychopharmacological agents withdrawals.

SOPHY project: an observational study of vaginal pH, lifestyle and correct intimate hygiene in women of different ages and in different physiopathological conditions. Part II.

AIM: The first part of the Study on pH and Hygiene (SOPHY) evidenced some interesting correlations between clothing and the frequency of candidosis and bacterial vaginosis, between vaginal pH and satisfactory sexual activity, and between education and sexuality. SOPHY second part explored the effect of intimate hygiene, appropriately chosen within natural plant extracts, according to the women's different ages and conditions, on vaginal pH, candidosis, bacterial vaginosis, and satisfactory sexual activity. METHODS: The second part of the study enrolled 2 641 women randomized into different subgroups (prepubertal, fertile, pregnancy, breastfeeding, premenopause and menopause). The most appropriate detergent for the woman's intimate hygiene was recommended by 264 gynecologists on the basis of age and physio-pathological status of the patients: extract of Salvia officinalis for adolescents, child-bearing age and pre-menopause; extract of Camomilla recutita in menopause; extract of Thymus vulgaris during pregnancy and lactation, and in the presence or risk of vaginal infections. Each product had to be used once or twice a day for four weeks. RESULTS: The natural plant extracts used for intimate hygiene showed a positive clinical effect favouring the reduction of vaginal pH, the improvement of symptoms and the quality of sexual activity in all age/conditions observed. CONCLUSION: SOPHY evidenced that an appropriate intimate hygiene can be an important tool in women's everyday life.

SOPHY project: an observational study of vaginal pH and lifestyle in women of different ages and in different physiopathological conditions. Part I.

AIM: The importance of vaginal pH and vaginal flora in maintaining a well-balanced vaginal ecosystem is well known and has been widely described. However, no systematic nationwide studies have been carried out concerning the correlation between vaginal pH, life style and different physiopathological conditions in women of different ages. METHODS: SOPHY (Study on pH and Hygiene) collected data concerning the lifestyle, vaginal pH, and the presence of symptoms, stratified into different subgroups (prepuberal, fertile, pregnancy, postpartum, premenopause and menopause) in a representative sample of the Italian gynecological population (264 gynaecologists for a total of 2 641 women) with the aid of a specific Internet site for data entry. RESULTS: A more acid vaginal pH was related to a better satisfactory sexual activity and to more healthy genital condition. A positive relationship was detected between education level and good perception of sexuality. Certain clothing habits and a higher frequency of candidiasis and bacterial vaginosis was shown. CONCLUSION: SOPHY revealed some interesting correlations between clothing and the frequency of candidiasis and bacterial vaginosis, between vaginal pH and satisfactory sexual activity, and between education and sexuality. SOPHY had a considerable educational impact, leading the physicians and women to consider vaginal pH as an important aspect of everyday life.

A strain of Salmonella enterica serovar Virchow isolated in Turkey and carrying a CTX-M-3 extended-spectrum beta-lactamase.

A multiply resistant strain of Salmonella enterica subsp. enterica serovar Virchow was isolated in November 2002 from a catheterized patient admitted to the SSK Training Hospital in Ankara, Turkey. This isolate showed an antimicrobial susceptibility pattern compatible with the presence of a CTX-M-type ESBL, namely resistance to cefotaxime, aztreonam and cefepime, and intermediate susceptibility to ceftazidime. On checking for the presence of the bla(TEM), bla(SHV), and bla(CTX-M )resistance genes by PCR, negative results were obtained with the primers specific for SHV and TEM genes, while positive results were obtained with those specific for CTX-M-type genes. After sequencing, the beta-lactamase was identified as CTX-M-3. This is the first report of this enzyme in Salmonella Virchow and represents a further disquieting threat to the therapy of infections caused by Salmonella isolates.

Soy isoflavones, lactobacilli, Magnolia bark extract, vitamin D3 and calcium. Controlled clinical study in menopause.

AIM: Affective and behavioural disorders possibly concomitant to the vasomotor menopausal symptoms worsen quality of life. A rational formulation containing soy isoflavones (60 mg), lactobacilli (500 millions spores), calcium (141 mg) and vitamin D3 (5 microg) was added of Magnolia bark extract (60 mg) and magnesium (50 mg) (Estromineral serena, ES). The Magnolia extract active principles interact with GABA system and exhibit a sedative central action. Magnesium intervenes in enzymatic reactions of the energetic metabolism and protects the bone integrity. Aim of this controlled study was to compare the clinical activity and safety of ES versus calcium+vitamin D3 (Ca+D) in menopause. METHODS: A controlled, randomised, multicentre study was carried out in symptomatic menopausal women with sleep or mood alterations. Women received 1 tablet/day of ES or Ca+D for 24 weeks. Symptoms during the treatment and final judgements on efficacy and acceptability were evaluated. RESULTS: Eighty-nine women (44 ES and 45 Ca+D, mean age 53.8 years, in menopause since 56.6 months) participated to the study. Flushing, nocturnal sweating, palpitations, insomnia, asthenia, anxiety, mood depression, irritability, vaginal dryness, dyspareunia, and libido loss, significantly decreased in severity and frequency during ES versus Ca+D treatment even since the fourth week. Woman wellbeing (good/very good 66.7% vs 20%) judgement on efficacy (72.7% vs 17.1%) and acceptability (93.9% vs 31.4%) were significantly better for ES. CONCLUSIONS: The controlled study showed the efficacy of Magnolia extract and magnesium on psycho-affective and sleep disturbances in menopause, in addition to the effects of isoflavones on vasomotor symptoms. A global natural approach to menopause with ES evidenced its therapeutic usefulness and safety.

[Clinical significance of thyroid nodule calcification]. / Significato clinico delle calcificazioni nei noduli tiroidei.

To confirm the predictive value of calcifications in thyroid nodules as a risk factor for malignancy and to detect specific aspects for tumours, in a set of 175 patients--30 papillary carcinoma (PC) and 145 multinodular goiters (MNG) with dominant nodule--calcifications were detected by ultrasound scan. Calcifications were significantly more frequent in PC than in MNG (40% vs 20.7% p < 0.05) but their considered characteristics (size, number, position, location in the gland, sonographic features of the nodule) did not show any particular difference between PC and MNG. The frequency of calcifications in our series was higher in older patients (mean age 58.7 +/- 13.3 vs 51.1 +/- 12.7 in patients without calcifications, p < 0.001) and this could imply that their onset is time-dependent. Calcifications can be a useful indicator of enhanced risk, to be considered in the overall process of surgical decision making.

Betahistine produces post-synaptic inhibition of the excitability of the primary afferent neurons in the vestibular endorgans.

Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the action of betahistine in the vestibular endorgans. Experiments were done in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM; n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with the nitric oxide synthase inhibitor NG-nitro-L-arginine (3 microM) and with the cholinergic antagonists atropine (10 microM; n = 3) and d-tubocurarine (10 microM; n = 3) were studied. The action of betahistine when co-administered with these drugs was the same as that in control experiments, indicating that its effects did not include nitric oxide production or the activation of cholinergic receptors. In contrast, 0.01-1 mM betahistine reduced the excitatory action of kainic acid (10 microM; n = 6) and quiscualic acid (1 microM; n = 13). These results indicate that the action of betahistine on the spike discharge of afferent neurons seems to be due to a post-synaptic inhibitory action on the primary afferent neuron response to the hair cell neurotransmitter.

Action mechanism of betahistine in the vestibular end organs.

Betahistine has been used to treat several vestibular disorders of both central and peripheral origin. The objective of this work was to study the betahistine action mechanism at the vestibular end organs. Experiments were carried out in wild larval axolotl (Ambystoma tigrinum). Multiunit extracellular recordings were obtained from the semicircular canal nerve using a suction electrode. Betahistine (10 microM to 10 mM, n = 32) inhibited the basal spike discharge of the vestibular afferent neurons with an IC50 of 600 microM. To define the site of action of betahistine, its interactions with antagonists of nitric oxide sintethizing enzyme, cholinergic drugs, and excitatory amino acids were studied. Betahistine 1 mM (n = 5) was coadministered with NG-nitro-L-arginine 3 microM. The action of betahistine remained as in control experiments. Betahistine 1 mM reduced the excitatory action of carbachol (200 microM, n = 5) in a 30 +/- 3.4%. Cholinergic antagonists atropine (10 microM, n = 3) and d-tubocurarine (10 microM, n = 3) did not modify betahistine actions. Betahistine 1 mM also reduced kainic acid (10 microM, n = 4) excitatory action in 45.5 +/- 9.8%. These results corroborate that betahistine has a peripheral inhibitory action in the spike discharge of the afferent neurons in the vestibule. This action seems to involve neither NO production nor modifications in the release of acetylcholine from the efferent fibers. The inhibitory action of betahistine seems to be due to a postsynaptic binding site on the afferent neurons.

Effects of betahistine and of its metabolites on vestibular sensory organs.

Betahistine is widely used in the treatment of peripheral and central vestibular disorders. Till now the anti-vertigo effect of the drug was though to be mainly due to an action of betahistine on inner ear or cerebral microcirculation or on some structures of the CNS, chiefly the vestibular nuclei. Vertigo, however is, in most cases, of peripheral origin but it remains unknown whether betahistine, or some of its metabolities, may directly affect the vestibular system at peripheral level. Pharmacokinetic studies have in fact demonstrated that betahistine is transformed, mainly at the hepatic level, in aminoethylpyridine (M1), hydroxyethylpyridine (M2) and, finally, in pyridylacetic acid (M3) which is excreted with the urine. All these substances are therefore present in the body fluids of subjects treated with betahistine, and thus might have pharmacological effects. The goal of the present study was to investigate whether betahistine or some of its metabolites could exert any effect on vestibular receptors. To this end, the effects of the drugs (10(-7)-10(-2) M) have been examined on frog semicircular canals, an animal model well suited for this purpose. The effects of betahistine and of its metabolites have been evaluated by recording ampullar receptor activity both at rest and during mechanical stimulation of the sensory organ. The results demonstrated that both betahistine and one of its metabolites, the aminoethylpyridine (M1), exert effects quite similar on ampullar receptors; both these substances in fact could reduce greatly ampullar receptor resting discharge but had scanty effects on mechanically-evoked responses. This observation might justify betahistine and possibly M1 anti-vertigo effects. In fact vertigo is normally due to uncontrolled changes in vestibular receptor resting discharge. It is therefore probable that any factor able to reduce vestibular receptor resting firing rate and, in consequence, its variations, may have, as final effect, an anti-vertigo action. The observation that betahistine and M1 have similar effects might be of some clinical interest. In fact, on the basis of our data, the hypothesis may be put forward that the anti-vertigo action of betahistine is at first achieved by betahistine itself and then sustained and prolonged in time by M1.

Immunologic events and long-term survival after combined heart and kidney transplantation: a 12-year single-center experience.

BACKGROUND: In this study we compare the incidence of cardiac rejection and long-term survival after combined heart and kidney transplantation (HK) and single heart transplantation (H). Combined HK transplantation is a surgical option for patients with irreversible cardiac and renal failure. However, long-term results of combined HK transplantation on immunologic events and patient survival remain unknown. METHODS: Between 1988 and 1997, 12 consecutive patients underwent combined HK transplantation (HK group) at a single institution. A control group (H group) of 24 single heart transplant recipients operated on within the same period was matched for age, pre-operative pulmonary vascular resistance, hepatic insufficiency and gender mismatch. Recipients and donors were ABO compatible without HLA antigen matching. All patients received immediate triple immunosuppression that included cyclosporine. Because of early renal dysfunction, cyclosporine was switched to anti-thymocyte globulin in 5 patients from the HK group and in 1 patient from the H group (p = 0.01). RESULTS: Actuarial freedom from heart rejection at 6 months and at 1 year following transplantation averaged 90 +/- 9% and 70 +/- 14% in the HK group, and 65 +/- 10% and 49 +/- 11% in the H group, respectively (p = 0.023). Actuarial survival at 1, 5 and 12 years was not significantly different between groups, at 66%, 55% and 28% in the HK group, and 66%, 44% and 32% in the H group, respectively (p = 0.66). CONCLUSION: The incidence of cardiac rejection was significantly lower. Long-term survival in the HK group was similar to that in the H group. Putative mechanisms of decreased cardiac rejection in the HK group include allogeneic stimulation, donor-derived dendritic cells and induction by anti-thymocyte globulins. The need for long-term immunosuppression may be reduced after combined heart and kidney transplantation.

Binding affinity profile of betahistine and its metabolites for central histamine receptors of rodents.

In order to clarify the interaction of betahistine (BH) and its metabolites [aminoethylpyridine (AEP) and hydroxyethylpyridine (HEP)] for receptors that mediate the physio-pharmacological activities of histamine, we performed in vitro competition binding studies to obtain their binding affinity profile for H(1)-, H(2)- and H(3)-histamine receptors prepared from rodent brains. Crude synaptosomal membranes were incubated in the absence (total binding) or presence of the unlabelled ligands used to saturate the specific binding, or with different concentrations of BH, AEP or HEP. Receptor binding methods were validated by running known standard drugs together with the test compounds. Like histamine, only BH interacted with H(1)-histamine receptors with comparable affinity (around 10(-5)M). BH and its metabolite AEP both interacted with the H(3)-histamine receptors, with microM affinity. HEP still showed some affinity for the H(3)-receptors but with a K(i)only 1/50 that of the parent compound. Histamine showed 10(-8)M affinity for the H(3)-receptor sites and was the only ligand to interact with H(2)-histamine receptors, all the others giving affinities above the mM range. Hill coefficients (as slopes of the sigmoidal inhibition isotherms) were close to unity for BH against H(1)- and H(3)-binding sites and for AEP against H(3)-sites, indicating that these interactions take place in the absence of cooperativity. Histamine and HEP interacted with H(1)- and H(3)-receptors with a Hill coefficient less than unity for the former and higher than unity for the latter (presence of negative and positive cooperativity, respectively). The results suggest that BH and its metabolites may act as neurotransmitter modulators of the histaminergic system.

Effects of bradykinin on coronary blood flow and vasomotion in transplant patients.

OBJECTIVES: To evaluate the effects of exogenous bradykinin on coronary epicardial and microcirculatory tone in transplant patients (HTXs), and to compare them with the effects of acetylcholine. BACKGROUND: Coronary endothelial dysfunction has been reported to occur early after heart transplantation, most notably when acetylcholine was the endothelium-function marker used. The effects of bradykinin on coronary vasomotion are unknown in HTXs. METHODS: Sixteen HTXs were compared 3.6 +/- 1.7 months after transplantation to seven control subjects. Coronary flow velocity was measured using guide-wire Doppler. Diameters (D) of three segments of the left coronary artery and coronary blood flow (CBF) were assessed at baseline, after 3-min infusions of increasing bradykinin doses (50, 150 and 250 ng/min) then of increasing acetylcholine doses (estimated blood concentrations of 10(-8), 10(-7) and 10(-6) M). RESULTS: Bradykinin induced similar dose-dependent increases in D and CBF in both groups: D was 11 +/- 12%, 19 +/- 14% and 22 +/- 16% (all p < 0.0001), and CBF was 50 +/- 40%, 130 +/- 68% and 186 +/- 77% (all p < 0.0001). Acetylcholine induced significant epicardial vasodilation in control subjects and vasoconstriction in HTX, as well as a marked increase in CBF in both groups. Acute allograft rejection, present in 8 of the 16 HTXs, did not modify responses to bradykinin, but was associated with a smaller CBF increase in response to acetylcholine (p < 0.05). CONCLUSIONS: The coronary vasodilating effects of bradykinin are preserved early after heart transplantation, even in the presence of acute allograft rejection. Although there is an abnormal vasoconstricting response to acetylcholine reflecting endothelium dysfunction, the endothelium remains a functionally active organ in heart transplant recipients.