Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function.

BACKGROUND: Oral immunotherapy (OIT) successfully desensitizes patients with food allergies, but the immune mechanisms mediating its efficacy remain obscure. OBJECTIVES: We tested the hypothesis that allergen-specific regulatory T (Treg) cell function is impaired in food allergy and is restored by anti-IgE antibody (omalizumab)-supplemented OIT. METHODS: Peanut-specific T effector (Teff) and Treg cell proliferative responses, activation markers and cytokine expression were analysed by flow cytometry in 13 peanut-allergic subjects before the start of omalizumab-supplemented OIT and periodically in some subjects thereafter for up to 2 years. Peripheral blood regulatory T cells (Treg cells) were analysed for their peanut-specific suppressor function before and at 1 year following OIT. This study was registered on ClinicalTrials.gov (NCT01290913). RESULTS: Proliferation of allergen-specific Teff and Treg cells precipitously declined following the initiation of omalizumab therapy prior to OIT, followed by partial recovery after the initiation of OIT. At baseline, peanut-specific Treg cells exhibited a Th2 cell-like phenotype, characterized by increased IL-4 expression, which progressively reversed upon OIT. Peanut-specific Treg cell suppressor activity was absent at the start of omalizumab/OIT therapy but became robust following OIT. Absent peanut-specific Treg cell function could also be recovered by the acute blockade of IL-4/IL-4R receptor signalling in Treg cells, which inhibited their IL-4 production. CONCLUSIONS AND CLINICAL RELEVANCE: OIT supplemented by omalizumab promotes allergen desensitization through an initial omalizumab-dependent step that acutely depletes allergen-reactive T cells, followed by an increase in allergen-specific Treg cell activity due to the reversal of their Th2 cell-like programme. Improved Treg cell function may be a key mechanism by which OIT ameliorates food allergy.

Antioxidants and reactive oxygen species in follicular fluid of women undergoing IVF: relationship to outcome.

BACKGROUND: The role of free radicals and reactive oxygen species (ROS) in female reproductive function is still unclear. The present study was designed to investigate their relationship with ovulation, fertilization and conception. METHODS: Follicular aspirates obtained from women undergoing IVF following controlled ovarian stimulation were evaluated using the ferric reducing antioxidant power (FRAP) assay for baseline total antioxidant capacity (TAC). Both the baseline TAC and the decline in TAC over 72 h (two-point assay) were used as markers of oxygen radical activity. RESULTS: A total of 303 follicular aspirates from 63 women were analysed. Two hundred and eighteen (71.9%) yielded oocytes, 169 (77.5%) of these fertilized and 134 (79.3%) of these embryos survived until the time of embryo transfer. Baseline TAC was no different in follicular fluid whether the follicle contained an oocyte or not, but was significantly higher in fluid from follicles whose oocyte successfully fertilized and significantly lower in fluid from follicles where the resultant embryo survived to transfer. The decline in TAC was lower when the oocytes fertilized and higher in association with embryo viability, but the differences were not statistically significant. CONCLUSIONS: These results provide further evidence that ROS play a role in female reproductive function.

Sperm concentrations and quality in beta-thalassaemia major.

We report semen analyses in eight patients with beta-thalassaemia major, with poor results in all but the youngest. The causation is multi-factorial, with iron deposition in the pituitary gland resulting from life-long dependence on blood transfusions being a major factor. We speculate on other contributing causes, but further research is required to elucidate these. Improving haematological care means that these men are increasingly surviving to adult life. Relevant techniques to enable them to achieve their desire for fatherhood are considered.

Ovarian electrocautery: responders versus non-responders.

The endocrine and biophysical attributes of 29 patients with polycystic ovarian disease (PCOD) were examined before and after laparoscopic ovarian electrocautery to establish the criteria which determined their clinical response. Patients with high luteinizing hormone (LH) levels (> 12 IU/l) had a better response than patients with lower LH values but a high LH: follicle stimulating hormone (FSH) ratio (> or = 2:1). However, the body mass index, ovarian volume or pretreatment testosterone values were not helpful in predicting the clinical outcome. Both responders (n = 22) and non-responders (n = 7) showed a decline in LH and testosterone and an increase in FSH 6-h mean values, following 15-min blood sampling 1 month after surgery, compared to the corresponding pretreatment levels. The magnitude of change was significantly higher for LH (p < 0.01) in responders but there was no difference in the corresponding values of the other hormones between the two groups (p > 0.05). Accordingly, unsupplemented ovarian electrocautery is better reserved for the treatment of patients with PCOD and high LH values. Four of the 17 patients who had second-look diagnostic laparoscopy showed minimal to mild pelvic adhesions and all patients had patent Fallopian tubes. The performance of a second-look diagnostic laparoscopy is not indicated as a routine procedure in all cases following surgery.

The aetiology of galactorrhoea in women with regular menstruation and normal prolactin levels.

Fourteen primary infertile women with expressible galactorrhoea associated with regular ovulatory cycles and normal basal prolactin levels (group A) were matched for age and weight with 14 infertile women with regular menstruation but no galactorrhoea (group B). Both groups showed equivalent increases in prolactin levels after stimulation with 200 micrograms thyrotrophin-releasing hormone (TRH) during the follicular and luteal phases of the menstrual cycle. Patients in group A had a greater increase in luteinizing hormone levels after 100 micrograms i.v. injection of a luteinizing hormone-releasing hormone during the follicular phase (P less than 0.05). Following a 60 mg oral dose of buspirone hydrochloride on day 22 of the menstrual cycle, patients in group A had a greater increase in prolactin levels than patients in group B (P less than 0.01). This reflects hyper-responsive 5-hydroxytryptamine type 1A (5HT1A) receptors in group A patients and may explain the presence of galactorrhoea in these patients despite normal basal and post-TRH prolactin levels.

Implications of ultrasonically diagnosed polycystic ovaries. I. Correlations with basal hormonal profiles.

The incidence of ultrasonically diagnosed polycystic ovaries (PCO) was studied in 389 Arab patients with different types of menstrual dysfunction and 100 normal women with regular menstruation. Two-hundred-and-forty-six patients (63.2%) were found to have PCO but only 206 (53.0%) were confirmed as cases of polycystic ovarian disease (PCOD) on endocrine grounds. Polycystic ovaries were diagnosed in 50% of patients with hyperprolactinaemia, 36.4% with hypothyroidism, 23.7% with hypothalamic dysfunction, 100% with adrenal 21-hydroxylase deficiency and in 16.0% of normal women. More women with PCOD presented with oligomenorrhoea or dysfunctional uterine bleeding (77.7%) and hirsutism (72.3%) but obesity had no discriminating value between the groups with different diagnoses. Ultrasonic diagnosis of PCO should be supplemented with an endocrine biochemical assessment to prevent overdiagnosis of PCOD and to exclude other endocrine dysfunctions.

Implications of ultrasonically diagnosed polycystic ovaries. II. Studies of dynamic and pulsatile hormonal patterns.

Studies of 6-h hormone pulse patterns distinguished patients with polycystic ovarian disease (PCOD) from those with hyperprolactinaemia or hypothyroidism associated with ultrasonically diagnosed polycystic ovaries (PCO). No specific derangement in the gonadotrophin pulse pattern was responsible for these changes, as shown in patients with and without PCO in the latter two groups. These changes may reflect an abnormal ovarian response to normal or abnormal gonadotrophic drive. Out of 26 patients with PCO and elevated dehydroepiandrosterone sulphate (DHEA-S) levels, only three patients (11.5%) proved to have adrenal 21-hydroxylase deficiency. Ultrasonic visualization of polycystic ovaries must be supplemented with an endocrine biochemical assessment. Moreover, mild elevation of DHEA-S, without a concurrently high 17 alpha-hydroxyprogesterone level was not diagnostic of adrenal hyperplasia.

Slow release intrauterine insemination versus the bolus technique in the treatment of women with cervical mucus hostility.

Thirty-eight infertile women with cervical mucus hostility were divided at random into two groups for intrauterine insemination with prepared husband's semen. Eighteen women started with slow release (treatment A) and 20 with bolus (treatment B) intrauterine insemination in a cross-over study for four alternating cycles. Insemination was timed 30-36 h after a positive luteinizing hormone (LH) surge or injection of 5000 IU of human chorionic gonadotrophin, given at a follicular diameter of 18 mm during ultrasonically monitored, unstimulated cycles. A Grasby auto-syringe driver (type MS16) was used for the slow release intrauterine insemination to deliver 50 x 10(3) motile spermatozoa every minute for 3 h. Bolus intrauterine insemination was performed by deposition of 0.6 ml of prepared semen without changing the count from the swim-up portion of the washed spermatozoa. A total of 13 patients conceived, nine from 60 cycles of treatment A and four from 66 cycles of treatment B (chi-squared = 2.7143, P less than 0.05 using one-tailed statistics).

Polycystic ovaries: do these represent a specific endocrinopathy?

Serum pituitary gonadotrophins, oestradiol, testosterone and insulin pulse patterns were examined at 15-min intervals for 6 h in 40 women with a previous diagnosis of polycystic ovarian disease (PCO) based on clinical, endocrinological and ultrasound data. Age, duration of symptoms, body mass index (BMI) and ovarian volume showed no correlation with the 6-h mean value of any hormone and testosterone blood levels did not correlate with those of insulin. Some patients had high and others low LH pulse pattern components, and few had an inverted LH:FSH ratio. Morphological polycystic ovarian changes may be a reflection of various rather than a single pattern of gonadotrophin secretion.

Ovarian electrocautery versus human menopausal gonadotrophins and pure follicle stimulating hormone therapy in the treatment of patients with polycystic ovarian disease.

Eighty-eight clomiphene citrate-resistant infertile patients with oligomenorrhoea or amenorrhoea attributable to polycystic ovarian disease were divided at random into three groups. Twenty-nine patients were treated with ovarian electrocautery, 30 with human menopausal gonadotrophins (hMG) and 29 with pure follicle stimulating hormone (FSH). Successful ovulation was induced in 71.4, 70.6 and 66.7% of the cycles in the groups respectively. Ten patients conceived after electrocautery and pure FSH therapy while 15 conceived after hMG medication (chi-squared = 1.6464, P = 0.439). The six-cycle cumulative pregnancy rate in the three consecutive groups was 52.1, 55.4, and 38.3%. Four further pregnancies were achieved after treating 10 patients in the electrocautery group with clomiphene citrate (100 mg/day for 5 days) for 25 cycles. The rate of pregnancy wastage in the corresponding groups was 21.4, 53.3 and 40% (chi-squared = 3.127, P = 0.2039). Ovarian electrocautery is equally effective as hMG and pure FSH in the treatment of PCO patients resistant to clomiphene citrate therapy.

Diagnosis of pathologically confirmed Symmers' periportal fibrosis by ultrasonography: a prospective blinded study.

Symmers' periportal fibrosis of the liver is the major cause of morbidity and mortality in Schistosoma mansoni infection. The diagnosis is best established definitively by a wedge biopsy of the liver. The ability of abdominal ultrasonography to diagnose this condition was prospectively compared with two independent pathological examinations of wedge biopsies of the liver. Both pathologists and the ultrasonographer were unaware of the clinical diagnosis and each other's findings. Twenty-eight of 41 patients had Symmers' fibrosis by pathological examination and all were diagnosed correctly by ultrasonography prior to surgery. Symmers' fibrosis was not diagnosed by ultrasound in any of 10 patients without Symmers' fibrosis on biopsy. In 3 patients the diagnosis of Symmers' fibrosis was uncertain because the pathologists disagreed as to its presence. These results confirm the findings of previous studies and establish that ultrasonography is at least as sensitive as wedge biopsy in diagnosing Symmers' fibrosis.

Louse-borne relapsing fever in the Sudan. A historical review and a clinico-pathological study.

A small outbreak of louse-borne relapsing fever in Khartoum (May-June 1974) provided material for a clinico-pathological study. The history of the disease in the Sudan is reviewed and the clinical and laboratory findings in 32 patients are presented. Fever, headache, jaundice, epistaxis and hepatosplenomegaly were the commonest clinical findings; thrombocytopenia was detected in 93% of cases. Although elevated levels of fibrin degradation products were found in most patients, disseminated intravascular coagulation could not be diagnosed. Hepatocellular derangement was found in 68% of cases, while 78% had high blood urea. In five autopsied bodies there was bronchopneumonia, interstitial edema with focal myocardial fibrosis, hepatic necrosis, splenic infarcts, increase in size and cellularity of the glomeruli and brain edema and congestion. Intracranial haemorrhage was found in three of the autopsied cases.