SOCS3 mediates feedback inhibition of the leptin receptor via Tyr985.

During leptin signaling, each of the phosphorylated tyrosine residues on the long form of the leptin receptor (LRb) mediates distinct signals. Phosphorylated Tyr(1138) binds STAT3 to mediate its tyrosine phosphorylation and transcriptional activation, while phosphorylated Tyr(985) binds the tyrosine phosphatase SHP-2 and reportedly mediates both activation of ERK kinases and inhibition of LRb-mediated STAT3 activation. We show here that although mutation of Tyr(985) does not alter STAT3 signaling by erythropoietin receptor-LRb (ELR) chimeras in transfected 293 cells at short times of stimulation, this mutation enhances STAT3 signaling at longer times of stimulation (>6 h). These data suggest that Tyr(985) may mediate feedback inhibition of LRb signaling by an LRb-induced LRb inhibitor, such as SOCS3. Indeed, SOCS3 binds specifically to phosphorylated Tyr(985) of LRb, and SOCS3 fails to inhibit transcription by ELR following mutation of Tyr(985), suggesting that SOCS3 inhibits LRb signaling by binding to phosphorylated Tyr(985). Additionally, overexpression of SOCS3, but not SHP-2, impairs ELR signaling, and the overexpression of SHP-2 blunts SOCS3-mediated inhibition of ELR signaling. Thus, our data suggest that in addition to mediating SHP-2 binding and ERK activation during acute stimulation, Tyr(985) of LRb mediates feedback inhibition of LRb signaling by binding to LRb-induced SOCS3.

Incidence of herpes genitalis in Northern Ireland in 1973-83 and herpes simplex types 1 and 2 isolated in 1982-4.

During 1973 - 83 there was a pronounced rise in the number of new cases of herpes genitalis in Northern Ireland. This study of 127 patients with herpes genitalis shows that 30% had herpes simplex virus type 1 (HSV 1) and 70% had herpes simplex virus type 2 (HSV 2) infections. Of 41 sexual contacts who attended, only seven had herpes genitalis (caused in each case by HSV 2); another patient had a history of genital lesions, and one other of oral lesions, but HSV was not isolated from either patient. None of the other sexual contacts had a history of oral or genital infection. Of 31 women with herpes genitalis who consented to undergoing cervical cytology, five had atypical changes (all had primary herpes genitalis). Of these, four were infected with HSV 1 and one with HSV 2.

Crohn's disease of the vulva--two further cases.

Crohn's disease of the vulva is a rare disease, only eight cases having been described in the literature (Parks, Morson & Pegum, 1965; Mountain, 1970; Ansell & Hogbin, 1973; Devroede et al., 1975; Kao, Paulson & Askin, 1975; Levine, Barton & Grier, 1982). Two additional cases are presented, one of whom is the sixth reported with metastatic Crohn's disease of the vulva.

HLA tissue typing and chronic vulval dystrophy.

Tissue typing was performed on 25 patients who attended the Royal Victoria Hospital with chronic vulval dystrophy (CVD). Age-matched control groups who had pernicious anaemia only and achlorhydria only were also tissue typed as these conditions had been found more frequently in our patients with CVD. When these three groups were compared with age-matched control groups of blood donors and patients with gynaecological disorders other than CVD, no specific tissue type was found in patients with CVD nor in those with pernicious anaemia or achlorhydria only.

Vulval dystrophies: new approaches.

In describing vulval skin changes, all terms such as leucoplakia, kraurosis vulvae and lichen sclerosus et atrophicus should be discarded in favour of 'chronic vulval dystrophy'. Initial biopsy is mandatory to establish the precise diagnosis. From a review of the literature and from our own studies we believe that vulval dystrophy is not usually a premalignant condition, a risk of carcinoma exiting only in dystrophic vulvas with associated atypia. For such patients the treatment is local vulvectomy; otherwise, because of the high rate of recurrence of chronic vulval dystrophy following surgery, the treatment should primarily be medical. Gastrointestinal peptides have been isolated from the vulval skin and a working hypothesis of the aetiology of vulval dystrophy is presented.

Rheumatoid arthritis, ankylosing spondylitis, and Reiter's syndrome occurring simultaneously. Case report.

Features of rheumatoid arthritis, ankylosing spondylitis and Reiter's disease occurred simultaneously in the same patient. This is a rare finding and appears to be the first published report of such a case.

PUVAtherapy for psoriasis and other skin diseases an initial report.

Fifty-two patients with severe and resistant psoriasis were treated with 8-methoxypsoralen followed by high intensity long wave ultraviolet light over a 12-month period at the Royal Victoria Hospital, Belfast. One hundred per cent clearing of the plaques of psoriasis was obtained with an average dose of energy of 53.5 joules in 43 (96 per cent) of 45 patients and the other two materially improved. Seven are still in the clearing phase. Early side effects were uncommon. There was no clinically significant change in laboratory or ophthalmological findings. Of the nine patients who complained of arthritis, four had radiological evidence and one showed radiological improvement after PUVA. In this study all seven patients who had been using large doses of topically applied steroid cream (up to 200 g Dermovate per week for two years) did not show adrenal suppression.

The central action of clonidine and its antagonism.

1. We have examined the central actions of clonidine (2-(2-6-dichlorphenylamine)-2-imidazoline hydrochloride). It has been confirmed that when infused into the vertebral artery at 2 mug/min, it caused a decrease in blood pressure and a slight increase in heart rate. The same dose given intravenously or into the carotid artery had no effect.2. Intravertebral clonidine also greatly reduced the reflex response to carotid occlusion and the effects of an intravertebral infusion of angiotensin (1 ng/kg)/min.3. This central action of clonidine was antagonized by the adrenergic neurone blocking drug bethanidine (4-5 mg/kg intravenously) even after the cervical cord had been transected at C(4)-C(6) suggesting that bethanidine also has central actions.4. Other drugs which also antagonized the central effects of clonidine were guanethidine (4-5 mg/kg intravenously), bretylium (10 mg/kg intravenously) and phentolamine (0.2 mg/kg intravenously).5. It is suggested that there are central adrenergic neurones which inhibit cardiovascular autonomic reflexes and that the central autonomic effects of clonidine are due to stimulation of inhibitory adrenoceptors. The antagonism by adrenergic neurone blocking drugs of the effect of clonidine could therefore be due to blockade of these inhibitory pathways.6. The central action of clonidine could only be demonstrated when a high concentration was infused into the vertebral artery and could not be shown with oral doses of (20 mug/kg)/day for seven days. It is concluded that the hypotensive action of therapeutic doses is unlikely to be due to the central action of clonidine.

Central autonomic effects of prostaglandin F2 alpha on the cardiovascular system of the dog.

1. Prostaglandin F(2alpha) infused into the vertebral artery of the anaesthetized greyhound in doses which had no effect when given intravenously ((8-64 ng/kg)/min) caused an increase in blood pressure and heart rate.2. This response was not significantly altered by beta-adrenoceptor blockade with propranolol (10 mg i.v.) or by cervical cord section at C(4-6).3. The tachycardia was abolished and the pressor response greatly reduced by vagotomy or atropine (250 mug/kg i.v.).4. The pressor response which remained after vagotomy was abolished by subsequent sympathetic blockade with bethanidine (2-3 mg/kg i.v.) or bretylium (10 mg/kg i.v.).5. In contrast to the effects of propranolol or cervical cord section bethanidine (4-5 mg/kg i.v.) or bretylium (10 mg/kg i.v.) significantly reduced blood pressure and heart rate responses to intravertebral prostaglandin F(2alpha). This result suggests that bethanidine and bretylium have some central actions.6. It is concluded that the cardiovascular effects of intravertebral infusions of prostaglandin F(2alpha) are mediated by the autonomic nervous system and that the preferential pathway is withdrawal of vagal tone to the heart.

Cardiovascular effects of prostaglandins mediated by the central nervous system of the dog.

1. Prostaglandins A(1), E(1), F(1alpha) and F(2alpha) were infused into the vertebral artery of the chloralose-anaesthetized greyhound and the resulting cardiovascular responses were compared with those obtained on intravenous and intracarotid infusions in the same dose range.2. Infusions of PGF(2alpha) intravertebrally (4-64 (ng/kg)/min) caused an increase of blood pressure, tachycardia and a fall of central venous pressure. Cardiac output was increased and peripheral resistance was essentially unchanged. There was never any response to intravenous or intracarotid PGF(2alpha) infusions in this dose range.3. PGF(1alpha) was found to have similar effects to PGF(2alpha) but it was much less potent.4. PGE(1) infusions (4-360 (ng/kg)/min) into the vertebral artery caused a tachycardia which was greater than that obtained with intracarotid or intravenous infusions, but there was no significant effect on blood pressure.5. Infusions of PGA(1) caused a small fall of blood pressure accompanied by an increase of heart rate and the dose response relationships were similar for all three routes of administration.6. It is concluded that some prostaglandins can activate cardioregulatory centres within the territory of distribution of the vertebral artery. Prostaglandin F(2alpha) is the most potent of these.