Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

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Diabetes mellitus in patients receiving hypertransfusion for thalassemia major is usually attributed to damage to beta cells. To determine whether iron overload leads to insulin resistance before the development of insulin deficiency, insulin was infused (by euglycemic insulin-clamp technique) into 12 children with thalassemia (4 of whom were prepubertal, and 8 pubertal) who had normal or only moderately impaired glucose tolerance and who were receiving chelation therapy. Although insulin-stimulated glucose metabolism in the prepubertal children with thalassemia was similar to that in controls (normal prepubertal children) (319 +/- 23 vs. 314 +/- 41 mg per square meter of body-surface area per minute, P not significant), the response to insulin was markedly impaired in the pubertal children with thalassemia (155 +/- 18 vs. 224 +/- 15 mg per square meter per minute in normal pubertal controls, P less than 0.01). Plasma insulin levels rose excessively after oral glucose administration in the pubertal subjects with thalassemia, but not in the prepubertal patients (P less than 0.001). Furthermore, in response to a standard hyperglycemic stimulus, insulin levels in the pubertal patients rose to two to three times greater than normal and C-peptide levels became significantly elevated. Our data suggest that insulin resistance and increased insulin secretion develop in older children with thalassemia treated with long-term hypertransfusion therapy before the development of diabetes.

The paper describes in detail the operative hazards and post–operative complications of ovariohysterectomy and indicates how they may be treated and possibly avoided. Résumé. La communication décrit en détail les risques opératoires et les complications postopératoires d'ovariotomie et d'hysterectomie, et indique comment on peut les traiter et probablement les éviter. Zusammenfassung. Ein Bericht der in Einzelheit die operativen Gefahren und postopera‐tiven Komplikationen von einer Overiohysterektomie beschreibt und hinweist wie man sie behandelt und moglicherweise vermeidet.

Summary A retrospective analysis was performed on 48 cases of suspected neoplasia involving the equine external genitalia. Forty nine squamous cell carcinomata (SCC) and 23 squamous papillomata (SP) were identified. Two cases of epithelial hyperplasia and one case of habronemiasis were also recognised histopathologically. The glans penis was the most common site of tumour development accounting for 53 per cent of cases of SCC and 61 per cent of SP. The urethral diverticulum, urethral process or urethra was involved in 27.6 per cent (8/29) of cases of SCC. Twelve per cent (5/41) of cases of SCC were confirmed to have metastatic involvement of the local lymph nodes. Papillomata showing pre‐malignant changes were identified in five cases. Seventy five per cent (36/48) of the animals presented were ponies. All were geldings, mean age 16.5 years. Penile amputation and urethrostomy, preputial ablation and proximal urethrostomy or local excision were used in the surgical management of these animals; three cases were inoperable and destroyed at presentation. Oedema, haemorrhage and stenosis of the urethrostomy site were encountered as post operative complications. Sixty six per cent (6/9) of animals with SCC of the glans penis (without urethral involvement), which had a known history over the follow up period, treated by penile amputation and urethrostomy survived for longer than 18 months. Similarly, of those with urethral involvement only 28.6 per cent (2/7) survived for a similar follow‐up period. SCC not uncommonly affects the external genitalia of aged pony geldings and frequently the glans penis. If the lesion is identified before local metastasis occurs, penile amputation and urethrostomy is indicated and the prognosis is favourable.

Butyrate analogues have been shown to increase fetal hemoglobin (HbF) production in vitro and in vivo. Sodium phenylbutyrate (SPB), an oral agent used to treat individuals with urea-cycle disorders, has been shown to increase HbF in nonanemic individuals and in individuals with sickle cell disease. We have treated eleven patients with homozygous beta thalassemia (three transfusion dependent) and one sickle-beta- thalassemia patient with 20 g/d (forty 500-mg tablets) of SPB for 41 to 460 days. All patients showed an increase in the percent of F reticulocytes associated with treatment, but only four patients responded by increasing their Hb levels by greater than 1 g/dL (mean increase, 2.1 g/dL; range, 1.2 to 2.8 g/dL). None of the transfusion- dependent thalassemia subjects responded. Increase in Hb was associated with an increase in red blood cell number (mean increase, 0.62 x 10(12)/L), and mean corpuscular volume (mean increase, 6 fL). Changes in percent HbF, absolute HbF levels, or alpha- to non-alpha-globin ratios as measured by levels of mRNA and globin protein in peripheral blood did not correlate with response to treatment. Response to treatment was not associated with the type of beta-globin mutation, but baseline erythropoietin levels of greater than 120 mU/mL was seen in all responders and only two of eight nonresponders to SPB. Compliance with treatment was greater than 90% as measured by pill counts. Side effects of the drug included weight gain and/or edema caused by increase salt load in 2/12, transient epigastric discomfort in 7/12, and abnormal body odor in 3/12 subjects. Two splenectomized patients who were not on prophylactic antibiotics developed sepsis while on treatment. We conclude that SPB increases Hb in some patients with thalassemia, but the precise mechanism of action is unknown.

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