Loss-of-function mutations in IGSF1 cause an X-linked syndrome of central hypothyroidism and testicular enlargement.

Congenital central hypothyroidism occurs either in isolation or in conjunction with other pituitary hormone deficits. Using exome and candidate gene sequencing, we identified 8 distinct mutations and 2 deletions in IGSF1 in males from 11 unrelated families with central hypothyroidism, testicular enlargement and variably low prolactin concentrations. IGSF1 is a membrane glycoprotein that is highly expressed in the anterior pituitary gland, and the identified mutations impair its trafficking to the cell surface in heterologous cells. Igsf1-deficient male mice show diminished pituitary and serum thyroid-stimulating hormone (TSH) concentrations, reduced pituitary thyrotropin-releasing hormone (TRH) receptor expression, decreased triiodothyronine concentrations and increased body mass. Collectively, our observations delineate a new X-linked disorder in which loss-of-function mutations in IGSF1 cause central hypothyroidism, likely secondary to an associated impairment in pituitary TRH signaling.

A comparison of dose distribution from Manchester-style and Fletcher-style intracavitary brachytherapy applicator systems in cervical cancer.

PURPOSE: During intracavitary brachytherapy (ICBT) for cervical cancer, the choice of applicator system remains rather arbitrary. However, as the applicator geometry may play an important role in dose distribution, thereby improving the therapeutic ratio, this study was conducted to compare the Manchester-style and Fletcher-style applicator systems. MATERIAL AND METHODS: After completion of EBRT, 22 patients with cervical cancer (stage IIA-IIIB) underwent intracavitary brachytherapy. Two different types of applicators: Manchester-style and Fletcher-style were used for each patient for alternate insertions. The purpose was to compare the dose distribution obtained when two different applicators were applied to the same patient. CT based computerized treatment planning was done and dose was prescribed to point A. After optimization, height, width and thickness of the 100% isodose curve, as well as the 100% isodose volume were noted. Dose received by the urinary bladder and rectum were noted. RESULTS: The 100% isodose volume and its maximum width were significantly greater (P value < 0.0001 in both occasions) when Manchester-style applicator was used. However, the dose received by 0.1 cc, 1.0 cc and 2.0 cc of the urinary bladder were all significantly greater (P value < 0.0001) with the Manchester-style applicator. No significant difference was found in rectal doses. CONCLUSIONS: The larger 100% isodose volume, as well as the greater width achieved with the use of Manchester-style applicator can be helpful in circumstances where the tumour is large in size. However, this must be balanced against the increased dose received by the urinary bladder.

Inhibition of Th2 adaptive immune responses and pulmonary inflammation by leukocyte Ig-like receptor B4 on dendritic cells.

We previously established that the inhibitory receptor LILRB4 mitigates LPS-induced, neutrophil-dependent pathologic effector mechanisms in inflammation. We now report that LILRB4 on dendritic cells (DCs) counterregulates development of an adaptive Th2 immune response and ensuing inflammation in a model of allergic pulmonary inflammation, initiated by inhalation sensitization with OVA and LPS followed by airway challenge with OVA. We found that Lilrb4(-/-) mice had significantly exacerbated eosinophilic pulmonary inflammation, as assessed in bronchoalveolar lavage and lung tissue, as well as elevated levels of OVA-specific IgE and Th2 cytokines produced by OVA-restimulated lymph node cells. LILRB4 was preferentially expressed on MHC class II(high)CD86(high) OVA-bearing DCs in lung-draining lymph nodes after sensitization or challenge. Moreover, the lymph nodes of Lilrb4(-/-) mice had significantly more of these mature DCs after challenge with OVA, which was accompanied by significantly more IL-4-producing lymphocytes, compared with Lilrb4(+/+) mice. Sensitization of naive Lilrb4(+/+) mice by transfer of OVA-LPS-pulsed Lilrb4(-/-) bone marrow-derived DCs was sufficient to confer exacerbated allergic lung pathology upon challenge with OVA, compared with mice that received Lilrb4(+/+) bone marrow-derived DCs. Our findings establish that maturation and migration of pulmonary DCs to lymph nodes in response to Ag and an innate immune stimulus is associated with upregulated expression of LILRB4. In addition, this receptor attenuates the number of these mature DCs and attendant IL-4-producing lymphocytes in the lymph nodes, and accordingly, the ability of DCs to elicit pathologic Th2 pulmonary inflammation.

Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases.

BACKGROUND: Hypersensitivity reactions (HSRs) to chemotherapeutic drugs, including mAbs, often require that the provoking medication be discontinued, thus raising a dilemma for the caregiver: further use could precipitate a severe, even fatal, allergic reaction on re-exposure, but alternative drugs might be poorly tolerated or much less effective compared with the preferred agent. OBJECTIVE: We have developed a standardized rapid desensitization protocol for achieving temporary tolerization to drug allergens. In this study we evaluate the safety and efficacy of this protocol. METHODS: Ninety-eight patients who had HSRs in response to treatment with carboplatin, cisplatin, oxaliplatin, paclitaxel, liposomal doxorubicin, doxorubicin, or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records. RESULTS: Of the 413 desensitizations performed, 94% induced mild or no reactions. No life-threatening HSRs or deaths occurred during the procedure, and all patients received their full target dose. Most reactions occurred during the first desensitization. Reactions were most commonly reported at the last step of the protocol. Desensitizations through the intravenous and intraperitoneal routes were equally effective. CONCLUSIONS: Our standardized 12-step protocol for rapid drug desensitization is safe and effective and has been adopted as the standard of care at our institutions in treating patients with HSRs to chemotherapeutic drugs, including mAbs.