Novel Inactivating Mutation of the FSH Receptor in Two Siblings of Indian Origin With Premature Ovarian Failure.

CONTEXT: Inactivating FSH receptor (FSHR) mutations can affect ovarian function, resulting in variable clinical presentations ranging from primary amenorrhea to premature menopause. FSHR mutations have been largely reported in the Finnish population, but in patients of Asian Indian descent, the incidence of FSHR mutations is extremely rare. CASE DESCRIPTION: Two female siblings of Indian descent were diagnosed with primary ovarian failure and hypergonadotropic hypogonadism. The daughters were the result of a consanguineous marriage between second cousins. A combination of comparative genomic hybridization plus single nucleotide polymorphism array and whole exome sequencing was conducted on the family to identify potential causative genetic variants. CONCLUSION: Both daughters were found to have a novel pathogenic variant in FSHR (c.1253T>G, p.Ile418Ser), inherited as an autosomal recessive trait from heterozygous parents. This loss of function mutation is located in exon 10 of FSHR affecting the second transmembrane helix of the FSHR protein. The transmembrane domain of FSHR is highly conserved across species and is involved in signal transduction. The FSHR c.1253T>G variant is next to a known pathogenic variant, rs12190966 (c.1255G>A, p.Ala419Thr), previously reported in a Finnish woman with primary amenorrhea.

Fabrication and evaluation of a near-infrared hyperspectral imaging system.

This paper describes modifications to a hyperspectral imaging microscope that extend its capabilities into the near-infrared (950-1300 nm). The major changes include installing a grating, charge-coupled device camera, and lenses and filters appropriate for infrared wavelengths. Calibration of the system and validation with lead sulfide quantum dots of known emission wavelength is reported. Cells from the breast carcinoma cell line SkBr3 were scanned with lead sulfide quantum dots that emit at 1100 nm as the background and an image which contains the integrated spectral data is presented. We also demonstrate that this instrument is capable of detecting the photoluminescence spectra of single-walled carbon nanotubes dispersed in aqueous solution.

Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients.

This study was designed to (a) estimate the contribution of tacrolimus nephrotoxicity to episodes of renal allograft dysfunction investigated by needle biopsy, (b) describe the temporal evolution of nephrotoxicity and its response to therapy, and (c) ascertain how often renal dysfunction is associated with concurrent extra-renal toxicity. Patients were selected based on a rising serum creatinine, normal ultrasound, and biopsy findings leading to a reduction in the dose of tacrolimus and a fall in serum creatinine. Twenty two (17%) cases of nephrotoxicity were identified amongst 128 consecutive kidney transplant biopsies with sufficient clinical data for analysis. There were 13 males and 9 females, 17-75 yr in age. Tacrolimus was administered initially as a 0.075-0.1 mg/kg/d IV continuous infusion followed by an oral dose of 0.15 mg/kg twice daily. The onset of nephrotoxicity in this study occurred 1-156 wk post-operatively. The mean baseline creatinine was 212.2 +/- 168.0 mumol/l (range 88.4-875.2) and rose 40.6% +/- 14.2% (range 11-66) during episodes of nephrotoxicity (p < 0.001). The highest recorded plasma and whole-blood tacrolimus levels during the toxic episodes were respectively 2.7 +/- 0.8 ng/ml (range 1.1-3.5) and 31.6 +/- 10.6 ng/ml (range 14.5-50.5). The drug levels were considered to be beyond the therapeutic range in 18/22 (82%) patients. The highest tacrolimus level preceeded the rise in serum creatinine in 20 cases by an interval of 1.6 +/- 1.8 d. A mean reduction in tacrolimus dosage of 41% +/- 21% (range 11-89) led to a 86% +/- 18% (range 45-100) fall in the serum creatinine within 1-14 d (p < 0.001). Interactions between tacrolimus and clarithromycin, diltiazem, or itraconazole modified the pharmakokinetic parameters in three cases. Serum potassium > 5.0 mequiv/l was recorded in 9/22 (41%) cases. Three or more elevations in blood glucose > 7.7 mmol/l (140 mg/dl) were recorded in 4/11 (36%) non-diabetic patients. Hand tremors were seen in two (9%) cases and elevated diastolic blood pressure > 90 mmHg in seven (32%) patients. In conclusion, tacrolimus nephrotoxicity accounted for 17% of graft dysfunction episodes investigated by biopsy. Concurrent hyperglycemia, hyperkalemia, or tremors were noted in several patients. Nephrotoxicity responded well to reduction in the drug dosage.