Multigene testing of moderate-risk genes: be mindful of the missense.

BACKGROUND: Moderate-risk genes have not been extensively studied, and missense substitutions in them are generally returned to patients as variants of uncertain significance lacking clearly defined risk estimates. The fraction of early-onset breast cancer cases carrying moderate-risk genotypes and quantitative methods for flagging variants for further analysis have not been established. METHODS: We evaluated rare missense substitutions identified from a mutation screen of ATM, CHEK2, MRE11A, RAD50, NBN, RAD51, RINT1, XRCC2 and BARD1 in 1297 cases of early-onset breast cancer and 1121 controls via scores from Align-Grantham Variation Grantham Deviation (GVGD), combined annotation dependent depletion (CADD), multivariate analysis of protein polymorphism (MAPP) and PolyPhen-2. We also evaluated subjects by polygenotype from 18 breast cancer risk SNPs. From these analyses, we estimated the fraction of cases and controls that reach a breast cancer OR≥2.5 threshold. RESULTS: Analysis of mutation screening data from the nine genes revealed that 7.5% of cases and 2.4% of controls were carriers of at least one rare variant with an average OR≥2.5. 2.1% of cases and 1.2% of controls had a polygenotype with an average OR≥2.5. CONCLUSIONS: Among early-onset breast cancer cases, 9.6% had a genotype associated with an increased risk sufficient to affect clinical management recommendations. Over two-thirds of variants conferring this level of risk were rare missense substitutions in moderate-risk genes. Placement in the estimated OR≥2.5 group by at least two of these missense analysis programs should be used to prioritise variants for further study. Panel testing often creates more heat than light; quantitative approaches to variant prioritisation and classification may facilitate more efficient clinical classification of variants.

The thermally injured ear: a systematic approach to reconstruction.

The ears are special and unique structures that ordinarily are ignored during our daily routines. A thermal injury of relatively moderate proportions can irreparably alter their shape and appearance. Many reconstructive techniques have been garnered to restore these delicate structures. Herculean efforts will consistently fall short of these goals if tissue preservation is not in the forefront of our treatment protocol. Iontophoresis coupled with topical antimicrobial agents have been shown to ameliorate cartilage loss, allowing for delayed operative intervention, when more consistent results may be obtained. Early radical resection of ear soft tissue or structural cartilage should be an endeavor of last resort in all but a few instances, such as unresponsive suppurative chondritis. Segmental restoration of the injured ear allows for dismantling of the various parts to recreate the whole. A facsimile of the original is possible if the major visible distinguishing landmarks are salvaged. Flap resurfacing of exposed cartilage yields closer tissue match, color, and texture, and it affords a greater proclivity for survival than does graft closure. Sacrifice of the helical lip relegates the ear to that of a flat, less-than-optimal appearance. Tissue expansion coupled with cutaneous flap closure will usually preclude this situation. Skin grafting is a valuable tool in our armamentarium but should be used judiciously in situations where graft coverage is either necessary or desired to produce enhanced results. In such instances, the thickness of the graft must be considered, ranging from an almost translucent quality for the antihelix to that of a much thicker graft for the helix. Application and direction of the graft will be determined by the underlying surface contours. Until the reconstruction has been completed, burn patients and their families usually do not view the injured ear that has been snatched from the fires of adversity. The unveiling frequently effects a felicitous atmosphere, because they perceive a relatively normal-looking ear. The final result is all that matters.

Fluoxetine-induced psoriasis.

BACKGROUND: A number of medications have been reported to induce psoriasis. We report two cases of fluoxetine-related psoriasis and discuss similarities between lithium-, trazodone hydrochloride-, and fluoxetine-induced psoriasis. OBSERVATIONS: Two women being treated for depression with fluoxetine developed psoriasis after 6 and 12 months' exposure. This time frame is clinically similar to that observed with lithium-induced psoriasis. CONCLUSIONS: The occurrence of lithium- and fluoxetine-induced psoriasis may not be random. Both drugs modulate serotonergic function, a factor that may contribute to the pathophysiology of psoriasis. If a patient on acute or long-term fluoxetine therapy develops psoriasis, the drug should be considered as a possible etiologic agent.

NMR water-proton spin-lattice relaxation time of human red blood cells and red blood cell suspensions.

NMR water-proton spin-lattice relaxation times were studied as probes of water structure in human red blood cells and red blood cell suspensions. Normal saline had a relaxation time of about 3000 ms while packed red blood cells had a relaxation time of about 500 ms. The relaxation time of a red cell suspension at 50% hematocrit was about 750 ms showing that surface charges and polar groups of the red cell membrane effectively structure extracellular water. Incubation of red cells in hypotonic saline increases relaxation time whereas hypertonic saline decreases relaxation time. Relaxation times varied independently of mean corpuscular volume and mean corpuscular hemoglobin concentration in a sample population. Studies with lysates and resealed membrane ghosts show that hemoglobin is very effective in lowering water-proton relaxation time whereas resealed membrane ghosts in the absence of hemoglobin are less effective than intact red cells.

Nd:YAG laser posterior capsulotomy does not produce elevation of intraocular pressure in cynomolgus monkeys.

The mechanism of the intraocular pressure (IOP) elevation commonly seen in patients following neodymium (Nd):YAG laser posterior capsulotomy is unclear. Substance P, a potent polypeptide that is released into the eye after trigeminal nerve stimulation, may be the cause. In rabbits, topical application of nitrogen mustard causes a rise in IOP which is blocked by capsaicin, a presumed substance P depletor. In the present study, six eyes of three cynomolgus monkeys underwent extracapsular lensectomies. After 2 to 3 months, capsaicin was administered by retrobulbar injection on one side of each animal, and vehicle on the contralateral side. One day later, Nd:YAG laser posterior capsulotomies were performed using 31 mJ (total energy) per eye. Diurnal IOP measurements were made before and after the retrobulbar injections and the capsulotomies. Ten weeks later, laser capsulotomies were repeated using 200 mJ/eye without pretreatment with any potential blockers. None of the six eyes, each undergoing two separate capsulotomies 10 weeks apart, showed a postoperative rise in IOP. These results demonstrate that the cynomolgus monkey is a poor model for studying IOP elevation that often occurs following Nd:YAG laser posterior capsulotomy.

Multiple dosing of prostaglandin F2 alpha or epinephrine on cynomolgus monkey eyes. I. Aqueous humor dynamics.

After obtaining baseline intraocular pressure (IOP) measurements for 1 week, prostaglandin (PG) F2 alpha (250 micrograms in 50 microliters saline) or epinephrine 2% solution (50 microliters) was topically applied twice daily for 2 weeks to one eye of six cynomolgus monkeys for each agent tested. Contralateral control eyes received their respective vehicles. PGF2 alpha significantly reduced IOP beginning 2 to 3 hr after the first dose, persisting thereafter. A significant (P less than 0.05) hypotensive effect remained for at least 10 hr after the first dose and at least 14 hr after the sixth dose. At 4 hr after the seventh dose, the mean reduction was 10.2 +/- 3.5 (+/- SD) mmHg below baseline (P less than 0.0025). At this time, there was also a significant (P less than 0.01) mean reduction of IOP in the contralateral vehicle-treated eyes of 6.0 +/- 3.3 (+/- SD) mmHg below baseline, which did not appear to be secondary to diurnal fluctuations, repeated tonometry, experimental manipulation, or inadvertent drug transfer. Epinephrine significantly (P less than 0.05) reduced IOP beginning 3 hr after the first dose, but this reduction was minimal and not consistent. Neither PGF2 alpha nor epinephrine altered aqueous flow as measured by fluorophotometry 2 to 6 hr after the fifth dose. Outflow facility could not be assessed by indentation tonography because IOP was often too low at the time of measurement. Whereas PGF2 alpha did not alter pupil size, epinephrine caused significant pupillary dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Variations in red blood cell proton T1 relaxation times that correspond to menstrual cycle changes.

A study was made of the relationship of proton T1 relaxation times and stage of the menstrual cycle. Preliminary data show that these indicators of red blood cell hydration status may be useful as objective markers of premenstrual tension.

Amino acids in bipolar affective disorders: increased glycine levels in erythrocytes.

The authors measured the concentrations of 20 amino acids in the erythrocytes and plasma of 13 female bipolar patients and 10 female normal controls. The concentration of glycine in the erythrocyte was significantly elevated in the patient group. No differences were present in the plasma. Preliminary findings indicate that the high glycine levels were present in patients who were depressed, manic, or in remission and were unaffected by electroshock therapy.