How reassuring is a normal breast ultrasound in assessment of a screen-detected mammographic abnormality? A review of interval cancers after assessment that included ultrasound evaluation.

AIM: To review factors resulting in a false-negative outcome or delayed cancer diagnosis in women recalled for further evaluation, including ultrasound, after an abnormal screening mammogram. MATERIALS AND METHODS: Of 646,692 screening mammograms performed between 1 January 1995 and 31 December 2004, 34,533 women were recalled for further assessment. Nine hundred and sixty-four interval cancers were reported in this period. Forty-six of these women had been recalled for further assessment, which specifically included ultrasound evaluation in the preceding 24 months, and therefore, met the inclusion criteria for this study. Screening mammograms, further mammographic views, ultrasound scans, clinical findings, and histopathology results were retrospectively reviewed by two consultant breast radiologists. RESULTS: The interval cancer developed in the contralateral breast (n=9), ipsilateral breast, but different site (n=6), and ipsilateral breast at the same site (n=31) as the abnormality for which they had recently been recalled. In the latter group, 10 were retrospectively classified as a false-negative outcome, nine had a delay in obtaining a biopsy, and 12 had a delay due to a non-diagnostic initial biopsy. Various factors relating to these outcomes are discussed. CONCLUSION: Out of 34,533 women who attended for an assessment visit and the 46 women who subsequently developed an interval breast cancer, 15 were true interval cancers, 10 had a false-negative assessment outcome, and 21 had a delay to cancer diagnosis on the basis of a number of factors. When there is discrepancy between the imaging and histopathology results, a repeat biopsy rather than early follow-up would have avoided a delay in some cases. A normal ultrasound examination should not deter the radiologist from proceeding to stereotactic biopsy, if the index mammographic lesion is suspicious of malignancy.

Postnatal development of a large auditory nerve terminal: the endbulb of Held in cats.

The endbulbs of Held are formed by the ascending branches of myelinated auditory nerve fibers and represent one of the largest synaptic endings in the brain. Most of the developmental changes in structure occur during the first 30 postnatal days of age. The neonatal endbulb begins as a flattened expansion with many filopodia, resembling a growth cone and characterized by numerous puncta adherentia and synapses associated with small postsynaptic densities; the most impressive feature of the ending at this age is its highly irregular plasma membrane that interdigitates with that of the postsynaptic spherical bushy cell. During these first 30 days, the number of puncta adherentia diminishes, postsynaptic densities nearly double in size, intermembraneous cisternae emerge, and plasma membranes flatten. These features endow the endbulb with an adult-like appearance. On the other hand, synaptic vesicle density increases progressively from approximately 50/microm2 at birth to 100/microm2 at adulthood. Mitochondria size remains constant over this developmental period but mitochondrial volume fraction increases until 60 days postnatal. Although many features of endbulb morphology stabilize by 30 days, other features suggest that endbulb development continues into the third month of age. Many of these observations correlate with the maturation of physiological response properties and suggest issues for further study.

Contact allergy to corticosteroids in patients using inhaled or intranasal corticosteroids for allergic rhinitis or asthma.

BACKGROUND: Patients using topically applied corticosteroids are at risk of developing allergic contact hypersensitivity. OBJECTIVE: To assess prevalence of allergic contact hypersensitivity reactions to inhaled or intranasal corticosteroids. METHODS: A prospective study of 30 adult patients using inhaled or intranasal corticosteroids for conditions such as allergic rhinitis was performed. We used epicutaneous patch testing to determine the prevalence of allergic contact hypersensitivity to corticosteroids and common additives (propylene glycol and benzalkonium chloride) in inhaled and nasal corticosteroid preparations in this population. RESULTS: Of 30 patients, 4 (13%) had positive patch test results. 3 (10%) were allergic reactions and 1 (3%) was an irritant reaction. Half of the reactions were to a corticosteroid (budesonide) and half were to a common preservative in nasal preparations (benzalkonium chloride). CONCLUSION: This study supports other clinical evidence that contact dermatitis/mucositis from inhaled or intranasal corticosteroid products can occur. The corticosteroids or added agents such as preservatives can be causative and may result in allergic or irritant reactions, which can be relevant to clinical symptoms.

Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea.

BACKGROUND: Hypoglossal nerve stimulation has been demonstrated to relieve upper airway obstruction acutely, but its effect on obstructive sleep apnea is not known. OBJECTIVE: To determine the response in obstructive sleep apnea to electrical stimulation of the hypoglossal nerve. METHODS: Eight patients with obstructive sleep apnea were implanted with a device that stimulated the hypoglossal nerve unilaterally during inspiration. Sleep and breathing patterns were examined at baseline before implantation and after implantation at 1, 3, and 6 months and last follow-up. RESULTS: Unilateral hypoglossal nerve stimulation decreased the severity of obstructive sleep apnea throughout the entire study period. Specifically, stimulation significantly reduced the mean apnea-hypopnea indices in non-rapid eye movement (mean +/- SD episodes per hour, 52.0 +/- 20.4 for baseline nights and 22.6 +/- 12.1 for stimulation nights; P<.001) and rapid eye movement (48.2 +/- 30.5 and 16.6 +/- 17.1, respectively; P<.001) sleep and reduced the severity of oxyhemoglobin desaturations. With improvement in sleep apnea, a trend toward deeper stages of non-rapid eye movement sleep was observed. Moreover, all patients tolerated long-term stimulation at night and did not experience any adverse effects from stimulation. Even after completing the study protocol, the 3 patients who remained free from stimulator malfunction continued to use this device as primary treatment. CONCLUSION: The findings demonstrate the feasibility and therapeutic potential for hypoglossal nerve stimulation in obstructive sleep apnea.

Oral corticosteroid use is effective for cutaneous hemangiomas: an evidence-based evaluation.

OBJECTIVES: To determine the efficacy of systemic corticosteroid therapy in treating enlarging, problematic cutaneous hemangiomas and to assess the relationship of dose to response and adverse effects. DESIGN: A quantitative systematic literature review was performed and inclusion and exclusion criteria were applied. SETTING: Patients were treated in primary care, referral centers, and institutional practices. Most patients were ambulatory, although some required hospitalization. PATIENTS: Inclusion criteria were original case series with a minimum of 5 patients with enlarging, problematic cutaneous hemangiomas treated with systemic corticosteroids. Exclusion criteria were being older than 2 years, receiving simultaneous other treatments, being lost to follow-up, or having insufficient information. Twenty-four original case series met inclusion criteria; 10 case series remained (184 patients) after exclusion criteria were applied. INTERVENTION: Patients were given a mean prednisone equivalent daily dose of 2.9 mg/kg (95% confidence interval [CI], 2.7-3.1 mg/kg) for a mean of 1.8 months (95% CI, 1.5-2.2 months). MAIN OUTCOME MEASURES: Response and rebound rates and dose-response and adverse effects-response relationships in responders vs nonresponders. RESULTS: Response was 84% (95% CI, 78%-89%; range, 60%-100%) and rebound was 36% (95% CI, 29%-44%; range, 0%-65%). A significant difference was found between the mean dose administered to responders vs nonresponders (P<.001). No significant difference was observed as to the occurrence of adverse effects (P =.3). CONCLUSION: Systemic corticosteroid treatment seems to be effective for problematic cutaneous hemangiomas of infancy.

Promoter strength in adenovirus transducing vectors: down-regulation of the adenovirus E1A promoter in 293 cells facilitates vector construction.

Most adenovirus transducing vectors have the cytomegalovirus major immediate-early (CMV) or the Rous sarcoma virus long terminal repeat (RSV) promoter driving expression of the transgene. Both of these promoters are highly active in transfection and transduction assays in 293 cells, in which transducing vectors are constructed and grown, and in HeLa cells. The CMV promoter exhibits rapid activation while the RSV promoter exhibits a lag prior to the onset of viral DNA replication in transduction assays. While the use of very strong promoters facilitates expression of the transgene, high-level expression of certain gene products hinders virus construction and growth. For such genes, the use of the adenovirus type 5 E1A promoter offers advantages. The E1A promoter exhibits modest activity in HeLa cells after transfection or transduction, but very little activity in 293 cells, suggesting that the E1A promoter would permit construction and growth of vectors encoding deleterious gene products that could not be constructed with the CMV and RSV promoters. This idea was tested through attempts to construct viruses encoding the immunoglobulin loop 6 and transmembrane regions of the prostaglandin F2alpha receptor regulatory protein (FPRP), a product that inhibits adenovirus vector construction for reasons that are not clear. Only the E1A promoter permitted construction and growth of the transducing vector encoding the fragment of FPRP.

Oral griseofulvin remains the treatment of choice for tinea capitis in children.

Tinea capitis is one of the most common infections of children. The standard treatment is griseofulvin. Itraconazole and terbinafine have in large part replaced griseofulvin in the treatment of onychomycosis and, in addition to fluconazole and ketoconazole, are evolving treatments for tinea capitis. The purpose of this review is to compare the efficacy, safety, and cost of oral antifungal agents for tinea capitis. Small, open-label studies of itraconazole, terbinafine, and fluconazole have reported encouraging results, suggesting that these drugs may be effective alternatives to griseofulvin; however, in large controlled studies griseofulvin continues to exhibit greater or equal efficacy. Ketoconazole appears to be the least efficacious. All five drugs appear relatively safe, however, only griseofulvin has a long track record of safety, is Food and Drug Administration (FDA) approved for the treatment of tinea capitis in children, and has the least known drug interactions. Fluconazole is FDA approved for use in children more than 6 months of age, yet not for the treatment of tinea capitis. Oral griseofulvin and terbinafine tablets are the least expensive of the antifungal agents; griseofulvin suspension is, however, more expensive than fluconazole suspension. For the combined reasons of efficacy, safety, and cost, and a long track record of use, we feel oral griseofulvin is still the present treatment of choice for tinea capitis. Newer antifungals are currently under investigation, and their role in treating tinea capitis in children is still being defined.

Pyoderma gangrenosum. A comparison of typical and atypical forms with an emphasis on time to remission. Case review of 86 patients from 2 institutions.

Pyoderma gangrenosum (PG) is an idiopathic, inflammatory, ulcerative disease of undetermined cause. The diagnosis is based on clinical and pathologic features and requires exclusion of conditions that produce ulcerations. An atypical bullous variant (atypical pyoderma gangrenosum, APG) exists with clinical features similar to those of Sweet syndrome. Because PG is a rare disease, few large case series have been reported. Pyoderma gangrenosum was first recognized as a unique disease entity in the first half of the 20th century. Cumulative knowledge of PG is based on a handful of case series and multiple individual case reports. To augment that knowledge, we present our experience with a large number of patients over a significant time. We performed a retrospective analysis of the medical records of 86 patients with PG who were evaluated and treated over 12 years at 2 university-based dermatology departments. The mean (+/- standard deviation) age of onset of PG and APG, respectively, was 44.6 +/- 19.7 years and 52.2 +/- 15.3 years. Lower extremity involvement was most common in PG, whereas upper extremity involvement was most common in APG. Associated relevant systemic diseases were seen in 50% of patients. Inflammatory bowel disease was the most common association in patients with PG, whereas hematologic disease or malignancy was most common in those with APG. Although a few patients were managed with local measures or nonimmunosuppressive treatment, the majority required oral corticosteroid therapy, often with systemic immunosuppressive treatment. PG patients required a mean 11.5 +/- 11.1 months of treatment to achieve remission compared with 9.0 +/- 13.7 months for patients with APG. Five patients (5.8%) had disease that was extremely refractory to multiple intensive therapies. The prognosis and disease associations for PG and APG appear to be different. Compared with PG, APG is more often associated with hematologic disease or malignancy, and remits more quickly.

Congenital syphilis: subtle presentation of fulminant disease.

The incidence of congenital syphilis has experienced a fourfold to fivefold increase in 6 years. It is a completely preventable disease whose clinical spectrum ranges from asymptomatic infection, to fulminant sepsis, to death. Congenital syphilis was diagnosed in a 6-week-old infant whose mother was negative for the disease by prenatal screen. The otherwise well child presented with a generalized, papulosquamous eruption of 3 weeks' duration but within hours multisystem failure developed from overwhelming treponemal sepsis. Factors related to increased incidence, problems in serodiagnosis, manifestations of the early versus late forms of the disease, and recommendations for evaluation and treatment are illustrated by this patient and are discussed.

Differential effects of gentamicin on the distribution of cochlear function in albino and pigmented guinea pigs.

It has been suggested that the high affinity of melanin pigment for aminoglycoside antibiotics may cause these drugs to bind preferentially to the pigmented inner ear, producing greater ototoxicity than in the amelanotic albino cochlea. However, evidence of greater ototoxicity in albinos has led to the hypothesis that melanin inhibits the toxicity of these drugs in the pigmented inner ear. On the other hand, ototoxicity in the pigmented animals may simply be delayed relative to the albinos, only to become equal or even more severe with time. The present study was conducted to determine whether a relatively low dose of gentamicin (68.5 mg/kg) would produce differential ototoxicity between albino and pigmented guinea pigs which would persist long after drug exposure had stopped. Nine pigmented and eight albino guinea pigs were given gentamicin sulfate for 14 consecutive days, and were then allowed a two-month recovery period before cochlear analysis; 11 pairs of saline-injected or untreated albino and pigmented guinea pigs served as controls. The results showed that the gentamicin-treated albinos had significantly elevated thresholds for the compound action potential from the auditory nerve (CAP), and significantly lower endocochlear potentials (EP) and cochlear microphonic (CM) input-output voltage functions when compared to their respective controls, or to either group of pigmented guinea pigs. The CAP in drug-treated pigmented animals did not differ significantly from controls, and the differences in EP and CM were marginally significant. The results indicate that the pigmented cochlea is less susceptible to gentamicin than the albino cochlea, and support the hypothesis that melanin may inhibit aminoglycoside ototoxicity in the pigmented inner ear.

Ongoing proliferation of melanocytes in the stria vascularis of adult guinea pigs.

The intermediate cells of the stria vascularis are melanocytes derived from the neural crest. These internalized pigment cells have been thought to be a static population, distinct from those found in the skin. However, this investigation demonstrates that the melanocytes of the adult stria vascularis undergo continuous replication. Cell proliferation was studied using [3H]-thymidine autoradiography and bromodeoxyuridine (BrdU) immunohistochemistry. Single or multiple injections of [3H]-thymidine within a six hour period labeled a mean of 9 intermediate cells. In pigmented guinea pigs, single daily injections of [3H]-thymidine for 2 or 4 days labeled a mean of 24 and 69 intermediate cells, respectively; Pigmented guinea pigs given BrdU once daily for 2 or 4 days labeled a mean of 38 and 75 intermediate cells. By contrast, albino littermates also given BrdU averaged only 23 and 42 labeled intermediate cells in the same 2 and 4 day experiments. The mean number of proliferating cells/mm of stria per 24 h was 1.54 in the pigmented animals and 0.88 in the albinos. Both the total number and density of labeled intermediate cells were significantly smaller in the albino than the pigmented guinea pigs. These results demonstrate that the melanocytes in the stria vascularis undergo continuous baseline mitosis, and at a rate comparable to the melanocytes of the skin. This surprising similarity promotes the speculation that the proliferative rate of the strial melanocytes may be influenced by some of the same factors known to affect replication and pigment production in the skin.

Sequence of a Leishmania major gene encoding an ubiquitin fusion protein.

A gene encoding an ubiquitin-tail protein fusion was isolated from the parasitic protozoan, Leishmania major, and sequenced. The L. major tail protein shares 97, 96, 67, 62, 62 and 61% sequence identity with the tail proteins of Trypanosoma brucei, Trypanosoma cruzi, yeast, Dictyostelium discoideum, human, and Arabidopsis thaliana, respectively. The putative 'zinc finger' nucleic acid-binding domain found in all ubiquitin 'tail' or 'extension' proteins described is also conserved in the L. major sequence. The upstream sequence indicated that this gene is not located at the end of a polyubiquitin sequence.

Turn-specific differences in the endocochlear potential between albino and pigmented guinea pigs.

Recent findings indicate that structural differences exist in the stria vascularis (SV) between albino and pigmented guinea pigs. In the higher cochlear turns, volume density for marginal cells in the albino SV is abnormally large, while that for intermediate cells (melanocytes) is abnormally small. These anatomical variations suggest that functional differences between albino and pigmented inner ears also may be found. To examine this possibility, four strains of guinea pigs were studied, consisting of Hartley albino (N = 9) and NIH outbred pigmented (N = 15) guinea pigs, as well as albino (N = 11) and pigmented (N = 15) guinea pig siblings born to mixed litters. Tracheotomy and carotid artery cannulation were performed. Animals were mechanically ventilated, with periodic samples drawn for arterial blood gas analysis. Blood pressure, heart rate and rectal temperature were monitored. Compound action potentials were measured first to assess cochlear viability. Positive endocochlear potentials (+EP) then were recorded, beginning with the fourth turn, followed by the first, second and third turns. Results showed that the +EP in albinos remained relatively constant across cochlear turns, but decreased significantly from base to apex in the pigmented inner ears. Across all animals, mean +EPs (mV +/- S.E.M.) for turns 1-4 in albinos were: 72.5 (2.5), 68.7 (2.3), 59.2 (2.7), 68.1 (3.3); pigmented values were: 72.9 (2.9), 66.9 (2.6), 53.8 (3.0), 57.0 (2.7). One-way ANOVAs did not show a significant difference in albino +EPs between any of the cochlear turns, but did indicate a highly significant difference between turns in the pigmented inner ears (P < 0.000004). Post hoc comparisons demonstrated +EPs in turns 3 and 4 were smaller than in turn 1. Since turn 3 was recorded last in these experiments, and was reduced in value relative to turn 4 in both groups, it is likely that cochlear deterioration contributed to this result more than any other factor. These results, combined with previous anatomical data, indicate that a diminution of melanocyte cell volume in the albino SV is accompanied by an increase in marginal cell volume density and larger +EPs in the higher cochlear turns, at least at resting levels.

Pharmaceutical excipients. Adverse effects associated with inactive ingredients in drug products (Part I).

Excipient reactions have resulted from the use of clearly toxic substances (e.g. diethyleneglycol), the use of certain excipients in a susceptible group (e.g. very low birthweight neonates, patients with large surface area burns, patients with a history of asthma or contact dermatitis), the alteration of an excipient mixture resulting in altered bioavailability (e.g. phenytoin), and the deliberate or inadvertent extradural administration of preserved medications intended for intravenous use. Inadvertent excipient overdose has also occurred when unusually large doses of a drug containing a preservative were used [chlorbutol in morphine, ethanol in glyceryl trinitrate (nitroglycerin)]. Most excipient problems are preventable with knowledge of the currently available formulation. Government drug regulatory agencies have largely prevented introduction of a new toxic excipient; however, the new use of previously approved (but not adequately studied) excipients continues to result in unfortunate tragedies (e.g. the E-ferol incident). Populations at risk should be monitored carefully. Very low birthweight infants (less than 100g) have a well-demonstrated intolerance to many excipients, particularly during the first 2 weeks of life. Research should be directed toward development of non-preserved medications and safer diluents for this population. Drugs and excipients which have previously been demonstrated to be safer in other populations (e.g. doxapram) should be meticulously studied in this age group before widespread use is recommended. Asthmatic patients comprise another population that are frequently sensitive to excipient toxicity. In some cases, as in sulphiting agents, which are ubiquitous in foods as well as in medications, total avoidance may not be possible and prophylactic therapy may be beneficial. Inactive ingredients are clearly not consistently inert in their biological activity and therefore should not be listed as such. A more useful and concise term is excipient. It is highly recommended that all pharmaceutical manufacturers list all their excipients and make this available to practitioners and drug information centres. Alternatively or additionally, the package insert should list these excipients in accordance with good manufacturing procedures. This disclosure will help to determine the relative frequency and magnitude of problems (bioequivalence, toxicity, etc.) that excipients may have in the population, as well as enabling susceptible patients to avoid inadvertent exposure.

Production of bacterial inoculants by direct fermentation on nutrient-supplemented vermiculite.

When supplemented with a nutrient source and moisture, sterile finely ground vermiculite can be used to directly ferment bacterial cultures to prepare bacterial inoculants. All tested bacterial species, including Rhizobium japonicum, R. phaseoli, R. meliloti, R. leguminosarum, Bacillus megaterium, and several Pseudomonas strains, grew at least 10,000-fold in 1 week at room temperature. The final product was stable and had no special storage or handling requirements. Due to the unique properties of vermiculite, direct fermentation of bacteria on nutrient-supplemented vermiculite offers a reliable process for manufacturing bacterial inoculants.

Planar relationships of the semicircular canals in rhesus and squirrel monkeys.

The technique of principal-component analysis was used to define anatomically the semicircular canal planes of the rhesus and squirrel monkeys with respect to the stereotaxic coordinate system. The analyses were performed on a series of points obtained from the dissected osseous labyrinths. A planar equation was defined for each canal plane in the stereotaxic coordinate system and angles were calculated between the 3 ipsilateral canal planes, between synergistic canal pairs and between each canal plane and the stereotaxic planes. The data from both species are similar: the ipsilateral canal planes are nearly orthogonal; synergistic pairs of canal planes are approximately parallel with angles of 2 degrees-12 degrees between pairs in the rhesus monkey and 13 degrees-16 degrees between pairs in the squirrel monkey. The horizontal canal planes form angles of 22 degrees and 18 degrees with the horizontal stereotaxic plane in the rhesus and squirrel monkeys, respectively. A head position of 15 degrees (pitch nose-down) was calculated to produce an optimal head position in both species for maximally stimulating the horizontal canals and minimally stimulating the vertical canals during horizontal angular acceleration. The radii of curvature (R) of the horizontal, anterior and posterior canals were also measured for both species using a calibrated reticle. These measurements indicate that the anterior canal of both species has the largest radius of curvature. This anatomical information is discussed in relation to the available physiological data.