Genetic differences based on a beef terminal index are reflected in future phenotypic performance differences in commercial beef cattle.

The increased demand for animal-derived protein and energy for human consumption will have to be achieved through a combination of improved animal genetic merit and better management strategies. The objective of the present study was to quantify whether differences in genetic merit among animals materialised into phenotypic differences in commercial herds. Carcass phenotypes on 156 864 animals from 7301 finishing herds were used, which included carcass weight (kg), carcass conformation score (scale 1 to 15), carcass fat score (scale 1 to 15) at slaughter as well as carcass price. The price per kilogram and the total carcass value that the producer received for the animal at slaughter was also used. A terminal index, calculated in the national genetic evaluations, was obtained for each animal. The index was based on pedigree index for calving performance, feed intake and carcass traits from the national genetic evaluations. Animals were categorised into four terminal index groups on the basis of genetic merit estimates that were derived before the expression of the phenotypic information by the validation animals. The association between terminal index and phenotypic performance at slaughter was undertaken using mixed models; whether the association differed by gender (i.e. young bulls, steers and heifers) or by early life experiences (animals born in a dairy herd or beef herd) was also investigated. The regression coefficient of phenotypic carcass weight, carcass conformation and carcass fat on their respective estimated breeding values (EBVs) was 0.92 kg, 1.08 units and 0.79 units, respectively, which is close to the expectation of one. Relative to animals in the lowest genetic merit group, animals in the highest genetic merit group had, on average, a 38.7 kg heavier carcass, with 2.21 units greater carcass conformation, and 0.82 units less fat. The superior genetic merit animals were, on average, slaughtered 6 days younger than their inferior genetic merit contemporaries. The superior carcass characteristics of the genetically elite animals materialised in carcasses worth €187 more than those of the lowest genetic merit animals. Although the phenotypic difference in carcass traits of animals divergent in terminal index differed statistically by animal gender and early life experience, the detected interactions were generally biologically small. This study clearly indicates that selection on an appropriate terminal index will produce higher performing animals and this was consistent across all production systems investigated.

Evidence- and consensus-based (S3) Guidelines for the Treatment of Actinic Keratosis - International League of Dermatological Societies in cooperation with the European Dermatology Forum - Short version.

BACKGROUND: Actinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing. OBJECTIVES: The goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients. METHODS: The guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies. RESULTS: Various interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately. CONCLUSIONS: International guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Pharmacoscintigraphy confirms consistent tamsulosin release from a novel triple-layered tablet.

Conventional modified release preparations of tamsulosin HCl have been linked to increased incidence of cardiovascular adverse events, possibly due to rapid drug peaks soon after ingestion. A 'flattened' absorption profile has been shown to reduce the occurrence of these unwanted effects while improving symptom control. The potential of a novel triple-layered tablet to effect prolonged release and continuous absorption of tamsulosin HCl in the gastrointestinal tract was investigated in this clinical study. Gastrointestinal (GI) transit behaviour was monitored by scintigraphic imaging of technetium-labelled tablets. Drug absorption levels were simultaneously determined through pharmacokinetic analysis of blood samples. A mean Cmax of 6 ± 3 ng/nL was achieved after 324 ± 184 min (mean tmax). The mean AUC0-24 was noted as 4,359 ± 1,880 ng/mL min. The mean gastric emptying and colon arrival times of the tablets were 105.2 ± 68.9 and 270.1 ± 32.0 min post-dose; giving a mean small intestine transit time of 164.9 ± 83.6 min. Variations in gastrointestinal transit did not appear to influence drug absorption. Correlation of scintigraphic and PK data indicated that tamsulosin HCl is released steadily throughout the entire GI tract, suggesting that the mechanism of drug release is independent of GI site allowing drug release even in the low moisture environment of the colon.

Take heart: bariatric surgery in obese patients with severe heart failure. Two case reports.

Bariatric surgery may be an effective treatment for obese heart failure patients, enabling access to cardiac transplantation and/or improvement of symptoms. We report the outcomes of two morbidly obese patients with end-stage heart failure, where obesity precluded cardiac transplantation and underwent laparoscopic gastric banding. A 42 year-old male with idiopathic dilated cardiomyopathy weighing 124.4 kg (BMI 42 kg/m(2)) lost 34 kg and was successfully transplanted 11 months later. A 40 year-old woman with familial dilated cardiomyopathy weighing 105 kg (BMI 40 kg/m(2)) lost 14 kg with sufficient symptomatic resolution to no longer require cardiac transplantation. In selected patients with severe heart failure and concomitant morbid obesity, bariatric surgery may be a reasonable treatment option.

Modulation of gastric pH by a buffered soluble effervescent formulation: A possible means of improving gastric tolerability of alendronate.

Gastrointestinal side-effects of alendronate (ALN) are believed to be associated with oesophageal lodging of tablets and perhaps reflux of gastric contents with alendronate under strongly acidic pH conditions. This leads to unfavourable posture restrictions when dosing. This clinical study evaluated gastric emptying and gastric pH after administration of Fosamax(®) tablets and a novel effervescent ALN formulation with a high buffering capacity. This novel formulation, EX101, was developed to potentially improve gastric tolerance. Gastric pH was monitored by nasogastric probes. Gastric emptying was determined simultaneously by scintigraphic imaging of (99m)Tc-DTPA labelled formulations. Both formulations tested rapidly cleared the oesophagus and there were no statistically significant or physiologically relevant differences in gastric emptying times. Mean pH at time to 50% gastric emptying of the radiolabel was significantly higher in EX101-treated subjects compared to those treated with Fosamax(®). At time to 90% gastric emptying of the radiolabel, mean pH values were comparable. Mucosal exposure to ALN at pH less than 3 is irritating to gastro-oesophageal tissue. Ingestion of Fosamax(®) resulted in ALN being present in the stomach at a pH below 3 within minutes. EX101 minimised the possibility of exposing the oesophagus (in case of reflux) to acidified ALN.

Do gastrointestinal transit parameters influence the pharmacokinetics of gefitinib?

The selective EGFR tyrosine kinase inhibitor, gefitinib has been shown to be active against certain human carcinomas. It had been noted that a proportion of volunteers consistently had lower gefitinib exposure following oral administration. The shape of the elimination profile in this subset was also different, showing a monophasic elimination pattern rather than the biphasic pattern observed in the majority of subjects. A gamma scintigraphic study was conducted to examine the relationship of gastrointestinal transit and drug absorption in a cohort of rapid clearance subjects (n=5) and normal profile volunteers (n=7). The fasted volunteer panel received a 250 mg gefitinib tablet labelled with [(111)In]-DTPA together with 240 mL [(99m)Tc]-labelled water. The rapid clearance cohorts were shown to have a faster mean gastric emptying T90 (37 min vs 74 min) and shorter small intestinal transit time (156 min vs 204 min), resulting in an earlier colonic arrival time (181 min vs 244 min). Mean plasma C(max) was lower (99.2 ng/mL vs 116 ng/mL) and AUC almost half in the rapid clearance group (2162+/-81 ngh/mL vs 4996+/-64 ngh/mL). These data suggest that gastrointestinal transit parameters play a role in the differences in the rapid clearance profile group, also contributing to the biphasic to monophasic switch. However, historical data show, at the recommended dose of 250 mg/day steady-state plasma concentrations adequate for clinical benefit are achieved in patients with non-small cell lung cancer.

Scintigraphic evaluation of colon targeting pectin-HPMC tablets in healthy volunteers.

The in vivo evaluation of colon-targeting tablets was conducted in six healthy male volunteers. A pectin-hydroxypropyl methylcellulose coating was compressed onto core tablets labelled with 4MBq (99m)Tc-DTPA. The tablets released in the colon in all subjects; three in the ascending colon (AC) and three in the transverse colon (TC). Tablets that released in the TC had reached the AC before or just after food (Group A). The other three tablets released immediately upon AC entry at least 1.5h post-meal (Group B). Release onset for Group B was earlier than Group A (343min vs 448min). Group B tablets exhibited a clear residence period at the ileocaecal junction (ICJ) which was not observed in Group A. Prolonged residence at the ICJ is assumed to have increased hydration of the hydrogel layer surrounding the core tablet. Forces applied as the tablets progressed through the ICJ may have disrupted the hydrogel layer sufficiently to initiate radiolabel release. Conversely, Group A tablets moved rapidly through the AC to the TC, possibly minimising contact times with water pockets. Inadequate prior hydration of the hydrogel layer preventing access of pectinolytic enzymes and reduced fluid availability in the TC may have retarded tablet disintegration and radiolabel diffusion.

Lichen planus esophagitis: report of three patients treated with oral tacrolimus or intraesophageal corticosteroid injections or both.

Clinically significant involvement of the esophagus is uncommon in patients who have lichen planus, a common disorder of squamous epithelium. In three patients who had oral, cutaneous, and esophageal lichen planus, endoscopic intralesional esophageal injection of corticosteroids (in all three patients) and oral tacrolimus (FH506) (in two patients) resulted in improvement in dysphagia, a less frequent need for dilation, and improvement in esophageal inflammation.

Interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis.

BACKGROUND: Coccidioides immitis is a soil-dwelling fungus found in arid regions of the Western Hemisphere. Interstitial granulomatous dermatitis is a histopathologic pattern that may be a reactive manifestation of diverse systemic diseases. OBJECTIVE: Our purpose was to describe clinical and histopathologic findings in 5 patients who presented with interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. METHODS: Medical records and skin biopsy slides from 5 patients were retrospectively reviewed. RESULTS: In each patient, edematous papules, nodules, and plaques developed abruptly during the onset of an acute febrile illness. Coccidioidomycosis was confirmed by serology. Skin biopsy specimens revealed interstitial granulomatous dermatitis with neutrophils, leukocytoclasis, and eosinophils. Fungal stains (5/5 cases) and fungal cultures (2/2 cases) revealed no organisms within the skin biopsy specimens. CONCLUSION: Interstitial granulomatous dermatitis may be a presenting feature of pulmonary coccidioidomycosis and may possibly represent a reactive manifestation of the infection.

Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis.

The evolution of human immunodeficiency virus type 1 infection is associated with a shift in the target cell population, driven by variability in coreceptor utilization resulting from diversity in env. To elucidate the potential consequences of these changes for Env-mediated fusion over the course of AIDS, we examined the biological properties of serial viral isolates and determined coreceptor utilization by the products of env cloned from two individuals, followed from the detection of seroconversion throughout the course of their infection. One had a typical course, and the other had an accelerated progression. Early isolates were non-syncytium inducing, and the corresponding Env exclusively utilized CCR5, whereas Env from late phases of infection showed restricted utilization of CXCR4 in both patients. Env from subject SC24, who had a standard progression, demonstrated multitropism, manifested by utilization of CCR3, CXCR4, and CCR5 in the intervening period. In contrast, Env from patient SC51, who experienced early conversion to the syncytium-inducing phenotype, developed dualtropic coreceptor utilization of CCR5 and CXCR4. Genetic analysis of env from each isolate revealed that those with an X4 phenotype formed a distinct subcluster within each subject. Analysis of chimeras constructed from R5 and multispecific env from patient SC24 demonstrated that while the V3 domain played a dominant role in determining coreceptor utilization, sequences in the V4-V5 region also contributed to the latter phenotype. Immunoprecipitation experiments confirmed that the hybrid Env proteins were expressed at similar levels. These experiments demonstrate that progression from the R5 to X4 phenotype may occur through a multi- or dual-tropic intermediate and that multiple domains contribute to this process.

A distinctive clade B HIV type 1 is heterosexually transmitted in Trinidad and Tobago.

HIV-1 transmission worldwide is predominantly associated with heterosexual activity, and non-clade B viruses account for the most spread. The HIV-1 epidemic in Trinidad/Tobago and the Caribbean shares many features with such heterosexual epidemics, including a prominent role for coincident sexually transmitted diseases. This study evaluates the molecular epidemiology of HIV-1 in Trinidad/Tobago during a period when abrupt transition from homosexual to heterosexual transmission occurred in the absence of injecting drug use, concomitant with a rapid rise in HIV-1 prevalence in the heterosexual population. Of 31 viral isolates studied during 1987-1995, all cluster with subtype B reference strains. In the analysis of full env genes from 22 early seroconverters, the Trinidad isolates constitute a significant subcluster within the B subtype. The Trinidad V3 consensus sequence differs by a single amino acid from the prototype B V3 consensus and demonstrates stability over the decade of this study. In the majority of isolates, the V3 loop of env contains a signature threonine deletion that marks the lineage of the Trinidad HIV-1 clade B epidemic from pre-1984. No phenotypic features, including syncitium induction, neutralization profiles, and chemokine receptor usage, distinguish this virus population from other subtype B viruses. Thus, although the subtype B HIV-1 viruses being transmitted in Trinidad are genetically distinguishable from other subtype B viruses, this is probably the result of a strong founder effect in a geographically circumscribed population rather than genetic selection for heterosexual transmission. These results demonstrate that canonical clade B HIV-1 can generate a typical heterosexual epidemic.

Contact sensitivities in palmar plantar pustulosis (acropustulosis).

Acropustulosis, or chronic palmar plantar pustulosis (PPP), is a phenomenon of recurrent sterile pustules, erythema, and scaling affecting the palms and soles. Its pathogenesis is unclear, and it is difficult to treat. The purpose of this study was to elucidate further the factors involved in causing PPP, thereby enhancing the ability to manage this disease. All cases of PPP seen at Mayo Clinic Scottsdale from 1987 to 1993 were reviewed. 21 patients with PPP were identified, 15 of whom had been patch tested. 9 of the 15 patients (60%) showed positive patch test results. Fragrance was the most common sensitivity, but nickel, formaldehyde, para-phenylenediamine, thiuram, neomycin, mercury, balsam of Peru, and cinnamic aldehyde sensitivities were demonstrated. Less important factors included atopy, fungal and bacterial infections, and irritation. Although the mechanism of this sterile pustulosis response does not depend solely on delayed hypersensitivity mechanisms, we believe that we have demonstrated such a large number of positive patch tests in this chronic pustular dermatosis that patch testing should be considered in the routine work-up of these patients.

The vascular calcification-cutaneous necrosis syndrome.

BACKGROUND: Although medial calcification of larger elastic arteries in chronic kidney failure and with advancing age is relatively common, calcification of the cutaneous vascular system is rare. OBJECTIVE: Our purpose was to describe three patients with the vascular calcification-cutaneous necrosis syndrome and review the cause, clinical and pathologic features, and treatment of this syndrome. METHODS: We describe three patients with ischemic necrotic ulcers and underlying cutaneous vascular calcification. The clinical setting was abnormal calcium metabolism from either chronic kidney failure or excessive vitamin D intake. RESULTS: The clinical findings in all patients consisted of multiple tender livedoid nodules and ulcerative plaques on the thighs and legs, which developed in the setting of abnormal calcium metabolism from either chronic kidney failure or excessive vitamin D intake. Histologic study demonstrated vascular calcification. Although this syndrome usually has a chronic course with significant morbidity and mortality, subtotal parathyroidectomy followed by kidney transplantation resulted in complete resolution in one of our patients. CONCLUSION: The clinical and histopathologic findings in the vascular calcification-cutaneous necrosis syndrome are unique. The pathogenesis is likely multifactorial. Treatment for the skin lesions is largely supportive.

Condom-related allergic contact dermatitis.

After 25 years of wearing a condom catheter, recurrent blisters and epidermal sloughing of the penile shaft developed in a patient. Patch testing revealed hypersensitivities to several allergenic components of the condom catheter (that is thiram and mercaptobenzothiazole). After immediate treatment with topically applied steroids, the condition improved and the patient successfully switched to a silicone condom without further irritation.

Basal cell carcinoma on the lower extremity.

From 1987 to 1990, 21 of 648 patients with basal cell carcinomas (BCCs) had their lesion located on the leg. Basal cell carcinomas in this location are uncommon. Women outnumbered men by 1.6:1. The majority of patients had types I and II skin. Most reported residence in the southwestern United States for many years. Recreational sun exposure was extensive and dominated by activities in which exposure of the legs was common. Most lesions were recognized clinically and located on the anterior lower leg. The most frequent histologic description was superficial BCC. Treatment was with electrodesiccation and curettage or excision.

Pseudosclerodermatous panniculitis after irradiation: an unusual complication of megavoltage treatment of breast carcinoma.

An unusual edematous and indurated erythema developed in four patients with breast carcinoma 1 to 6 months after conservative surgical treatment and irradiation. The radiation therapy consisted of megavoltage x-ray photon with or without either electron beam or iridium-192 interstitial boost. Several tissue biopsy specimens revealed pronounced lymphocytic dermal and fat inflammation in conjunction with focal areas of plasma cells. The connective tissue bundles were enlarged and hyalinized. Macrophages and isolated giant cells were noted in the dermis. One biopsy specimen showed elastic tissue in giant cell cytoplasm. No mucin, fibrin, formation of cysts, or calcification was present. Lipophages and hyaline connective tissue replaced some fat lobules. The radiation-induced changes of dilated and hyalinized blood vessels, endothelial cell hyperplasia, fibrosis associated with involution of epidermal appendages, and fibroblasts were present. This combination of radiation-related and inflammatory pathologic changes is unusual and emphasizes the remarkable qualities of this rare reaction. The clinical differential diagnoses of recurrent carcinoma, cellulitis, and connective tissue disease can be excluded by reviewing the pathologic characteristics.

Clinicopathologic spectrum of specific cutaneous lesions of disseminated coccidioidomycosis.

BACKGROUND: Disseminated coccidioidomycosis merits greater attention because the number of persons living and traveling in endemic areas is increasing. OBJECTIVE: Our purpose was to study the clinical and histopathologic findings in patients with specific cutaneous disseminated coccidioidomycosis. METHODS: In six patients with specific skin lesions of disseminated coccidioidomycosis, the diagnosis was confirmed by identification of the organism in tissue or by positive results of tissue culturing. RESULTS: Clinical lesions included solitary granulomatous plaques in two patients and multiple papular, nodular, or pustular lesions in four patients, two of whom also had subcutaneous abscesses. Identifying organisms directly in tissue was possible in only 8 of 17 biopsy specimens and in five of six patients. The histopathologic features showed various degrees of three primary patterns: (1) abscess formation with necrosis, (2) epithelial hyperplasia and granuloma formation with microabscesses, and (3) vascular and perivascular proliferative and inflammatory cell reactions at times suggesting vasculitis. Tissue eosinophilia, present in all patients, was striking in two (eosinophilic abscess formation) and notable in another (vascular inflammation with eosinophilia). CONCLUSION: Cutaneous manifestations of disseminated coccidioidomycosis may be more common and varied than usually recognized.

The evolution of Hodgkin's disease and necrobiotic xanthogranuloma syndrome.

We describe a woman in whom hypogammaglobulinemia and severe granulomatous cutaneous lesions had developed during childhood; subsequently, Hodgkin's disease and necrobiotic xanthogranuloma were diagnosed. This case illustrates an apparent association with disease activity and raises the question of a direct relationship of necrobiotic xanthogranuloma with lymphoproliferative disease.

Histopathologic features of the L-tryptophan-related eosinophilia-myalgia (fasciitis) syndrome.

Study of 18 biopsy specimens in 11 patients with L-tryptophan-related eosinophiliamyalgia (fasciitis) syndrome showed hyaline sclerodermoid changes. Dermal scleroderma was found in eight of nine punch biopsy specimens and eight of nine excisional biopsy specimens. Fascial scleroderma was found in eight excisional biopsy specimens. One specimen obtained by excision had no fascia present. Eleven biopsy specimens showed edema of the dermis, and 13 showed dilated lymphatic structures; thus, the clinical picture of edematous sclerosis was confirmed. Mucinous fasciitis was present in five excisional biopsy specimens, in conjunction with a large number of macrophages in four. Dermal mucinosis was present in 11 biopsy specimens. Lymphocytic and macrophage inflammation was minimal in 14 biopsy specimens and pronounced in only 4. Plasma cells were present in eight cases. Eosinophils were present in substantial numbers in three biopsy specimens and only occasionally in four. Eosinophilic spongiosis was observed in one patient. Lymphocytic inflammation was noted around a single muscle spindle and around large nerve trunks in three patients. No relationship was established between these pathologic features and the duration or dose of tryptophan, prednisone treatment, or duration of symptoms. Pathologic features of the L-tryptophan syndrome consist of hyaline sclerodermoid collagen in the dermis, the septa, and the fascia. Edema, focal mucinosis, and macrophage inflammation may be features that identify this event.