Treatment of facial erythema in patients with rosacea with topical brimonidine tartrate: correlation of patient satisfaction with standard clinical endpoints of improvement of facial erythema.

BACKGROUND: Once-daily brimonidine tartrate (BT) 0.5% gel was shown to provide significantly greater efficacy vs. vehicle for the treatment of facial erythema in patients with rosacea. OBJECTIVES: To demonstrate that patient satisfaction with overall appearance is correlated with reduction in facial erythema, as measured by clinician and patient assessments. METHODS: Data from two identical phase III, multicentre, randomized, controlled trials of moderate facial erythema of rosacea (study A: n = 260; study B: n = 293) with topical BT 0.5% compared to vehicle gel once-daily for 4 weeks were analysed. Correlations of Patient's Assessment of Appearance (PAA) with Clinician's Erythema Assessment (CEA) and Patient's Self-Assessment (PSA) of erythema were evaluated by calculation of gamma statistics. RESULTS: PAA correlated with CEA post-application on Days 1, 15 and 29 for the intent-to-treat population and provided a median gamma value of 0.57 (min = 0.28, max = 0.61). PAA and PSA was also highly correlated post-application on Days 1, 15 and 29; with a median gamma value of 0.87 (min = 0.66, max = 0.89). Subjects who achieved a clinically meaningful improvement in both CEA and PSA scales were more likely to report satisfaction with the overall appearance of their skin (P < 0.001). CONCLUSIONS: Both one- and two-grade improvements in facial erythema assessed by subjects (PSA) and clinicians (CEA) correlate well with PAA, a patient-centered representation of meaningful change.

Fluoride Varnish Application in the Primary Care Setting. A Clinical Study.

OBJECTIVES: The study objectives were twofold: 1. To examine how an intervention to apply fluoride varnish (FV) in a primary health setting to all young, low-income children was implemented and sustained and 2. To assess the feasibility of tracking medical care utilization in this population. STUDY DESIGN: The study included children age 1-5, insured through a government program, seen (7/1/2010-4/30/2012). Data on age, race, sex, clinic encounter, eligibility for and receipt of FV was obtained. The level of data in primary care, specialty care, urgent care and hospitalizations to assess feasibility of future patient tracking was also acquired.. RESULTS: Of 12,067 children, 85% received FV. Differences were found by age (youngest had highest rates). Small differences by race (81%-88%, highest in Blacks.) was found. No differences were found by sex. Ability to track over time was mixed. Approximately 50% had comprehensive data. However, primary care visit and hospitalization data was available on a larger percentage. CONCLUSIONS: FV programs can be introduced in the primary care setting and sustained. Further, long-term follow up is possible. Future study of such cohorts capturing health and cost benefits of oral health prevention efforts is needed.

Modular microsystem for the isolation, enumeration, and phenotyping of circulating tumor cells in patients with pancreatic cancer.

In this manuscript, we discuss the development and clinical use of a thermoplastic modular microsystem for the high-throughput analysis of CTCs directly from whole blood. The modular system offers some innovative features that address challenges currently associated with many CTC platforms; it can exhaustively process 7.5 mL of blood in less than 45 min with recoveries >90%. In addition, the system automates the postselection CTC processing steps and thus, significantly reduces assay turnaround time (from selection to enumeration <1.5 h as compared to >8 h for many reported CTC platforms). The system is composed of 3 functional modules including (i) a thermoplastic CTC selection module composed of high aspect ratio (30 µm × 150 µm) channels containing anti-EpCAM antibodies that is scalable in terms of throughput by employing channel numbers ranging from 50 to 320; the channel number is user selected to accommodate the volume of blood that must be processed; (ii) an impedance sensor module for label-less CTC counting; and (iii) a staining and imaging module for the placement of released cells into a 2D array within a common imaging plane for phenotypic identification. To demonstrate the utility of this system, blood samples from patients with local resectable and metastatic pancreatic ductal adenocarcinoma (PDAC) were analyzed. We demonstrate the ability to select EpCAM positive CTCs from PDAC patients in high purity (>86%) and with excellent yields (mean = 53 CTCs per mL for metastatic PDAC patients) using our modular system. In addition, we demonstrate the ability to detect CTCs in PDAC patients with local resectable disease (mean = 11 CTCs per mL).

The GI Simulated Clinic in the Era of COVID-19: a Comparison of Virtual to In-Person Delivery.

The COVID-19 pandemic has significantly impacted medical education; thus, there is a need to better understand the effectiveness of virtual learning compared to in-person learning. This is a single-center, cross-sectional study of first-year medical students who attended a gastroenterology simulated clinic activity in person in 2018 and 2019 or virtually in 2020. Participants were surveyed on the activity's relevance and effectiveness. Students' assessment of the virtual clinic's effectiveness and relevance was not significantly different from the in-person version of the activity. In addition, most students rated the virtual clinic as effective for learning about telemedicine.

Star Formation in W49A: Gravitational Collapse of the Molecular Cloud Core Toward a Ring of Massive Stars.

High-resolution molecular line and continuum radio images from the Hat Creek Radio Observatory and the Very Large Array suggest that the core of the W49A star-forming region is undergoing gravitational collapse. The radio continuum shows a 2-parsec ring of at least ten distinct ultracompact H-II regions, each associated with at least one O star. The ring is a region of large-scale, organized massive star formation. Recombination line velocities and HCO(+) excitation requirements indicate that the ring is rotating around 50,000 solar masses of material. Because the HCO(+) (1-0) line shows red-shifted absorption but blue-shifted emission, the molecular cloud core is believed to be collapsing toward the center of the ring. The HCO(+) radial velocities, as well as H-I, H(2)CO, and magnetic-field measurements, fit a simple model of inside-out gravitational collapse of a once magnetically supported cloud.

Distance and pairing effects on the brownDominant heterochromatic element in Drosophila.

We examined the behavior of the brownDominant (bwD) heterochromatic insertion moved to different locations relative to centric heterochromatin. Effects were measured as the degree of silencing of a wild-type brown eye pigment gene by bwD across a tandem duplication. A series of X-ray-induced effects were recovered at high frequency. Cis-acting enhancers were obtained by relocation of the duplication closer to autosomal heterochromatin. Enhancers were also recovered on the homologous chromosome when it was similarly rearranged, revealing a novel interhomologue effect whereby interactions occur between genetic elements near opposite ends of a chromosome arm rather than between paired alleles. Cis-acting suppressors were obtained as secondary rearrangements in which the duplication was moved farther away from heterochromatin. Suppression was correlated with loss of cytological association between bwD and the polytene chromocenter. Surprisingly, the distance from bwD to the chromocenter was not correlated with the strength of enhancement or suppression. We propose that bwD fails to coalesce with the chromocenter when its position along the chromosome places it beyond a threshold distance from heterochromatin, and this threshold depends upon the configuration of both the chromosome carrying bwD and its paired homologue.

Morning vs evening light treatment of patients with winter depression.

BACKGROUND: According to the phase-shift hypothesis for winter depression, morning light (which causes a circadian phase advance) should be more antidepressant than evening light (which causes a delay). Although no studies have shown evening light to be more antidepressant than morning light, investigations have shown either no difference or morning light to be superior. The present study assesses these light-exposure schedules in both crossover and parallel-group comparisons. METHODS: Fifty-one patients and 49 matched controls were studied for 6 weeks. After a prebaseline assessment and a light/dark and sleep/wake adaptation baseline week, subjects were exposed to bright light at either 6 to 8 AM or 7 to 9 PM for 2 weeks. After a week of withdrawal from light treatment, they were crossed over to the other light schedule. Dim-light melatonin onsets were obtained 7 times during the study to assess circadian phase position. RESULTS: Morning light phase-advanced the dim-light melatonin onset and was more antidepressant than evening light, which phase-delayed it. These findings were statistically significant for both crossover and parallel-group comparisons. Dim-light melatonin onsets were generally delayed in the patients compared with the controls. CONCLUSIONS: These results should help establish the importance of circadian (morning or evening) time of light exposure in the treatment of winter depression. We recommend that bright-light exposure be scheduled immediately on awakening in the treatment of most patients with seasonal affective disorder.

Reduced antibody response to streptavidin through site-directed mutagenesis.

Streptavidin provides an effective receptor for biotinylated tumoricidal molecules, including radionuclides, when conjugated to an antitumor antibody and administered systemically. Ideally, one would like to administer this bacterial protein to patients repeatedly, so as to maximize the antitumor effect without eliciting an immune response. Therefore, we attempted to reduce the antigenicity of streptavidin by mutating surface residues capable of forming high energy ionic or hydrophobic interactions. A crystallographic image of streptavidin was examined to identify residues with solvent-exposed side chains and residues critical to streptavidin's structure or function, and to define loops. Mutations were incorporated cumulatively into the protein sequence. Mutants were screened for tetramer formation, biotin dissociation, and reduced immunoreactivity with pooled patient sera. Patient antisera recognized one minor continuous epitope with binding locus at residue E101 and one major discontinuous epitope involving amino acid residues E51 and Y83. Mutation of residues E51, Y83, R53, and E116 reduced reactivity with patient sera to <10% that of streptavidin, but these mutations were no less antigenic in rabbits. Mutant 37, with 10 amino acid substitutions, was only 20% as antigenic as streptavidin. Rabbits immunized with either streptavidin or mutant 37 failed to recognize the alternative antigen. Biotin dissociated from mutant 37 four to five times faster than from streptavidin. Residues were identified with previously undescribed impact on biotin binding and protein folding. Thus, substitution of charged, aromatic, or large hydrophobic residues on the surface of streptavidin with smaller neutral residues reduced the molecule's ability to elicit an immune response in rabbits.

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.

L-carnitine and acetyl-L-carnitine status during hemodialysis with acetate in humans: a kinetic analysis.

The effects of the acetate content of hemodialysis fluids on the relation between L-carnitine (free carnitine, cr FC) and acetyl-L-carnitine (AC) have not previously been examined in detail. The net fluxes of FC, AC, and acetate between intra- and extracellular pools during hemodialysis were calculated using a kinetic model with dialysates containing three concentrations of FC (0, 40, and 80 mumol/L) and either 40 or 3 mmol acetate/L. Radioenzymatic assays of FC and AC were optimized for use with samples taken during hemodialysis. Acetate stimulated a tissue uptake of FC (P < 0.05) that could exceed the rate of FC delivery and was related to the dialysate FC composition (P < 0.02). There were associated changes in tissue AC output. With dialysate containing 40 mmol acetate/L, AC tissue output was directly related to the dialysate FC composition (P < 0.05). The AC tissue output was less with dialysate containing 3 mmol acetate/L (P < 0.05) but the significant increase with the provision of FC in the dialysate was retained (P < 0.05). Hemodialysis may therefore represent an acute period of relative carnitine deficiency when regeneration of free coenzyme A from acetyl coenzyme A consequent to metabolism of acetate is limited.

The effect of probucol and cholestyramine combination therapy in severe familial hypercholesterolaemia.

The relative effects of cholestyramine and probucol, alone and in combination, on serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and the ratio of TC to HDL-C (T/HDL-C) have been studied in a group of 10 subjects with severe familial hypercholesterolaemia. The combination of cholestyramine plus probucol was more potent than either agent alone in reducing TC. The use of probucol either alone or in combination reduced the HDL-C concentrations, but the ratio of T/HDL-C was not consistently affected. The effect of the combination therapy did not diminish after periods of at least 6 months and in some cases led to partial regression of long-standing xanthomata. The combination of probucol with cholestyramine did not give rise to additional side effects and it is considered to be a valuable addition to the regimens available for the treatment of severe familial hypercholesterolaemia.

Thrombotic thrombocytopenic purpura--remission following splenectomy. Report of a case and review of the literature.

A case of thrombotic thrombocytopenic purpura in which sustained remission followed splenectomy is described. Strong serologic evidence of concurrent infection with Mycoplasma pneumoniae was found in this case. Previously reported cases in which thrombotic thrombocytopenic purpura has been associated with infections are reviewed. An approach to management of this unusual and frequently fetal condition, is suggested, based on a detailed review of the recent literature.

ICI D7114 a novel selective beta-adrenoceptor agonist selectively stimulates brown fat and increases whole-body oxygen consumption.

1. ICI D7114 is a novel, beta-adrenoceptor agonist which stimulates whole body oxygen consumption in conscious rats, cats and dogs and brown adipose tissue (BAT) activity in conscious rats. Treatment of rats with ICI D7114 stimulated oxygen consumption (ED50, 0.04 mg kg-1, p.o.) and BAT mitochondrial guanosine diphosphate (GDP)-binding (ED50, 0.15 mg kg-1, p.o.) with no chronotropic effects on the heart at these doses. 2. Reference beta-adrenoceptor agonists, isoprenaline and clenbuterol, also stimulated oxygen consumption and BAT activity but were less selective because they also produced effects on heart rate at these doses. 3. Treatment of conscious rats with ICI D7114 did not attenuate the chronotropic effects on the heart of a subsequent isoprenaline challenge. 4. Administration of ICI D7114 or of its acid metabolite had no effect in a cat soleus muscle model of tremor or on blood potassium levels in the conscious dog, indicating lack of effects at beta 2-adrenoceptors. 5. The results indicate that ICI D7114 may have activity at atypical beta-adrenoceptors in brown adipose tissue leading to increased whole body oxygen consumption.

Immunophenotyping of childhood acute lymphoblastic leukemia in Saudi Arabia: second look.

Geographical variations in the incidence of disease are of considerable theoretical and practical importance. It has been claimed that the distribution of acute lymphoblastic leukemia (ALL) phenotypes in Saudi Arabia is different from that recorded in the Western literature. One hundred and twelve (112) patients under 15 years of age, diagnosed as ALL between January 1992 and May 1994 had immunophenotypes performed on their blast cells. Common ALL (cALL) together with pre-B-ALL, formed 86.5% of the total; B-cell 3%, T-cell 6% and null cell 4.5%. These figures are not significantly different from the Western literature. A previous claim from this institution in 1990, that both null and B-cell ALL were significantly increased compared with elsewhere, is not supported by the present figures. Age and sex distribution, and FAB classification, L1 77%, L2 20% and L3 3%, were also of the same order as described elsewhere and, in particular, there was no increase in the frequency of L3 subtype.

Ethylene oxide sterilisation--is it safe?

Tests show that ethylene oxide penetrates and can sterilise long narrow tubes in a hospital ethylene oxide steriliser. Residual ethylene oxide levels in plastic tubing after sterilisation have been estimated. Although initially the levels were very high, storage for four days at room temperature reduced them to a safe level. If adequate controls of the sterilising process and storage are carried out, sterilisation by ethylene oxide is considered to be safe for new plastics and clean equipment.

Metabolic studies with 'Nutrauxil', an enteral feed preparation.

A metabolic study was carried out in 6 patients requiring enteral feeding to investigate the effectiveness and tolerance of 'Nutrauxil', a ready-made liquid nutritional preparation, over a period of 8 days. The results of anthropometric and laboratory measurements, made initially and at the end of two 4-day periods, showed that the basic provision of 2000 kcal and 60 g protein per day with 'Nutrauxil' maintained patients in metabolic, electrolyte and nitrogen balance. No adverse effects were noted and the preparation was easy to administer. It was concluded that 'Nutrauxil' compared favourably with other enteral feed preparations with respect to its nutritional effectiveness on clinical, biochemical and economic grounds.

Plasma non-esterified fatty acid response to dialysate acetate concentration during haemodialysis in humans.

We have inhibited the in vitro generation of non-esterified fatty acids in plasma samples taken during haemodialysis by cooling the samples rapidly, centrifuging and freezing within 5 min of sampling and completing the assay on the same day. The relationship of non-esterified fatty acid concentrations during haemodialysis to the acetate concentration of the dialysate and the profile of circulating lipase activities was studied. With this sample-handling protocol we found lower non-esterified fatty acid concentrations than reported in many other studies and the results suggest that, under normal conditions of haemodialysis, the circulating non-esterified fatty acid concentrations and the associated risk of unwanted side-effects may have been previously over-estimated due to artefactual in vitro sample lipolysis. We also showed that, at the end of dialysis, when circulating lipase activities were least, the non-esterified fatty acid concentrations were lower (P < 0.05) with an acetate dialysate containing 37 mmol/l acetate than with a bicarbonate dialysate containing 3 mmol/l acetate.

The effect of surgery and nutritional regimen on plasma lipoproteins and fat metabolites in man.

Plasma lipoproteins and fat metabolites were measured before and during the first five post-operative days in patients undergoing elective abdominal surgery of moderate severity. They received nutrition as total parenteral nutrition (TPN) or 4% dextrose saline (D S ) or isotonic aminoacids (IAA). Surgery caused an immediate fall in total and very low density lipoprotein triglyceride and total high density lipoprotein cholesterol but a rise in the high density lipoprotein subfraction 2 cholesterol. The increase in total triglyceride after 5 post-operative days was due principally to changes in triglyceride not carried by very low density lipoprotein and was related to the type of nutrition provided. There was no evidence of impaired intra-vascular lipolysis.

External quality assurance in hematology. The programme of the Royal College of Pathologists of Australasia.

The Royal College of Pathologists of Australasia introduced a comprehensive national external quality assurance programme (QAP) in hematology in 1979. This now provides regular monthly trials of full blood counting, supplemented by 3-monthly sets of samples for a large variety of other tests for "state of the art" studies, together with case slides for diagnosis for 294 participants. In addition educational supplements are provided, based on one or other aspect of each major quarterly trial. The frequency and variety of tests and analysis of participants' results conform to suggested standards for similar national schemes elsewhere in the world. There is evidence that the programme has helped raise the standards of hematopathology in Australasia and has identified areas which require improvement. It is envisaged that the scheme will satisfy the requirements of state legislation designed to accredit pathology laboratories. Future development should include a refinement of objective methods of scoring performance, especially in areas such as morphology where participants' results cannot readily be expressed numerically.