Anti-tumour necrosis factor treatment increases circulating T helper type 17 cells similarly in different types of inflammatory arthritis.

We investigated changes in circulating T helper type 17 (Th17) cells following anti-tumour necrosis factor (TNF) in rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) patients. Peripheral blood mononuclear cells (PBMC) were isolated from 25 RA, 15 AS and eight PsA patients at baseline 4 and 12 weeks after treatment, and Th17 cell frequencies were analysed using interleukin (IL)-17 enzyme-linked immunospot (ELISPOT) and flow cytometry. A significant increase in IL-17-producing cells was observed by ELISPOT in RA and AS patients at 12 weeks. Flow cytometry confirmed significant increases in CD4(+) IL-17(+) cells at 12 weeks in RA and AS and 4 weeks in PsA patients. Anti-TNF treatment increases circulating Th17 cells in three different diseases.

Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis.

BACKGROUND: Systemic insulin resistance (IR) is a primary feature in non-alcoholic steatohepatitis (NASH), however, there remain limited data on tissue-specific insulin sensitivity in vivo. METHODS: We examined tissue-specific (adipose, muscle and liver) insulin sensitivity and inflammation in 16 European Caucasian patients with biopsy-confirmed NASH and in 15 healthy controls. All underwent a two-step hyperinsulinaemic euglycaemic clamp incorporating stable isotope measurements of carbohydrate and lipid metabolism with concomitant subcutaneous adipose tissue (SAT) microdialysis. RESULTS: Hepatic and muscle insulin sensitivity were decreased in patients with NASH compared with controls, as demonstrated by reduced suppression of hepatic glucose production and glucose disposal (Gd) rates following insulin infusion. In addition, rates of lipolysis were higher in NASH patients with impaired insulin-mediated suppression of free fatty acid levels. At a tissue specific level, abdominal SAT in patients with NASH was severely insulin resistant, requiring >sixfold more insulin to cause ½-maximal suppression of glycerol release when compared with healthy controls. Furthermore, patients with NASH had significantly higher circulating levels of pro-inflammatory adipocytokines than controls. CONCLUSION: NASH patients have profound IR in the liver, muscle and in particular adipose tissues. This study represents the first in vivo description of dysfunctional SAT in patients with NASH.

Effectiveness of 0.05% oxymetazoline (Vicks Sinex Micromist®) nasal spray in the treatment of objective nasal congestion demonstrated to 12 h post-administration by magnetic resonance imaging.

INTRODUCTION: This study aimed to assess the qualitative and quantitative utility of MRI imaging to illustrate the magnitude and duration of the effect of a standard 100 µg dose of oxymetazoline in a commercially available formulation that also contains aromatic oils. METHODS: This was a randomized, open label, single dose, parallel group study in 21 adult male and female subjects who reported moderate to severe nasal congestion due to acute upper respiratory tract infection or hay fever. MRI scans were acquired using a 3T Philips Achieva scanner with a 16 channel head receive coil. High resolution MRI scans of the nasal turbinates were obtained immediately prior to dosing (baseline) and at approximately 1, 8, 10, 11, and 12 h after dosing. The efficacy variables of primary interest were inferior turbinate total volume at 8 and 12 h post-dosing. The secondary efficacy variables analysed were inferior turbinate total volume at 1, 10, and 11 h post-dosing, middle turbinate total volume at 1, 8, 10, 11, and 12 h post-dosing. RESULTS: Changes from baseline volumes measured for the inferior and middle turbinates of subjects receiving the oxymetazoline formulation showed significant (P < 0.05) decreases at all times up to and including 12 h post-administration. No significant decreases from baseline were detected in subjects receiving a sham 'spray' (untreated control - spray bottles with no spray solution). Statistical ANCOVA results of inferior and middle turbinate volume indicated significant differences (P < 0.05) at all measurement points up to and including 12 h post-administration between the oxymetazoline treatment group and the untreated control with the only exception the middle turbinate volume at 10 h (P = 0.0896). The significant changes were likely to be clinically relevant though this was not measured in the study. No AEs were reported during this study and no other safety evaluations were made. CONCLUSIONS: This study showed that MRI assessment of nasal congestion in human volunteers is a robust, repeatable and viable measurement technique. The application of a 100 µg Vicks Sinex Micromist(®) nasal decongestant (0.05% oxymetazoline solution) delivered a highly significant reduction in inferior and middle turbinate volumes compared with the application of a control, measurable by the MRI method up to and including a 12 h post-dose scan.

Sorafenib for advanced hepatocellular carcinoma (HCC): impact of rationing in the United Kingdom.

BACKGROUND: The prognosis for hepatocellular carcinoma (HCC) is dependent upon tumour stage, performance status (PS), severity of underlying liver disease, and the availability of appropriate therapies. The unavailability of sorafenib may have a significantly adverse effect on the prognosis of UK patients with advanced HCC. During the study period, access to sorafenib was at the discretion of local health funding bodies, a process that may delay or deny access to the drug and that remains in place for Wales, Scotland, and Northern Ireland. Here, we attempt to address the impact of this system on patients with advanced HCC in the United Kingdom. METHODS: This is a retrospective study performed in the two largest specialist hepatobiliary oncology units in the United Kingdom. Funding applications were made to local funding bodies for patients with advanced HCC for whom sorafenib was considered appropriate (advanced HCC not suitable for loco-regional therapies, compensated chronic liver disease, PS 0-2). RESULTS: A total of 133 applications were made, of which 57 (43%) were approved and 76 (57%) declined. Demographics and prognostic factors were balanced between the two groups. This cohort had a number of adverse prognostic features: patients were predominantly PS 1-2; the majority had multifocal disease with the largest lesion being >5 cm; and macroscopic vascular invasion, metastases, and AFP >,000 ng ml(-1), were each present in one-third of cases. The median time from application to funding decision was 17 days (range 3-260 days). For the primary 'intention-to-treat' analysis, median overall survival was 4.1 months when funding was declined, and 9.5 months when funding was approved (hazard ratio (HR) 0.48; 95% CI 0.3186-0.7267; P=0.0005). CONCLUSION: These data support the use of sorafenib for patients with advanced HCC as an effective intervention. In the United Kingdom, this applies to a relatively small group of patients, estimated to total ∼800 per year who, unfortunately, do not survive long enough to themselves lobby for the availability of this drug. These data provide a comparison of sorafenib with supportive care and demonstrate the potential detrimental impact on patient outcomes of rationing health-care resources on the basis of cost.

Problematic Internet Use Among University Students in Jamaica.

The prevalence of problematic Internet use (PIU) and its associated negative outcomes among college students has been heavily researched in developed countries. However, despite the increased accessibility of the Internet and indicators which may suggest PIU in developing countries such as Jamaica, PIU in this context remains grossly understudied. This study surveyed 277 Jamaican university students and found evidence of PIU, with younger respondents (ages 18-23) at risk. The findings also indicate that the predictors of PIU in this sample are depressive symptomatology, avoidant-attachment, and low social connectedness (R 2 = .208, F[7, 269] = 10.112, p < .001). Findings from the current study highlight that problematic Internet use is of concern in this developing context and warrants further exploration.

Planck's Principle.

Two views about the Darwinian revolution are tested: that nearly all scientists in Great Britain had been converted to a belief in the evolution of species within 10 years after the publication of the Origin of Species, and that younger scientists were converted much more rapidly than older scientists. Both views are shown to be less than accurate.

Oral Candida infection and colonization in solid organ transplant recipients.

INTRODUCTION: Oral Candida carriage and infection have been reported to be associated with a greater risk for systemic infection in transplant recipients; however, a systematic analysis of the oral Candida titers and species has not been previously conducted. The objectives of this study were to determine the prevalence of oropharyngeal candidiasis, the oral carrier status, Candida titers and species in this population. METHODS: Ninety kidney and heart transplant subjects and 72 age-matched healthy controls were included. Swabs from the oral mucosa and a standardized amount of unstimulated saliva were plated on Chromagar Candida, and colony-forming units per millilitre were calculated. Initial speciation was based on colony color and was confirmed by standard germ tube, biotyping, or polymerase chain reaction assays. RESULTS: Infection with C. albicans was detected in seven transplant subjects and none of the controls. The transplant group had significantly higher oral Candida titers than the control group. There were no statistically significant relationships between the dose or type of immunosuppressants and oral Candida titers or infection. A significantly higher percentage of transplant subjects were colonized by more than one species, compared with control subjects. The most frequent species combination in transplant subjects was C. albicans and C. glabrata. C. glabrata was isolated from 13.5% of transplant carriers and none of the controls. CONCLUSIONS: Increased oral Candida infection and carriage titers were found in the transplant population. Although the majority of transplant patients were colonized by C. albicans, C. glabrata appears to emerge as the second most prevalent species.

Clarithromycin with low dose dexamethasone and thalidomide is effective therapy in relapsed/refractory myeloma.

A combination of clarithromycin, low dose of thalidomide and low dose dexamethasone was used in a phase II study to treat patients with relapsed and refractory myeloma. Thirty patients received clarithromycin 250 mg twice daily and thalidomide 50 mg at night on an ongoing basis with 4-d pulses of 10 mg dexamethasone given monthly. Eight patients had permitted escalation of thalidomide dosage up to 200 mg daily. The combination was well tolerated and could be given to elderly, infirm and severely cytopenic patients. Response rates were high, with 89% achieving at least 50% reduction in paraprotein and a 96% overall response rate. Although clarithromycin has only minimal anti-myeloma properties when used as a single agent, its combination with thalidomide and dexamethasone appears very effective, allowing these to be used in lower and more tolerable doses with good clinical effects.

Effects of creating a non-specific, virus-hostile environment in the nasopharynx on symptoms and duration of common cold.

The Common Cold remains the most frequent symptomatic viral infection in man. Current best therapies are all symptomatic. New pharmacological therapies are likely to be prescription-bound, and as most Common Cold infections are successfully treated without the intervention of a Physician, there is a need for effective non-prescription therapy options. Aim of this study is to propose a new type of approach, based on the concept of making a hostile biological environment for virus survival and spreading at the point of infection, the nasopharynx. The hypothesis was advanced that infections could be controlled using a physical biological approach to create an environment at the point of infection, that is inhibitory to the survival, and persistence of infecting virus, and of viruses newly released from infected mucosal epithelial cells. A nasal irrigation spray, designed to deliver a low pH gel to the nasal cavity, was developed and tested in this study. The study was a randomised, parallel, double-blind, placebo-controlled evaluation of three formulations of irrigation nasal spray in 441 subjects. The objective was to test whether the formulations reduced Cold severity and Cold duration compared to a placebo nasal spray. Subjects were recruited, and supplied with the product when healthy, and were instructed to begin treating and recording symptom severity once they experienced the "first signs" of a Common Cold. To qualify, subjects had to volunteer that they had at least one of the symptoms: sore/scratchy throat, runny nose or congested nose. The product was used 4 times daily, with at least 4 hours separating each dose, for a maximum of 7 days. Efficacy was assessed by an Interactive Voice Recall System whereby subjects were required to contact the investigation site, by telephone, twice daily when they were asked to assess the severity of their symptoms using a four point ordinal scale where 0 = "absent", and 3 = "severe". The symptoms assessed were sore throat, runny nose, blocked nose, cough and tired/run-down feeling. Two formulations demonstrated significant effects. A hydroxy methyl propyl cellulose based formulation reduced symptom severity compared with placebo by 17% and a Poloxamer based formulation reduced severity by 21%. Duration of illness was reduced with a hydroxy methyl propyl cellulose based formulation by 1.5 days to 2.4 days (according to the dose) and by a Poloxamer based formulation by 2.5 days. Results of this study suggest that the creation of a non virus-specific, inhibitory environment in the nasopharynx holds promise as an effective method of controlling the severity and duration of the Common Cold.

Two-dimensional fluorescence spectroscopy: a novel approach for controlling fed-batch cultivations.

In industrial fed-batch cultivations it is often necessary to control substrate concentrations at a low level to prevent the production of overflow metabolites and thus optimize the biomass yield. A new method for on-line monitoring and fed-batch control based on fluorescence measurements has been developed. Via instantaneous in situ measurements and multivariate data analysis a chemometric model has been established, which enables the rapid detection of ethanol production at aerobic Saccharomyces cerevisiae fed-batch cultivations. The glucose feed rate is controlled by predicting the metabolic state directly from the fluorescence intensities. Thus, ethanol production could be avoided completely while increasing the biomass yield accordingly. The robust instrumentation is suitable for industrial applications.

Bisexual branching processes in a genetic context: the extinction problem for Y-linked genes.

In this paper the inheritance of a Y-linked gene with alleles R and r in a population with both females and males is modelled using a two-type bisexual branching process. It is assumed that the reproductive distribution associated with the R allele can differ from the associated with the r allele and that females prefer to mate with a male having the R allele rather than with a male with the r allele. Under these assumptions, we provide some conditions for the extinction and/or survival of both alleles in the population. These conditions depend on the magnitudes of the average number of females and males per mating unit. Moreover, the almost sure extinction of the r allele is independent of the behaviour of the R allele. On the other hand, the survival of the R allele with positive probability may depend strongly on the reproductive behaviour of the other allele. Theoretical results are illustrated by means of simulated examples and some open problems are proposed to the reader as conjectures.

Multiple estrogen receptor assays in human breast cancer.

A review of assay results from more than 6000 patients revealed 232 patients in whom multiple breast cancer specimens were analyzed for estrogen receptor (ER). All assays were performed in a single laboratory. Specimens were considered estrogen receptor positive (ER+) if the ER level was greater than 10 fmol/mg protein and estrogen receptor negative (ER-) if the ER level was less than 3. ER values between 3 and 10 fmol/mg protein were considered borderline. Simultaneous assays were performed in 58 patients with 3% major discordance (i.e., one assay ER- and one assay ER+). Major discordance for sequential biopsies was 19% (16 of 82) when the initial assay was ER+ and 13% (eight of 63) when the initial assay was ER-. (Apparent change from ER- to ER+ status was observed in five of nine patients with primary tumors less than 2 cm in diameter, suggesting that an inadequate amount of tissue may have been submitted for initial ER analysis.) There was no significant relationship between the time interval between sequential biopsies and the rate of discordance. Marked decreases in ER levels and 78% discordance were seen if rebiopsy was performed within 2 months of tamoxifen treatment. When these tamoxifen cases were excluded from the analysis, neither intervening endocrine therapy nor chemotherapy significantly altered discordance rates.

Photodynamic alteration of cornea endothelium. Relation to bicarbonate fluxes and oxygen concentration.

Corneas were mounted in flux chambers and endothelial bicarbonate fluxes were determined following sensitization of endothelial cells with 5 . 10(-6) M rose bengal and exposure to light. Corneas exposed to light demonstrated an increased passive bicarbonate flux compared to corneas not photosensitized. Active bicarbonate flux was reduced after 5 min of light exposure, but not after 1 min of light exposure. The increase in passive bicarbonate flux was prevented by the addition of 200 microgram/ml catalase to the bathing solution; however, catalase had no effect on the photodynamic alteration of active flux. Neither 10 mM ascorbic acid nor 1.012 gram/l glutathione prevented the photodynamically induced increase in passive flux. Perfusion of corneas with 5 . 10(-6) M rose bengal dissolved in a sucrose-substituted Krebs-Ringer bicarbonate solution with a PO2 of 124 +/- 4.0 mmHg and exposed to light swelled at rates more rapid than corneas treated in a similar fashion but perfused with a solution with a PO2 of 20 +/- 4.6 mmHg. This study demonstrated that photodynamically induced corneal endothelial cell alteration results in increased passive bicarbonate flux, a time-dependent decrease in active bicarbonate flux, is oxygen dependent, and is at least in part secondary to H2O2 produced by the dismutation reaction of the superoxide free radical.

Thermoacoustic contrast of prostate cancer due to heating by very high frequency irradiation.

Applying the thermoacoustic (TA) effect to diagnostic imaging was first proposed in the 1980s. The object under test is irradiated by high-power pulses of electromagnetic energy, which heat tissue and cause thermal expansion. Outgoing TA pressure pulses are detected by ultrasound transducers and reconstructed to provide images of the object. The TA contrast mechanism is strongly dependent upon the frequency of the irradiating electromagnetic pulse. When very high frequency (VHF) electromagnetic irradiation is utilized, TA signal production is driven by ionic content. Prostatic fluids contain high levels of ionic metabolites, including citrate, zinc, calcium, and magnesium. Healthy prostate glands produce more ionic metabolites than diseased glands. VHF pulses are therefore expected to generate stronger TA signal in healthy prostate glands than in diseased glands. A benchtop system for performing ex vivo TA computed tomography with VHF energy is described and images are presented. The system utilizes irradiation pulses of 700 ns duration exceeding 20 kW power. Reconstructions frequently visualize anatomic landmarks such as the urethra and verumontanum. TA reconstructions from three freshly excised human prostate glands with little, moderate, and severe cancerous involvement are compared with histology. TA signal strength is negatively correlated with percent cancerous involvement in this small sample size. For the 45 regions of interest analyzed, a reconstruction value of 0.4 mV provides 100% sensitivity but only 29% specificity. This sample size is far too small to draw sweeping conclusions, but the results warrant a larger volume study including comparison of TA images to the gold standard, histology.

Portable blood pressure measurements: performance of Korotkov sound analysis techniques.

Noninvasive portable blood pressure systems (PBPS) are typically based on korotkov sound technique. The performance of related Korotkov sound analysis techniques was assessed in PBPS data obtained from nine normotensive and nine hypertensive men. Multiple-seated PBPS measurements were taken, each following 1 minute of quiet rest, moderate walking, and stair climbing; each PBPS measurement was accompanied by a simultaneous auscultatory measurement in the same arm. In subsequent manual PBPS data analysis, PBPS systolic and diastolic BPs were within 4 mm Hg of corresponding auscultatory BPs 86% and 88% of the time; BPs following rest and walking showed greater accuracy, while those following stair climbing were less accurate. Interestingly, automated analysis of diastolic PBPS data (using selective bandpass filtering, amplitude normalization, and comparator decision ratios) provided a level of accuracy similar to that obtained from manual data analysis. Overall, both manual and automated Korotkov sound analysis techniques can provide BP results that agree quite well with auscultatory determinations.

Acyclovir and vidarabine monophosphate: comparison of iontophoretic and intravenous administration for the treatment of HSV-1 stromal keratitis.

We determined the therapeutic efficacy of iontophoretic application of acyclovir and vidarabine monophosphate (ara-AMP) for the treatment of herpes simplex virus (HSV) type 1-induced stromal keratitis in rabbits. The therapeutic efficacy of intravenous administration of acyclovir was assessed in the same model. Stromal keratitis was produced by intrastromal injection of 10 microliters purified HSV-1, McKrae strain. Treatment began the first day after intrastromal injection. Iontophoresis (0.5 mAmp for four minutes) of 3.4 percent (0.1 M) ara-AMP and 5.0 percent (0.22 M) acyclovir was performed once daily for five consecutive days in two treatment groups. Intravenous administration of 50 mg acyclovir/kg was performed twice daily for eight consecutive days. Intravenous administration of NaCl (0.14 M) and ocular iontophoresis of NaCl (0.14 M) were performed as controls in the two treatment groups. At least two scorers performed a single masked evaluation of the disease severity (lesion scoring) of the conjunctiva, corneal epithelium, stroma, and iris by still lamp examination. The eyes were scored daily for 12 consecutive days, and then every other day up to day 22. Iontophoresis of acyclovir or ara-AMP significantly reduced the course of the disease compared with iontophoresis of NaCl. Intravenous administration of acyclovir significantly reduced the disease compared with intravenous NaCl. This suggests that iontophoresis of acyclovir or ara-AMP either alone or in combination with intravenous administration of acyclovir may be of value in the treatment of HSV-1 stromal keratitis.

Noncompliance in organ transplant recipients.

Noncompliance with medication and follow-up care was evaluated in 538 renal, 50 heart, and 13 liver transplant recipients. In a retrospective review of 260 kidney transplant recipients followed from three months posttransplant, the incidence of medication noncompliance was 18%. It was 15% in a prospective study of 196 kidney recipients from 1984 to 1987. Patients most likely to become noncompliant were young and in a lower socioeconomic group. There was no significant difference in the incidence of noncompliance with respect to cadaveric vs. living-related donor kidney source, or in male vs. female patients. There was a higher incidence of noncompliance in blacks and Hispanics, but that may have been due to a higher incidence of lower socioeconomic status in those groups. Noncompliance can occur many years posttransplant and was seen in heart and liver transplant recipients. In the retrospective study, 91% of kidney transplant recipients who were noncompliant with medications and follow-up care either lost their grafts or died. Noncompliant behavior was usually not predictable and was often without an identifiable reason. Efforts to increase compliance, such as better patient selection, more education, and simplified medical regimens may have reduced the incidence of noncompliance in recent patients.

A regional experience with emergency liver transplantation.

Liver transplantation for patients requiring life-support results in the lowest survival and highest costs. A ten year (1983-1993) regional experience with liver transplantation for critically ill patients was undertaken to ascertain the fate of several subgroups of patients. Of the 828 liver transplants performed at six transplant centers within the region over this period, 168 (20%) were done in patients who met today's criteria for a United Network of Organ Sharing (UNOS) status 1 (emergency) liver transplant candidate. Recipients were classified according to chronicity of disease and transplant number (primary-acute, primary-chronic, reTx-acute, reTx-chronic). Overall one-year survival was 50% for all status 1 recipients. The primary-acute subgroup (n = 63) experienced a 57% one-year survival compared with 50% for the primary-chronic (n = 51) subgroup (P = 0.07). Of the reTx-acute recipients (n = 43), 44% were alive at one year in comparison with 20% for the reTx-chronic (n = 11) group (P = 0.18). There was no significant difference in survival for the following: transplant center, blood group compatibility with donors, age, preservation solution, or graft size. For patients retransplanted for acute reasons (primary graft nonfunction (PGNF) or hepatic artery thrombosis [HAT]), survival was significantly better if a second donor was found within 3 days of relisting (52% vs. 20%; P = 0.012). Over the study period progressively fewer donor organs came from outside the region. No strong survival-based argument can be made for separating, in allocation priority, acute and chronic disease patients facing the first transplant as a status 1 recipient. Clearly patients suffering from PGNF or HAT do far better if retransplanted within 3 days. Establishing an even higher status for recipients with PGNF, perhaps drawing from a supraregional donor pool, would allow surgeons to accept more marginal donors, thus potentially expanding the pool, without significantly compromising patient survival. Retransplantation of the recipient with a chronically failing graft who deteriorates to the point of needing life-support is nearly futile, and in today's health care climate, not an optimal use of scarce donor livers.

Photodynamically induced alteration of cornea endothelial cell function.

Corneal endothelial cells were perfused in the specular microscope with varying concentrations of rose bengal. Corneas perfused with rose bengal in concentrations of 10(-6)M to 10(-5)M and exposed to light for periods of 0.5 to 5 min swelled at rates which were more rapid with both increasing concentration of rose bengal and increasing duration of light exposure. Corneas perfused with similar concentrations of rose bengal but not exposed to light did not swell. Combining rose bengal with 100 micrograms/ml superoxide dismutase did not reduce the corneal swelling following exposure to light, indicating that the photodynamically induced endothelial bengal perfusing solution eliminated corneal swelling following exposure of corneas to light. This indicates that the photodynamic effect of endothelium is secondary to cell functional alterations from the hydrogen peroxide produced during the dismutation reaction of superoxide free radical which is catalyzed by superoxide dismutase.

Effect of ambient pH on corneal endothelial sodium fluxes.

Sodium fluxes across the isolated rabbit corneal endothelium were measured as a function of ambient pH and bicarbonate concentrations. At pH 7, the net sodium flux (J endo str net) was effectively obliterated at all bicarbonate concentrations, relative to controls at pH 7.5. At pH 8, the net sodium flux was obliterated at 5 mM bicarbonate, was unchanged at 25 mM bicarbonate, and was enhanced at 40 mM bicarbonate, relative to controls at pH 7.5. The decrease in net sodium flux under these conditions relative to previously demonstrated maintenance of bicarbonate fluxes under almost identical conditions suggest that sodium and bicarbonate transverse the endothelium by different routes. In addition, changes in unidirectional fluxes, when ambient pH is decreased from 7.5 to 7, are not equal, illustrating that the fluxes probably occur via different pathways. A complex interrelationship exists between sodium, bicarbonate, and proton movement.