Liver Allograft Provides Immunoprotection for the Cardiac Allograft in Combined Heart-Liver Transplantation.

When transplanted simultaneously, the liver allograft has been thought to have an immunoprotective role on other organs; however, detailed analyses in simultaneous heart-liver transplantation (SHLT) have not been done to date. We analyzed patient outcomes and incidence of immune-mediated injury in 22 consecutive SHLT versus 223 isolated heart transplantation (IHT) recipients between January 2004 and December 2013, by reviewing 3912 protocol- and indication-specific cardiac allograft biopsy specimens. Overall survival was similar (86.4%, 86.4%, and 69.1% for SHLT and 93.3%, 84.7%, and 70.0% for IHT at 1, 5, and 10 years; p = 0.83). Despite similar immunosuppression, the incidence of T cell-mediated rejection (TCMR) was lower in SHLT (31.8%) than in IHT (84.8%) (p < 0.0001). Although more SHLT patients had preexisting donor-specific HLA antibody (22.7% versus 8.1%; p = 0.04), the incidence of antibody-mediated rejection was not different in SHLT compared with IHT (4.5% versus 14.8%, p = 0.33). While the left ventricular ejection fraction was comparable in both groups at 5 years, the incidence and severity of cardiac allograft vasculopathy were reduced in the SHLT recipients (42.9% versus 66.8%, p = 0.03). Simultaneously transplanted liver allograft was associated with reduced risk of TCMR (odds ratio [OR] 0.003, 95% confidence interval [CI] 0-0.02; p < 0.0001), antibody-mediated rejection (OR 0.04, 95% CI 0-0.46; p = 0.004), and cardiac allograft vasculopathy (OR 0.26, 95% CI 0.07-0.84; p = 0.02), after adjusting for other risk factors. These data suggest that the incidence of alloimmune injury in the heart allograft is reduced in SHLT recipients.

Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment.

In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 µg 5-FU/g rat colon content vs 4.66 µg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

Colon-specific delivery of 5-fluorouracil from zinc pectinate pellets through in situ intracapsular ethylcellulose-pectin plug formation.

Conventional fluid-bed and immersion film coating of hydrophilic zinc pectinate pellets by hydrophobic ethylcellulose is met with fast drug release. This study explored in situ intracapsular pellet coating for colon-specific delivery of 5-fluorouracil (5-FU). The solid coating powder constituted ethylcellulose and pectin in weight ratios of 11:0 to 2:9. Its weight ratio to pellets varied between 2:3 and 3:2. Pectin was used as excipient of core pellets and coating powder in view of its potential use in colon cancer treatment. Delayed 5-FU release and core pectin dissolution were attainable when the weight ratio of solid coating powder to pellets was kept at 3:2, and weight ratio of ethylcellulose and pectin in coating powder was kept at 8:3 with particle size of ethylcellulose reduced to 22 µm. In situ intracapsular wetting of pectin coat by dissolution medium resulted in the formation of ethylcellulose plug interconnecting with pellets through the binding action of pectin. Less than 25% of drug was released at the upper gastrointestinal tract. The majority of drug was released upon prolonged dissolution and in response to colonic enzyme pectinase, which digested core pellets.

Use of microwave in processing of drug delivery systems.

Microwave has received a widespread application in pharmaceuticals and food processing, microbial sterilization, biomedical therapy, scientific and biomedical analysis, as well as, drug synthesis. This paper reviews the basis of application of microwave to prepare pharmaceutical dosage forms such as agglomerates, gel beads, microspheres, nanomatrix, solid dispersion, tablets and film coat. The microwave could induce drying, polymeric crosslinkages as well as drug-polymer interaction, and modify the structure of drug crystallites via its effects of heating and/or electromagnetic field on the dosage forms. The use of microwave opens a new approach to control the physicochemical properties and drug delivery profiles of pharmaceutical dosage forms without the need for excessive heat, lengthy process or toxic reactants. Alternatively, the microwave can be utilized to process excipients prior to their use in the formulation of drug delivery systems. The intended release characteristics of drugs in dosage forms can be met through modifying the physicochemical properties of excipients using the microwave.

Drug release responses of zinc ion crosslinked poly(methyl vinyl ether-co-maleic acid) matrix towards microwave.

The drug release characteristics of beads made of poly(methyl vinyl ether-co-maleic acid) using Zn2+ as the crosslinking agent were investigated with respect to the influence of microwave irradiation. The beads were prepared by an extrusion method with sodium diclofenac as a model water-soluble drug. They were subjected to microwave irradiation at 80W for 5 and 20 min, and at 300W for 1 min 20s and 5 min 20s. The profiles of drug dissolution, drug content, drug-polymer interaction and polymer-polymer interaction were determined by dissolution testing, drug content assay, differential scanning calorimetry and Fourier transform infrared spectroscopy. Treatment of beads by microwave at varying intensities of irradiation can aid to retard the drug release with a greater reduction extent through treating the beads for a longer duration of irradiation. The treatment of beads by microwave induced the formation of multiple polymeric domains of great strength and extent of polymer-polymer and drug-polymer interaction. The release of drug from beads was retarded via the interplay of O-H, N-H, C-H, (CH2)n and C-O functional groups of these domains, and was mainly governed by the state of polymer relaxation of the matrix unlike that of the untreated beads of which the release of drug was effected via drug diffusion and polymer relaxation. In comparison to Ca2+ crosslinked matrix which exhibited inconsistent drug release retardation behavior under the influence of microwave, the extent and rate of drug released from the Zn2+ crosslinked beads were greatly reduced by microwave and the release of drug from these beads was consistently retarded in response to both high and low intensity microwaves.

Lung cancer mortality among silicotic workers in Hong Kong--no evidence for a link.

BACKGROUND: The link between silica dust/silicosis and lung cancer is still very controversial. We examined the relationship between silica dust exposure and/or silicosis and lung cancer in a large cohort of silicotic workers in Hong Kong. PATIENTS AND METHODS: All workers with silicosis in Hong Kong diagnosed during the period 1981-1998 were followed up till the end of 1999 to ascertain their vital status and causes of death. Standardized mortality ratio (SMR) for lung cancer and other major causes of death were calculated. Axelson's indirect method was used to adjust for smoking effect. Multiple Cox regression models were carried out to examine the exposure-response relationship between silica dust and lung cancer. RESULTS: About 10% (86) of all 853 deaths were from lung cancer, giving a SMR of 1.69 [95% confidence interval (CI) 1.35-2.09]. Lung cancer SMR for caisson and surface construction workers were 2.39 (95% CI 1.50-3.62) and 1.61 (95% CI 1.21-2.10), respectively, which became 1.56 (95% CI 0.98-2.36) and 1.09 (95% CI 0.82-1.42) after adjusting for smoking. No consistent exposure-response relationship was detected between silica dust or severity of silicosis and lung cancer death. CONCLUSION: Our cohort study did not offer positive support to a link between silica or silicosis and lung cancer.

Cutaneous melanoma: a population-based epidemiology report with 989 patients in Hong Kong.

Studies in white populations have confirmed advanced age as a risk factor for cutaneous melanoma, but in nonwhite populations, its role is less clear. To clarify a possible association in our local population, comprising 94.9% Chinese, a retrospective epidemiological study of 20 years of data on cutaneous melanoma between 1983 and 2002 from a central cancer registry in Hong Kong was conducted. There were 989 new cases and 378 death cases registered, and analysis showed that both the incidence and mortality rate of cutaneous melanoma increase with increasing age. Advanced age is thus confirmed as a risk factor for cutaneous melanoma in our local population. In an ageing population, the estimated future incidence and mortality rate of cutaneous melanoma are likely to increase.

Mortality from non-malignant respiratory diseases among people with silicosis in Hong Kong: exposure-response analyses for exposure to silica dust.

OBJECTIVES: To examine the exposure-response relationships between various indices of exposure to silica dust and the mortality from non-malignant respiratory diseases (NMRDs) or chronic obstructive pulmonary diseases (COPDs) among a cohort of workers with silicosis in Hong Kong. METHODS: The concentrations of respirable silica dust were assigned to each industry and job task according to historical industrial hygiene measurements documented previously in Hong Kong. Exposure indices included cumulative dust exposure (CDE) and mean dust concentration (MDC). Penalised smoothing spline models were used as a preliminary step to detect outliers and guide further analyses. Multiple Cox's proportional hazard models were used to estimate the dust effects on the risk of mortality from NMRDs or COPDs after truncating the highest exposures. RESULTS: 371 of the 853 (43.49%) deaths occurring among 2789 workers with silicosis during 1981-99 were from NMRDs, and 101 (27.22%) NMRDs were COPDs. Multiple Cox's proportional hazard models showed that CDE (p = 0.009) and MDC (p<0.001) were significantly associated only with NMRD mortality. Subgroup analysis showed that deaths from NMRDs (p<0.01) and COPDs (p<0.05) were significantly associated with both CDE and MDC among underground caisson workers and among those ever employed in other occupations with high exposure to silica dust. No exposure-response relationship was observed for surface construction workers with low exposures. A clear upward trend for both NMRDs and COPDs mortality was found with increasing severity of radiological silicosis. CONCLUSION: This study documented an exposure-response relationship between exposure to silica dust and the risk of death from NMRDs or COPDs among workers with silicosis, except for surface construction workers with low exposures. The risk of mortality from NMRDs increased significantly with the progression of International Labor Organization categories, independent of dust effects.

Renal MALToma: an unusual lymphoma in a patient with lupus.

Non-Hodgkin's Lymphomas (NHL) have been reported in association with autoimmune disorders particularly Sjogren's syndrome. We report a case of renal MALToma, an unusual NHL in an 84-year-old Caucasian lady with long-standing, non-aggressive Systemic Lupus Erythematosis with no associated Sjorgen's syndrome and who never received cytotoxics.

Impact of occupational stress and other psychosocial factors on musculoskeletal pain among Chinese offshore oil installation workers.

AIMS: To explore the relation between psychosocial factors and musculoskeletal pain in Chinese offshore oil installation workers. METHODS: Half of all offshore workers (being a representative sample) in a Chinese oil company were invited to complete a self-administered questionnaire providing information on sociodemographic characteristics, occupational stressors, type A behaviour, social support, coping style, health related behaviour, past injuries, and musculoskeletal pain. Factor analysis was used to identify the sources of occupational stress and the domains of type A behaviour and coping style. Logistic regression analyses were used to study the relations between psychosocial factors and musculoskeletal pain in each body region. RESULTS: The prevalence of musculoskeletal pain over the previous 12 months varied between 7.5% for elbow pain and 32% for low back pain; 56% workers had at least one complaint. Significant associations were found between various psychosocial factors and musculoskeletal pain in different body regions after adjusting for potential confounding factors. Occupational stressors, in particular stress from safety, physical environment, and ergonomics, were important predictors of musculoskeletal pain, as was coping by eating behaviour. CONCLUSIONS: These observations supported the widely accepted biopsychosocial model of musculoskeletal disorders and suggested that in future studies of work related musculoskeletal disorders, psychosocial factors must be given due consideration.

Pilot study of topical delivery of methotrexate by electroporation.

BACKGROUND: The topical administration of methotrexate (MTX) for the treatment of psoriasis and neoplastic diseases is restricted by the poor diffusion of MTX across the stratum corneum. OBJECTIVES: We applied electroporation to increase the transdermal transport of MTX. METHODS: Electrodes were placed either side-by-side on the surface of excised full thickness pig skin, or on a piece of skin clamped between compartments of a vertical diffusion chamber. Sixty rectangular electric pulses at 120 V, 1 ms and 1 Hz were applied across the skin. MTX was left on the skin surface for an additional 10 min to take advantage of diffusion through electropores. Cumulative drug transport was measured by radioactive tracing, using [3H]-methotrexate, from punch biopsy samples taken from under the cathode. The integrity of the radioisotope was verified by high-performance liquid chromatography. RESULTS: Using side-by-side electrodes, treatment with the pulses alone resulted in a 2.5-fold increase; adding anionic lipid enhancers to the pulses resulted in a 4.4-fold enhancement compared with passive diffusion. Concurrent iontophoresis for the 11-min time period made a nonsignificant contribution. To reduce tissue resistance we used 40 degrees C hyperthermia in a vertical diffusion chamber; transport was increased 11-fold to 53 microg cm(-2) (flux = 290 microg cm(-2) h(-1)). MTX penetration profiles indicated that more than half of the MTX was confined to the epidermis and papillary dermis. The tissue concentration in this superficial reactive unit was 1.7 mmol L(-1). CONCLUSIONS: Electroporation of MTX with an anion lipid enhancer under a mild hyperthermic environment provided a significant transdermal delivery within a short application time. The method may be an effective means of drug delivery for treating psoriasis or other MTX-sensitive disorders and avoids the potential systemic toxicity.

Depigmented extramammary Paget's disease.

BACKGROUND: Depigmented extramammary Paget's disease (EMPD) has been reported in a few cases. Depigmented macules or patches may be the only presenting sign or may coexist with the classical erythematous lesions. OBJECTIVES: To investigate the occurrence rate and clinical presentation of depigmentation in EMPD. METHODS: All pathology-proven cases of EMPD diagnosed in our department during 1990-2003 were retrieved. The clinical photographs were reviewed for evidence of local depigmentation. The pathological diagnosis of EMPD in the whitish lesions was confirmed by positive expression of cytokeratin 7 or carcinoembryonic antigen, and/or the presence of intracytoplasmic mucin. RESULTS: Of 19 cases of EMPD, six (30%) manifested depigmented lesions which were confirmed to be EMPD pathologically. In two patients, the hypopigmentation was associated with erythematous lesions at the initial presentation. In four others, the depigmentation developed later as local recurrence after excision, cryotherapy, photodynamic therapy or radiotherapy. The progressive enlargement of the depigmentation and the appearance of separate new white lesions in these four cases suggested that the localized depigmentation was unlikely to be simple postinflammatory hypopigmentation. CONCLUSIONS: Our study suggests that depigmented EMPD may not be rare. Localized depigmentation in the genital area can be an early sign of EMPD and its local recurrence. In patients with an established diagnosis of EMPD, appearance of new white lesions and continuous enlargement of depigmented patches should not be dismissed as simple treatment-induced postinflammatory hypopigmentation or another type of hypopigmented lesion without biopsy confirmation.

Small area variations of cancer mortality in Hong Kong--the roles of health care and socio-economic status.

Variations of cancer incidence and cancer mortality across small areas in Hong Kong were explored and attempt made to link them to socio-economic differences. The entire Hong Kong population during the period 1984-88 was divided into 65 small areas. The geographic distributions of incidence and mortality for ten most frequent sites of cancers (6 male and 4 female) were analyzed by separating the systematic variance from the random variance. A Poisson regression model was fitted for each cancer using the standardized incidence ratio (SIR) as a covariate for mortality. The geographic variations in SIR for the individual cancers were, in turn, analyzed similarly using a socio-economic score as the covariate. We found a statistically significant systematic variance in mortality for all six male cancers and three of the four female cancers studied. More than 50% of the systematic variance of mortality for nine cancers could be explained by the geographic variations in incidence, suggesting that other factors, like the provision and/or outcomes of health care services, played a minor role. There were statistically significant systematic variances in SIR for all male and female cancers. The socio-economic score accounted for over 50% of the systematic variance for three cancer sites. This study illustrated an approach to explore underlying explanations for the geographic variations of disease incidence and mortality. As more aggregate exposure data become available at the small area level, this type of ecological analysis would help in delineating the contributions of various factors and guide investigators in their search for the etiology background of diseases.

Household gas cooking: a risk factor for respiratory illnesses in preschool children.

AIMS: To explore the association of household gas cooking and respiratory illnesses in preschool children and their relation to outdoor air pollution. METHODS: Cross-sectional study among households that used gas stoves for cooking in two housing estates with contrasting air qualities in Hong Kong. A structured questionnaire was administered to parents of 426 children aged 0-6 years on their exposure to gas cooking and passive smoking, and the prevalence of respiratory illnesses. RESULTS: A total of 111 children (26.1%) were reported to have one or more respiratory illnesses (allergic rhinitis, asthma, bronchitis, sinusitis, and pneumonia). Of these, 21 (18.9%), 41 (36.9%), and 49 (44.1%) children were from households that cooked once, twice, and three times a day with gas. Hierarchical logistic regression models adjusting for socioeconomic, demographic, and indoor risk factors including passive smoking showed that household gas cooking was positively associated with respiratory illnesses. There was a dose-response relation between the frequency of gas cooking and the prevalence of respiratory illnesses in the estate with lower outdoor air pollution (OR = 6.1 and 3.2 respectively, for cooking three and two meals a day, compared to one meal a day). This relation was not observed in the more polluted estate. The association between the presence of a cigarette smoker in the household and the prevalence of respiratory illnesses was not significant. CONCLUSIONS: As gas cooking is common in urban households, the findings could have important public health implications.

In vitro/in vivo correlations between transdermal delivery of 5-aminolaevulinic acid and cutaneous protoporphyrin IX accumulation and effect of formulation.

BACKGROUND: Photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) has been widely reported for the treatment of a variety of neoplastic and non-neoplastic cutaneous diseases. Although different formulations containing variable amounts of ALA have been applied in PDT, the dose-response relationships between transdermal ALA delivery and cutaneous protoporphyrin IX (PpIX) accumulation have not been studied. OBJECTIVES AND METHODS: The objectives of this study were to investigate the effect of permeability barrier function, ALA concentration and formulation on the in vitro penetration of ALA through nude mouse skin and cutaneous PpIX formation at 2 h following a 2-h application of ALA to nude mouse skin in vivo, and to delineate the relationships in between. RESULTS: Results demonstrated that variations in barrier integrity, in addition to ALA concentration, profoundly influenced ALA delivery to generate PpIX. Saturable correlations were found to exist between PpIX concentrations in both the epidermis and dermis in vivo and its transdermal flux in vitro, and the relationships were well described by the Emax model. The established correlations based on pure aqueous solutions were applicable to different formulations containing hydroxypropylmethylcellulose as the gelling agent and ethylenediamine tetraacetic acid as the iron chelator. Moreover, incorporation of desferrioxamine, another iron chelator, in the formulation prolonged cutaneous PpIX accumulation in the skin in comparison with 3% ALA aqueous solution, but the peak PpIX levels were not increased. Application of a liposomal formulation resulted in similar prolongation in ALA-induced PpIX accumulation, as well as better epidermal targeting. CONCLUSIONS: Knowledge of the dose-response relationships and the effect of formulation is important for designing optimal formulations and treatment schedules for topical ALA-PDT.

Photodynamic therapy for Bowen's disease (squamous cell carcinoma in situ) of the digit.

BACKGROUND: Surgical excision is the preferred method of eradicating Bowen's disease (BD). However, when BD occurs on the digit, surgical intervention can sometimes lead to scar contracture and loss of function of the digit. OBJECTIVE: To evaluate the effectiveness of photodynamic therapy (PDT) in eradicating BD of the digit while preserving the full function of the digit. METHODS: Four patients of chronic arsenism with biopsy-proven BD on the digit were treated with PDT by using a newly designed light-emitting diode (LED) array with a peak wavelength of 630 nm (630 +/- 40 nm; 40 mW/cm2 at skin surface). After partial removal of the thickened horny layer and 16 hours of occlusion with a 2% aminolevulinic acid (ALA) solution, each lesion was irradiated with 240 J/cm2 in two fractions with a 90-minute interval. RESULTS: All patients experienced a significant burning, tingling sensation that was tolerable during the procedure except one who needed local anesthesia. All treated digits healed without scarring in 2 weeks. Posttreatment biopsy in one patient showed normal epidermis and a slight fibrosis in the papillary dermis. Three patients remained free of recurrence (75%) at 15-17 months (average 16 months) after one treatment. One patient's BD recurred at 8 months, but was successfully treated without recurrence after 20 months. CONCLUSION: Our preliminary study suggests that PDT using 2% 5-ALA solution and an LED array is an effective, noninvasive method to treat digital BD with the benefit of scar-free contracture and loss of digital function. Among the various factors that would affect the results of PDT, we feel that partial removal of the thickened horny layer is the most important step to achieve sufficient therapeutic effect in digital BDs.

Depigmented genital extramammary Paget's disease: a possible histogenetic link to Toker's clear cells and clear cell papulosis.

BACKGROUND: The histogenesis of extramammary Paget's disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget's disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker's clear cell/CCP hypothesis. METHODS: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4 x 3 cm hypopigmented-depigmented patch on the root of the penis. RESULTS: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD. CONCLUSIONS: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.

The decrease of mitochondrial NADH dehydrogenease and drug induced apoptosis in doxorubicin resistant A431 cells.

Doxorubicin (DOX) resistant A10A cells derived from human squamous carcinoma A431 cells were found to exhibit a smaller degree of apoptosis after DOX treatment as compared to their parent cells. Induction of reactive oxygen species (ROS) formation and mitochondrial depolarization by DOX were more pronounced in the parent cells than in the A10A cells. The fact that catalase suppressed the DOX effect on ROS induction, mitochondrial depolarization and apoptosis in both cell lines suggests an involvement of ROS in the DOX-induced apoptosis. To investigate the underlying mechanisms for DOX resistance in A10A cells, RT-PCR based differential display was used. One of the clones, which was down-regulated in the A10A cells, had sequence homology with part of the mitochondrial NADH dehydrogenase III (ND3) gene. NADH dehydrogenase plays an important role in generating ROS during DOX treatment. The results indicate that down-regulation of ND3 may at least in part contribute to the mechanism for A10A cells resistant to DOX-induced apoptosis.