Incentivizing Authorization for Deceased Organ Donation With Organ Allocation Priority: The First 5 Years.

The allocation system of donor organs for transplantation may affect their scarcity. In 2008, Israel's Parliament passed the Organ Transplantation Law, which grants priority on waiting lists for transplants to candidates who are first-degree relatives of deceased organ donors or who previously registered as organ donors themselves. Several public campaigns have advertised the existence of the law since November 2010. We evaluated the effect of the law using all deceased donation requests made in Israel during the period 1998-2015. We use logistic regression to compare the authorization rates of the donors' next of kin in the periods before (1998-2010) and after (2011-2015) the public was made aware of the law. The authorization rate for donation in the period after awareness was substantially higher (55.1% vs. 45.0%, odds ratio [OR] 1.43, p = 0.0003) and reached an all-time high rate of 60.2% in 2015. This increase was mainly due to an increase in the authorization rate of next of kin of unregistered donors (51.1% vs. 42.2%). We also found that the likelihood of next-of-kin authorization for donation was approximately twice as high when the deceased relative was a registered donor rather than unregistered (89.4% vs. 44.6%, OR 14.27, p < 0.0001). We concluded that the priority law is associated with an increased authorization rate for organ donation.

Preliminary marked increase in the national organ donation rate in Israel following implementation of a new organ transplantation law.

Israel's organ donation rate has always been among the lowest in Western countries. In 2008 two new laws relevant to organ transplantation were introduced. The Brain-Respiratory Death Law defines the precise circumstances and mechanisms to determine brain death. The Organ Transplantation Law bans reimbursing transplant tourism involving organ trade, grants prioritization in organ allocation to candidates who are registered donors and removes disincentives for living donation by providing modest insurance reimbursement and social supportive services. The preliminary impact of the gradual introduction and implementation of these laws has been witnessed in 2011. Compared to previous years, in 2011 there was a significant increase in the number of deceased organ donors directly related to an increase in organ donation rate (from 7.8 to 11.4 donors per million population), in parallel to a significant increase in the number of new registered donors. In addition the number of kidney transplantations from living donors significantly increased in parallel to a significant decrease in the number of kidney transplantations performed abroad (from 155 in 2006 to 35 in 2011). The new laws have significantly increased both deceased and living organ donation while sharply decreasing transplant tourism.

Use of monospecific antisera and cRNA probes to localize the major changes in keratin expression during normal and abnormal epidermal differentiation.

We report here the isolation and characterization of three antisera, each of which is specific for a single keratin from one of the three different pairs (K1/K10, K14/K5, K16/K6) that are differentially expressed in normal human epidermis and in epidermal diseases of hyperproliferation. We have used these antisera in conjunction with monospecific cRNA probes for epidermal keratin mRNAs to investigate pathways of differentiation in human epidermis and epidermal diseases in vivo and in epidermal cells cultured from normal skin and from squamous cell carcinomas in vitro. Specifically, our results suggest that: (a) the basal-specific keratin mRNAs are down-regulated upon commitment to terminal differentiation, but their encoded proteins are stable, and can be detected throughout the spinous layers; (b) the hyperproliferation-associated keratin mRNAs are expressed at a low level throughout normal epidermis when their encoded proteins are not expressed, but are synthesized at high levels in the suprabasal layers of hyperproliferating epidermis, coincident with the induced expression of the hyperproliferation-associated keratins in these cells; and (c) concomitantly with the induction of the hyperproliferation-associated keratins in the suprabasal layers of the epidermis is the down-regulation of the expression of the terminal differentiation-specific keratins. These data have important implications for our understanding of normal epidermal differentiation and the deviations from this process in the course of epidermal diseases of hyperproliferation.

The conversion of mouse skin squamous cell carcinomas to spindle cell carcinomas is a recessive event.

Squamous carcinomas of both human and rodent origin can undergo a transition to a more invasive, metastatic phenotype involving reorganization of the cytoskeleton, loss of cell adhesion molecules such as E-cadherin and acquisition of a fibroblastoid or spindle cell morphology. We have developed a series of cell lines from mouse skin tumors which represent different stages of carcinogenesis, including benign papillomas, and clonally related squamous and spindle carcinomas derived from the same primary tumor. Some spindle cells continue to express keratins, but with a poorly organized keratin filament network, whereas in others no keratin expression is detectable. All of the spindle cells lack expression of the cell adhesion molecule E-cadherin and the desmosomal component desmoplakin. Loss of these cell surface proteins therefore appears to precede the destabilization of the keratin network. At the genetic level, it is not known whether such changes involve activation of dominantly acting oncogenes or loss of a suppressor function which controls epithelial differentiation. To examine this question, we have carried out a series of fusion experiments between a highly malignant mouse skin spindle cell carcinoma and cell lines derived from premalignant or malignant mouse skin tumors, including both squamous and spindle carcinoma variants. The results show that the spindle cell phenotype as determined by cell morphology and lack of expression of keratin, E-cadherin, and desmoplakin proteins, is recessive in all hybrids with squamous cells. The hybrids expressed all of these differentiation markers, and showed suppression of tumorigenicity to a variable level dependent upon the tumorigenic properties of the less malignant fusion partner. Our results suggest that acquisition of the spindle cell phenotype involves functional loss of a gene(s) which controls epithelial differentiation.

Effects of a common insecticide on wetland communities with varying quality of leaf litter inputs.

Chemical contamination of aquatic systems often co-occurs with dramatic changes in surrounding terrestrial vegetation. Plant leaf litter serves as a crucial resource input to many freshwater systems, and changes in litter species composition can alter the attributes of freshwater communities. However, little is known how variation in litter inputs interacts with chemical contaminants. We investigated the ecological effects resulting from changes in tree leaf litter inputs to freshwater communities, and how those changes might interact with the timing of insecticide contamination. Using the common insecticide malathion, we hypothesized that inputs of nutrient-rich and labile leaf litter (e.g., elm [Ulmus spp.] or maple [Acer spp.]) would reduce the negative effects of insecticides on wetland communities relative to inputs of recalcitrant litter (e.g., oak [Quercus spp.]). We exposed artificial wetland communities to a factorial combination of three litter species treatments (elm, maple, and oak) and four insecticide treatments (no insecticide, small weekly doses of 10 µg L-1, and either early or late large doses of 50 µg L-1). Communities consisted of microbes, algae, snails, amphipods, zooplankton, and two species of tadpoles. After two months, we found that maple and elm litter generally induced greater primary and secondary production. Insecticides induced a reduction in the abundance of amphipods and some zooplankton species, and increased phytoplankton. In addition, we found interactive effects of litter species and insecticide treatments on amphibian responses, although specific effects depended on application regime. Specifically, with the addition of insecticide, elm and maple litter induced a reduction in gray tree frog survival, oak and elm litter delayed tree frog metamorphosis, and oak and maple litter reduced green frog tadpole mass. Our results suggest that attention to local forest composition, as well as the timing of pesticide application might help ameliorate the harmful effects of pesticides observed in freshwater systems.

Coordinate control of anchorage independence, actin cytoskeleton, and angiogenesis by human chromosome 1 in hamster-human hybrids.

A panel of hybrids previously derived from fusions between a chemically transformed hamster cell line and normal human fibroblasts (A. Stoler and N. Bouck, Proc. Natl. Acad. Sci. USA, 82: 570-574, 1985) has been used to test whether or not anchorage independence, lack of actin cables, and angiogenic activity, three characteristics of transformed cells considered necessary but not sufficient for neoplasia, are coordinately regulated. In these hybrids anchorage independence is initially suppressed and those hybrids where it remains suppressed have been shown to retain human chromosome 1. Here we show that suppressed hybrids also display actin microfilament cables characteristic of normal cells and are unable to elicit an angiogenic response in the rat cornea assay. In contrast, those hybrids in which anchorage independence is expressed and which have lost human chromosome 1 have an actin cytoskeleton resembling that of the transformed parent and are potently angiogenic.

Unusual patterns of keratin expression in the overlying epidermis of patients with dermatofibromas: biochemical alterations in the epidermis as a consequence of dermal tumors.

Dermatofibromas are frequently associated with acanthosis of the overlying epidermis. Using monospecific antisera and cRNA probes, we have examined the pattern of expression of keratin and keratin mRNA in the affected epidermis of patients with these dermal tumors. Our studies reveal several abnormalities in keratin expression within the thickened areas of overlying epidermis. In two of 15 patients, we detected K6 and K16, keratins which are frequently associated with epidermal diseases of hyperproliferation but are not present in normal epidermis. In both cases, K6 and K16 were found in suprabasal layers, similar to that seen for psoriasis and squamous cell carcinomas. Expression of K6 and K16 in skin samples from patients with dermatofibromas seemed to be dependent upon how near was the tumor to the overlying epidermis, and possibly upon the degree of cellularity within the tumor mass. A second aberration in keratin expression, and one which did not appear to be linked to K6/K16 expression, was the altered expression of the basal epidermal keratin K14. Expression of this keratin and its mRNA was variable, often extending into multiple suprabasal layers and including both basal-like and squamous-like cells. In contrast to the expression of K6/K16, aberrant expression of K14 was a relatively frequent event, occurring in greater than 70% of the dermatofibroma skin samples examined. These observations provide the first biochemical evidence in support of previous morphologic studies, indicating that alterations in epidermal differentiation can occur as a consequence of dermal skin tumors.

p21WAF1/CIP1 protein expression in primary ovarian cancer.

p21WAF1/CIP1 protein is a cyclin-dependent kinase inhibitor, able to prevent the CDK2/cyclin E induced retinoblastoma protein (pRB) phosphorylation, thus inhibiting cell cycle progression at G1 phase. p21WAF1/CIP1 protein levels were examined in a series of 102 ovarian tissue samples including normal ovary, primary ovarian tumors, omental metastasis, recurrent disease and residual tumor after chemotherapy exposure, by Western blot analysis. The association of p21WAF1/CIP1 status with clinicopathological parameters and clinical outcome was also investigated. p21WAF1/CIP1 protein was detectable in 76 out of 102 (74%) ovarian tissue samples. We observed a significant trend of p21 levels to gradually increase from normal ovarian tissues (median 0 a.u.) through primary ovarian cancers (median 0.19 a.u.), omental metastases (median 0.33 a.u.) and recurrence of disease (median 0.44 a.u.) (p=0.015). In the group of stage III-IV ovarian cancer patients, p21-positive cases showed a more favourable prognosis with respect to p21-negative cases: the 3-year time to progression (TTP) rate was 58% for p21-positive compared with 33% of p21-negative cases (p=0.036). In conclusion, p21WAF1/CIP1 expression levels seem to be correlated with tumor status at the time of diagnosis and can predict TTP in a selected group of patients.

Growth inhibitory effects and radiosensitization induced by fatty aromatic acids on human cervical cancer cells.

Evidences have been reported that phenylacetic (PA) and phenylbutyric (PB) fatty aromatic acids can exert tumor growth inhibition in vitro and in vivo. Moreover, clinical trials also showed some activity for these drugs to modulate the expression of genes implicated in tumor growth, metastasis, immunogenicity, and to potentiate the efficacy of cytotoxic agents. The aim of the study was to examine the effects of PA and PB on the growth as well as sensitization to cisplatin and radiation in human cervical cancer cells. The effects of PA and PB on the proliferative activity and apoptosis induction in cervical tumor tissue was investigated. Both PA and PB exhibited a time- and dose-dependent antiproliferative activity in SW756 and ME180 cell lines: after 72-h treatment, the IC50 (concentration able to inhibit 50% of cell growth) of PB was 1.9 +/- 0.2 mM and 1.5 +/- 0.2 mM in SW756 and ME180 cells, respectively, while the IC50 of PA was 13.0 +/- 1.7 mM and 10.0 +/- 1.2 mM in SW756 and ME180 cells, respectively. In tumor tissue biopsies obtained from patients affected by squamous cervical cancer, both drugs resulted in a marked reduction of the percentage of bromodeoxyuridine-labeled cells compared with untreated samples [19.0 +/- 1.63% in untreated tissues with respect to 1.30 +/- 0.54% and 4.20 +/- 2.50% of stained cells after treatment with PA (30 mM) (P < 0.0001) and PB (5 mM) (P < 0.0001), respectively]. Moreover, analysis of the staining with M30 monoclonal antibody revealed that PA (30 mM) and PB (5 mM) were able to produce a marked increase in the number of stained apoptotic nuclei with respect to untreated samples. Finally, PB and PA were shown to enhance the sensitivity of SW756 to radiation and to exert an additive effect when combined with cisplatin. A significant reduction of the processed form of p21ras and rhoB proteins in the membrane fraction of cells exposed to PA and PB was observed. When farnesol, which is able to circumvent the enzymatic step inhibited by PA and PB, was added to the medium only a partial reversal of the growth inhibition and potentiation of sensitivity to radiation induced by PA and PB were found. In conclusion, the growth inhibitory properties of fatty aromatic acids suggest that these molecules could represent the prototype of a new class of compounds with some therapeutic potential in cervical cancer.

Helical CT scanning for CAD/CAM subperiosteal implant construction.

Subperiosteal implant is the treatment of choice for the fully or partially edentulous atrophic mandible if grafting procedures are not contemplated to give the jaw sufficient available bone for endosseous implants. The main disadvantage of the standard technique for the construction of this implant is that it requires two surgical procedures. However, it is an accepted and proven technique with a long-term survival rate. This paper discusses the use of the CT scan subperiosteal implant, which provides a result similar to that of the standard subperiosteal implant, but requires only one surgical procedure. The accuracy of fit of the CT scan subperiosteal implant is similar to that of the implant fabricated by means of a standard two-surgical-impression technique. New updated CT scan machines use faster helical scanners and offer a great improvement over previous CT scan machines. The new CT scan machines reduce the chance of patient movement, produce a more accurate CT scan, and enable a more accurate model of the mandible or maxilla to be developed. This paper discusses the production of a well-fitting CT scan subperiosteal implant by a trained, knowledgeable, and cooperative team of dentist, CT scan technician, and radiologist, all of whom understand the technical means to achieve their goal.

Part I. Reconstruction after total mandibulectomy with free cranial and microvascular iliac crest grafts as preparation for implants.

A young Ecuadorian girl underwent a total mandibulectomy due to infected fibrous dysplasia. In the subsequent 16 years, she was unable to speak intelligibly or masticate, surviving on liquids alone. After referral to the United States, the patient underwent six major surgical procedures that reconstructed her mandible from cranial and microvascular iliac crest grafts. The reconstruction improved her appearance and prepared her for insertion of dental implants and the eventual construction of a prosthetic device. These resulted in both functional and esthetic benefits.

Part II. Mandibular reconstruction: combined intra-oral and in vitro placement of osseointegrated implants into a free and vascularized bone graft.

A 28-year-old Hispanic girl underwent a complete mandibular reconstruction many years following full mandibulectomy for fibrous dysplasia. Because of infectious complications, both free cranial and microvascular iliac crest grafts were used. The patient had osseointegrated implants placed directly into the grafted mandible. Osseointegrated implants were also placed into a segment of free iliac crest bone, in vitro, and then grafted laterally onto the reconstructed mandible. Prosthetic reconstruction was then carried out to restore the patient to normal function, health, comfort, and esthetics.

Radiation shielding in oral implantology: a case example.

Patients who are to receive implant therapy and are about to undergo radiation treatment require a means to eliminate, or reduce, the amount of radiation received by the implants and their osseous housing. This requirement is even more important if the implants were recently inserted and osseointegration (Sigma) has not yet been achieved. Lead shielding of the implant sites protects the fixtures and the surrounding bone so that osseointegration can be achieved and maintained.

Genes and cancer.

Cancer can be considered a genetic disorder of somatic cells. Strong evidence comes from several areas: (1) chromosomal analysis reveals cancer cells have abnormal karyotypes; (2) some inherited syndromes are associated with an increased risk of cancer and for others, cancer itself occurs as an inherited trait; (3) cells can become malignant by a variety of agents that damage DNA, and (4) some types of viruses can induce tumours. One common thread has been the normal cellular sequences transduced by viruses and mutated to become oncogenic (oncogenes) are the same sequences to become activated by nonviral mechanisms. These oncogenes appear involved in cell proliferation and/or differentiation and their products apparently function in the signal transduction pathway from the cell exterior to the nucleus. In addition, evidence from familial studies indicate mutations associated with gene inactivation or loss of function are also important in the aetiology of tumour formation. These genes, termed tumour suppressor genes, seem to be involved in the negative control of cellular proliferation. Cancer is a multistep process and it is now becoming clear that the different stages involve genetic alterations in both oncogenes and tumour suppressor genes.