A proposal for the use of advance directives in the treatment of incompetent mentally ill persons

[M]y question is how these patients while competent might be able to give their own informed consent to treatment, despite being both unwilling and incompetent to do so when treatment is to be begun, thereby reducing the need to relax the dangerousness criteria for involuntary commitment. It is uncontroversial that the dangerousness requirement would be too restrictive for all treatment of mental illness. When competent patients voluntarily seek and/or accept treatment for their mental illness, neither public policy nor medical practice restricts treatment to those patients judged to be dangerous. Instead, criteria should be and generally are comparable to those for the treatment of physical illness -- whether the patient is ill, in this case mentally ill, and likely to benefit from treatment. Through use of advance directives, it would be possible for mentally ill persons who are currently refusing treatment to give prior consent, while competent and with their disease in remission, to treatment at a later time when they are incompetent, have become noncompliant, and are refusing treatment. My proposal is certainly not entirely novel, since others have made similar proposals under the heading of Ulysses contracts and voluntary commitment contracts. Addressing briefly some of the criticisms of these earlier proposals will bring out one fundamental difference between them and my proposal here for a new use of advance directives -- whether the patient must then be incompetent when the contract or directive made earlier is later invoked -- a difference I shall argue strongly favors my proposal.     

Mechanisms and consequences of somatic mosaicism in humans

Somatic mosaicism -- the presence of genetically distinct populations of somatic cells in a given organism -- is frequently masked, but it can also result in major phenotypic changes and reveal the expression of otherwise lethal genetic mutations. Mosaicism can be caused by DNA mutations, epigenetic alterations of DNA, chromosomal abnormalities and the spontaneous reversion of inherited mutations. In this review, we discuss the human disorders that result from somatic mosaicism, as well as the molecular genetic mechanisms by which they arise. Specifically, we emphasize the role of selection in the phenotypic manifestations of mosaicism.     

Possible involvement of central pacemakers in clinical disorders of movement.

This review considers the evidence for possible involvement of central nervous system pacemaker neurons in several clinical disorders of movement. Two basic types of tremor are discussed from this point of view, i.e., 4--7/sec parkinsonian tremor, of possible thalamocortical origin, and 7--11/sec essential tremor of possible olivo-cerebellar origin. The importance of motor programs and abnormalities in their utilization are considered with reference to the loss of motor function in parkinsonism (? loss of motor programs), and the inappropriate release of such programs as a possible basis for the involuntary movements seen in other movement disorders, such as chorea, athetosis, dystonia, and hemiballismus. The possible role of pacemaker neurons controlling such programs is considered. Finally, the subject of locomotion and the pacemaker model of the spinal locomotor pattern generator for stepping are considered in relation to clinical disorders of gait. While critical evidence is lacking for pacemaker inovlvement in any of these disorders, their possible role is emphasized.     

Reconstructive breast surgery: referring physician knowledge and learning needs

Despite the positive impact that reconstructive breast surgery can have on a woman's quality of life, the percentage of eligible candidates that have this procedure remains surprisingly low. The authors hypothesized that this may be attributable to inadequate knowledge, inadequate information, and/or misinformation available to physicians caring for these patients. A needs assessment of primary care physicians, general surgeons, oncologists, and plastic surgeons was conducted to determine referring physicians' current level of knowledge of reconstructive breast surgery and to discover potential learning needs. This comprised a survey, focus groups, and individual interviews. Referring physicians rated their own knowledge of reconstructive breast surgery as low. Plastic surgeons rated their referring physicians' knowledge as even lower. Specific learning needs were identified, as large discrepancies between referring physicians' self-reported knowledge of individual breast reconstruction topics and their own opinion of their relevance were revealed. In addition, despite evidence to the contrary, more than one-third of referring physicians indicated a belief that a breast reconstruction delayed the detection of local cancer recurrence and adversely interfered with adjuvant oncologic therapy. This lack of knowledge and misinformation may be negatively affecting patient referrals to plastic surgeons, as more than one-third of referring physicians and 90 percent of plastic surgeons believed that eligible candidates were not being offered referrals because of inadequate referring physician knowledge of this topic. Furthermore, patients older than 49 years were not being referred despite the fact that plastic surgeons would consider these patients as potential surgical candidates. Referring physician gender affected both referral patterns and perceived importance of reconstructive breast surgery. Finally, personal beliefs and past experiences played a role both in physicians' decisions to refer patients and in patients' decisions to have breast reconstructions. These deficiencies in information, knowledge, and learning needs should be addressed by educational interventions during residency training and through continuing education endeavors.     

Tumours and malformations in the adult offspring of cyclophosphamide-treated and control male rats--preliminary communication

Adult offspring aged 52-104 weeks, from male Sprague-Dawley rats treated chronically with cyclophosphamide (CP) were examined for tumours and gross abnormalities. Litter size at birth and at weaning was found to be greatly reduced as a result of paternal CP treatment. No unusual abnormalities were found at post-mortem examination but there was an increase in the incidence of hydronephrosis in offspring from CP-treated males compared with offspring from control males. This increase could have been indirectly caused by CP-treatment through reduced litter size. Histological examination of 26 tumours showed a variety of tumour types in the offspring of CP-treated and control males. Two of the four uterine tumours in offspring from CP-treated males were examined histologically; one was a sarcoma and the other an adenocarcinoma. Although no uterine tumours were found in offspring from control males, it is not clear whether this difference in frequency was treatment-related. The most common tumour site in female offspring from both CP-treated and control males was the mammary gland, and all six of these tumours which were examined histologically were adenofibromas. Abnormal karyotypes were observed in 2 out of 21 offspring showing abnormalities from CP-treated males and none out of 2 offspring with abnormalities from control males. These were not associated with tumours. It was concluded from this limited study that there was no clear evidence of increased tumour incidence in the offspring from CP-treated males. There was an indication that abnormal karyotypes may have been caused by the paternal CP treatment and these abnormalities persisted into adulthood.     

The origin of DNA genomes and DNA replication proteins

In recent years, it has became clear that most proteins involved in cellular DNA precursor synthesis or DNA replication have been 'invented' more than once, indicating that the transition from RNA to DNA genomes was more complex than previously thought. Several authors have suggested that DNA viruses, which often encode their own version of these proteins, played an important role in this process. The nature of the genome of the last universal cellular ancestor (LUCA) -- that is, RNA or DNA, prokaryotic-like or eukaryotic-like -- remains in dispute. A hyperthermophilic LUCA would have suggested a circular, double-stranded DNA genome; however, recent data favor a mesophilic or moderately thermophilic LUCA.     

Biochemical characterization of an endoxylanase from Pseudozyma brasiliensis sp. nov. strain GHG001 isolated from the intestinal tract of Chrysomelidae larvae associated to sugarcane roots

Endo-xylanases play a key role in the hydrolysis of xylan and recently they have attracted much attention due to their potential applications on the biofuel and paper industries. We isolated a Pseudozyma brasiliensis sp. nov. strain from the intestinal tract of Chrysomelidae larvae that parasitize sugarcane roots. This basidiomycetous yeast produces a xylanase designated PbXynA which was purified and characterized. The molecular weight of PbXynA is 24 kDa, it belongs to the GH11 family and its optimum pH and optimum temperature are 4.0 and 55 °C, respectively. PbXynA has as secondary structure predominantly β-sheets and sigmoidal kinetic behavior with elevated speed conversion from substrate-to-products (V_max = 2792.0 μmol product/min/mg protein). It is highly activated by bivalent cations such as Ca²⁺, however in the presence of Cu²⁺ xylanase activity was inhibited. It has a high specific activity and produces xylooligosaccharides that have a variety of industrial applications, indicating PbXynA has a great biotechnological potential.     

Fungal entomopathogens: new insights on their ecology

An important mechanism for insect pest control should be the use of fungal entomopathogens. Even though these organisms have been studied for more than 100 y, their effective use in the field remains elusive. Recently, however, it has been discovered that many of these entomopathogenic fungi play additional roles in nature. They are endophytes, antagonists of plant pathogens, associates with the rhizosphere, and possibly even plant growth promoting agents. These findings indicate that the ecological role of these fungi in the environment is not fully understood and limits our ability to employ them successfully for pest management. In this paper, we review the recently discovered roles played by many entomopathogenic fungi and propose new research strategies focused on alternate uses for these fungi. It seems likely that these agents can be used in multiple roles in protecting plants from pests and diseases and at the same time promoting plant growth.     

Plasma fibronectin

Fibronectin (FN) is a glycoprotein (disulfite-bonded dimer of 200 to 220 Kd submits) found in a soluble form in blood (concentration 250--500 microg/ml), it can be removed from it by cryoprecipitation and affinity chromatography on gelatin or heparin-agarose. It is also found in an insoluble fibrillar form as a component of connective tissue matrix like collagen, proteoglycans... FN fundamentally forms molecular complexes with collagen, fibrinogen or fibrin, heparin, activated factor XIII, bacteria, cellular membranes..., these various proteins binding with now well known functional "domains" on subunits. Thus FN mediates adhesion of cells to cells as well to biomaterials or tissue, cell migration and chemotactic activity, tissue stromal organization... The transformed cultured cells in presence of oncogen virus loose ability to secrete FN which contribute to their invasive tendency. FN also interacts with hemostatic and fibrinolytic systems, as component of the subendothelium (secreted, like Willbrand factor, by endothelial cells) and of platelet alpha-granules released by stimulated platelets. FN could then provoke platelet spreading on the subendothelium surface after collagen-platelet adhesion, triggered by Willebrand factor, has happened. FN is a part of the fibrinous clot. It participates in anchorage of the clot to subendothelium and mediates its colonisation by fibroblasts, first step to wound reparation. Lastly FN probably has an important role in organism defence. It acts as a non-immunological opsonin, promoting phagocytosis by RES macrophages of bacteria, cellular or fibrin fragments, immune complexes... present in blood. Plasmatic FN concentration is strongly decreased in several ill patients following major trauma, extensive burns, shock, sepsis, with or not evidence of DIVC, of respiratory distress... SABA and various other authors have obtained good results after injections of FN (as cryoprecipitates or concentrated fractions). It is yet necessary to confirm therapeutic role of FN.     

Role of p53 family in birth defects: lessons from zebrafish

p53 Protein family is an important teratologic suppressor, but in certain conditions it can cause congenital abnormalities. p53 Family performs this dual role in development by integrating information from cell's interior with that from the environment to determine the choice between life and death. Understanding of p53 family developmental functions may lead to new therapeutic approaches for treatment and prevention of birth defects. Zebrafish is becoming the vertebrate system of choice for studying p53 family role in development.     

FISH panels for hematologic malignancies

Cytogenetic analysis of hematological malignancies has played a crucial role in the diagnosis and clinical management of patients, as well as in providing fundamental insights into the genetic basis of the pathogenesis of these diseases. Leukemias and lymphomas have lent themselves readily to karyotypic analysis and undoubtedly represent the greatest successes of cytogenetics in human cancer. Several cytogenetic changes have been shown to have considerable prognostic significance also and are being used as measurable targets for response to therapy. Molecular characterization of the recurrent cytogenetic abnormalities has identified genes involved in leukemogenesis and formed a basis for specific treatment strategies. Fluorescence in situ hybridization (FISH) analysis, since its introduction, has revolutionized the field and enabled a more precise determination of the presence and frequency of genetic abnormalities. It is particularly indispensable where metaphase cytogenetics may be difficult in the largely quiescent cells of some hematological malignancies, particularly the lymphoid disorders. FISH probes have been used extensively to detect nonrandom abnormalities in interphase nuclei and the true incidence of chromosome abnormalities has been proven to be much higher than that detected by conventional chromosomal analysis. The avail- ability of a comprehensive line of commercial probes for rapid identification of critical genetic aberrations has contributed to the widespread use of this technique. It has also led to the current practice in most laboratories to test for genetic aberrations by using FISH panels that have been designed to detect genetic changes important not only in the diagnosis of leukemias and lymphomas, but also because of their association with prognosis, to identify high-risk populations in specific hematological cancers, so they can be targeted for aggressive therapy.     

The role of Herceptin in early breast cancer

Herceptin is widely regarded as the most important development in the treatment of breast cancer since Tamoxifen and the development of the multidisciplinary team (MDT). It is particularly exciting from an oncological polint of view as it represents success in the emerging field of specific targeted therapies to specific molecular abnormalities in tumour cells. This review will focus on the nature of the Her2 overexpression and the role of herceptin in the treatment of early breast cancer.     

Small-molecule inhibitors of cathepsin L incorporating functionalized ring-fused molecular frameworks

Cathepsin L is a cysteine protease that is upregulated in a variety of malignant tumors and plays a significant role in cancer cell invasion and migration. It is an attractive target for the development of small-molecule inhibitors, which may prove beneficial as treatment agents to limit or arrest cancer metastasis. We have previously identified a structurally diverse series of thiosemicarbazone-based inhibitors that incorporate the benzophenone and thiochromanone molecular scaffolds. Herein we report an important extension of this work designed to explore fused aryl–alkyl ring molecular systems that feature nitrogen atom incorporation (dihydroquinoline-based) and carbon atom exclusivity (tetrahydronaphthalene-based). In addition, analogues that contain oxygen (chromanone-based), sulfur (thiochroman-based), sulfoxide, and sulfone functionalization have been prepared in order to further investigate the structure–activity relationship aspects associated with these compounds and their ability to inhibit cathepsins L and B. From this small-library of 30 compounds, five were found to be strongly inhibitory (IC₅₀ <500 nM) against cathepsin L with the most active compound (7-bromodihydroquinoline thiosemicarbazone 48) demonstrating an IC₅₀ = 164 nM. All of the compounds evaluated were inactive (IC₅₀ >10,000 nM) as inhibitors of cathepsin B, thus establishing a high degree (>20-fold) of selectivity (cathepsin L vs. cathepsin B) for the most active cathepsin L inhibitors in this series.     

Electromyographic analysis during pull,forward punch,elevation and overhead throw after conservative treatment or capsular shift at patient with multidirectional shoulder joint instability

PurposeThe aim of this study was to compare the muscle activity of patients with multidirectional instability treated in a conservative or complex manner (capsular shift with postoperative rehabilitation) and the muscle activity of stable shoulder joints before and after treatment during pull, push, and elevation of upper extremities and during overhead throw.ScopeThe study was carried out on 34 patients with multidirectional shoulder instability treated non-operatively, on 31 patients with multidirectional shoulder instability treated operatively, and on 50 healthy subjects. Signals were recorded by surface EMG from eight different muscles. The mean and standard deviation of the maximum amplitude of normalized voluntary electrical activity for the different movement types and time broadness values during overhead throw were determined for each muscle in all groups and compared with each other.ConclusionThe centralization of the glenohumeral joint and the reduction of instability is attempted to be ensured by the organism through increasing the role of rotator cuff muscles (p = 0.009) and decreasing the role of the deltoid, biceps brachii, and pectoralis maior muscles (p = 0.007). At patients after short-term and long-term conservative treatment, the maximum amplitude of normalized voluntary electrical activity of stabilizer muscles is significantly higher (p = 0.006), and that of accelerator muscles is significantly lower (p = 0.005) and the time broadness is significantly longer (p = 0.01) than that of the control group. At patients after complex treatment (open capsular shift with postoperative conservative rehabilitation) the characteristic of the muscle pattern is similar (p = 0.19) to the control group.The complex treatment resolves the labral ligamentous abnormalities by operative treatment and restores the impaired muscular control by postoperative rehabilitation, whereas the conservative treatment restores only the muscular control.     

Telomere erosion in human pluripotent stem cells leads to ATR-mediated mitotic catastrophe

It is well established that short telomeres activate an ATM-driven DNA damage response that leads to senescence in terminally differentiated cells. However, technical limitations have hampered our understanding of how telomere shortening is signaled in human stem cells. Here, we show that telomere attrition induces ssDNA accumulation (G-strand) at telomeres in human pluripotent stem cells (hPSCs), but not in their differentiated progeny. This led to a unique role for ATR in the response of hPSCs to telomere shortening that culminated in an extended S/G2 cell cycle phase and a longer period of mitosis, which was associated with aneuploidy and mitotic catastrophe. Loss of p53 increased resistance to death, at the expense of increased mitotic abnormalities in hPSCs. Taken together, our data reveal an unexpected dominant role of ATR in hPSCs, combined with unique cell cycle abnormalities and, ultimately, consequences distinct from those observed in their isogenic differentiated counterparts.     

Plasma prolactin,blood metabolites and milk production in bromocryptine-treated crossbred goats

To determine the effect of bromocryptine on plasma prolactin, metabolites and milk production, six healthy crossbred goats in their second or third lactation were selected from the institute’s goat herd. The goats were injected with bromocryptine @ 5 mg per day intramuscularly for a period of 5 days during 55–60 days of lactation (period I) and treatment was repeated after 14 days for an additional 5 days (period II). Blood samples were collected for 5 consecutive days before, during and after administration of bromocryptine during both periods of the study. Milk samples were collected on days coinciding with the days of blood sampling. During period I, bromocryptine administration decreased (P < 0.01) milk yields by 27.4%. After withdrawal of bromocryptine the yields increased (P < 0.01); however, during period II, bromocryptine treatment did not decrease milk yields. During period I bromocryptine treatment suppressed prolactin level (P < 0.01) which coincided with decrease in milk yield, but in period II such decreases in prolactin did not coincide with changes in milk yields. Fat content increased (P < 0.01) after bromocryptine administration in both periods. A decrease (P < 0.01) in protein and lactose content indicated a possible role of prolactin in the synthesis of these constituents by the mammary gland cell in goats. Blood glucose and NEFA were not affected by bromocryptine in period I but in period II an increase in blood glucose with a simultaneous decrease in NEFA was observed (P < 0.01).From this study it is concluded that prolactin has a role in the maintenance of milk secretion through protein synthesis by the mammary gland. However, it does not seem to have any direct role on milk fat synthesis.     

Cancer cells resist hyperthermia due to its obstructed activation of caspase 3

AimIt is well known that inducing hyperthermia is a type of cancer treatment but some research groups indicate that this treatment is not effective. This article finds and explains the mechanism of this treatment and its possible problems.BackgroundHyperthermia is commonly known as a state when the temperature of the body rises to a level that can threaten one’s health. Hyperthermia is a type of cancer treatment in which body tissue is exposed to high temperatures (up to 45 °C). Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues. However, this mechanism is not known.Materials and MethodsWe recently treated cancer cells with different temperatures ranging from 37 °C to 47 °C and further measured their caspase 3 secretion by ELISA, western blot and cell survival rate by microscope.ResultsWe found that most cancer cells are able to resist hyperthermia more than normal cells most likely via non-activation of caspase3. We also found that hyperthermia-treated (≥41°) cancer cells extend a long pseudopod-like extension in comparison to the same cancer cells under normal conditions.ConclusionOur data here indicates that cancer cells have resistance to higher temperatures compared to normal cells via non-activation of caspase 3. This is a significant issue that needs to be brought to attention as the medical community has always believed that a high temperature treatment can selectively kill cancer/tumor cells. Additionally, we believe that the pseudopod-like extensions of hyperthermia-treated cancer cells must be related to its resistance to hyperthermia.     

Role of the IL-6-JAK1-STAT3-Oct-4 pathway in the conversion of non-stem cancer cells into cancer stem-like cells

Previous studies have demonstrated that a small subset of cancer cells is capable of tumor initiation. The existence of tumor initiating cancer stem cells (CSCs) has several implications in terms of future cancer treatment and therapies. However, recently, several researchers proposed that differentiated cancer cells (non-CSCs) can convert to stem-like cells to maintain equilibrium. These results imply that removing CSCs may prompt non-CSCs in the tumor to convert into stem cells to maintain the equilibrium. Interleukin-6 (IL-6) has been found to play an important role in the inducible formation of CSCs and their dynamic equilibrium with non-stem cells. In this study, we used CSC-like human breast cancer cells and their alternate subset non-CSCs to investigate how IL-6 regulates the conversion of non-CSCs to CSCs. MDA-MB-231 and MDA-MB-453 CSC-like cells formed mammospheres well, whereas most of non-stem cells died by anoikis and only part of the remaining non-stem cells produced viable mammospheres. Similar results were observed in xenograft tumor formation. Data from cytokine array assay show that IL-6 was secreted from non-CSCs when cells were cultured in ultra-low attachment plates. IL-6 regulates CSC-associated OCT-4 gene expression through the IL-6-JAK1-STAT3 signal transduction pathway in non-CSCs. Inhibiting this pathway by treatment with anti-IL-6 antibody (1 μg/ml) or niclosamide (0.5–2 μM)/LLL12 (5–10 μM) effectively prevented OCT-4 gene expression. These results suggest that the IL-6-JAK1-STAT3 signal transduction pathway plays an important role in the conversion of non-CSCs into CSCs through regulation of OCT-4 gene expression.     

Inhibition of myoblast differentiation in vitro by a protein isolated from liver cell medium

We have recently discovered that cells of Coon's Buffalo rat liver (BRL) line secrete a protein which is a potent inhibitor of skeletal myoblast differentiation in vitro. Using ion exchange and molecular exclusion chromatography, we have prepared this protein, which we designate "differentiation inhibitor" (DI), from the materials secreted by BRL cells maintained in serum-free medium. It is a relatively heat- stable protein which is inactivated by treatment with trypsin and mercaptoethanol and has an apparent molecular weight in the range 30,000--36,000. It exhibits no detectable mitogenic or lectin activity and differs from previously reported inhibitors of myoblast differentiation in several respects. It is active in all skeletal myoblast systems tested (Yaffe's L6 line as well as primary cultures of rat, chick, and Japanese quail myoblasts), and it blocks fusion, elevation of creatine kinase, and increased binding of alpha- bungarotoxin. Parallel fractionation of fetal bovine serum (FBS) and chick embryo extract (CEE) yields a peak of activity which similarly inhibits myoblast differentiation. We suggest that the differentiation inhibitor from BRL cells may correspond to the differentiation- inhibiting component(s) of FBS and CEE, and we call attention to the possibility that such a substance could play a role in embryonic growth of myoblasts and in satellite cell formation.     

Bile acids: the role of peroxisomes

It is well established that peroxisomes play a crucial role in de novo bile acid synthesis. Studies in patients with a peroxisomal disorder have been indispensable for the elucidation of the precise role of peroxisomes. Several peroxisomal disorders are associated with distinct bile acid abnormalities and each disorder has a characteristic pattern of abnormal bile acids that accumulate, which is often used for diagnostic purposes. The patients have also been important for determining the pathophysiological consequences of defects in bile acid biosynthesis. In this review, we will discuss all the peroxisomal steps involved in bile acid synthesis and the bile acid abnormalities in patients with peroxisomal disorders. We will show the results of bile acid measurements in several tissues from patients, including brain, and we will discuss the toxicity and the pathological effects of the abnormal bile acids.