Thromboprophylaxis in carriers of antiphospholipid antibodies (APL) without previous thrombosis: "Pros" and "Cons"

The presence of anti-phospholipid (aPL) is necessary but not sufficient to induce a thrombotic event. The "second hit" hypothesis suggested that an additional trigger may be needed to develop a vascular event in aPL carriers. In this article, pro and con of primary thromboprophylaxis in aPL carriers is deeply discussed, concluding that univocal data are not available, due to conflicting results of available clinical trials. However, in clinical practice the primary thromboprophylaxis is not indicated in all unselected asymptomatic aPL carriers, and the best strategy begin with the assessment of the peculiar risk profile of the subject. Thus, it is mandatory to eliminate modifiable prothrombotic risk factors (i.e. smoking, oral contraceptive), to treat the irreversible risk factors (i.e. hypertension, diabetes) and to introduce an aggressive prophylaxis with subcutaneous LMWH in high-risk situations (i.e. surgical procedures with prolonged immobilization). A different evaluation should be addressed to aPL carriers with a concomitant autoimmune disease that are considered as an additional pro-thrombotic risk factor. Similarly, concomitant positivity for more than one anti-phospholipid test confer a stronger risk of developing the thrombotic manifestations. Specific trials with larger cohorts of patients are needed to better clarify this issue.     

All in the family: disclosure of "unwanted" information to an adolescent to benefit a relative

Ethical assessments of clinical decisions are typically based on the preferences and interests of the individual patient. However, some clinical interventions, such as genetic testing or organ donation, may involve multiple family members. In these cases, one family member may have the potential to benefit, while another family member is exposed to potential physical or psychological risk. In the research setting, the balancing of benefits and risks between family members may be further complicated by uncertainty about their magnitude and likelihood. In addition, when the individual facing these apparently uncompensated risks is a child, the situation becomes particularly ethically complicated, as we appreciated in a recent case. Investigators at the National Cancer Institute were faced with a decision about whether it would be appropriate to disclose apparently "unwanted" research test results (length of telomeres in leukocyte subsets) to an adolescent about risk of future disease (dyskeratosis congenita), possibly causing psychological harm and an ethical wrong. These issues were not expected at the outset of the family's study participation but rather emerged with new data about the research tests. Disclosure of the research finding was an important consideration in order to avoid using the adolescent as a stem-cell donor for his sister. Disclosure to the adolescent could not be justified by merely considering the immediate interests and preferences of the adolescent. However, an expanded ethical analysis that considers the adolescent's familial context offers a more complete picture of the adolescent's interests and preferences which provides justification for disclosure.     

"Candidatus Neoehrlichia mikurensis," Anaplasma phagocytophilum, and lyme disease spirochetes in questing european vector ticks and in feeding ticks removed from people

To estimate the likelihood of people coming into contact with the recently described tick-borne agent "Candidatus Neoehrlichia mikurensis," we compared its prevalence to those of Lyme disease spirochetes and Anaplasma phagocytophilum in questing adult Ixodes ricinus ticks collected in various Central European sites and examined ticks, which had been removed from people, for the presence of these pathogens. Whereas spirochetes infected questing adult ticks most frequently (22.3%), fewer than a third as many ticks were infected by "Ca. Neoehrlichia mikurensis" (6.2%), and about a sixth harbored A. phagocytophilum (3.9%). On average, every twelfth encounter of a person with an I. ricinus tick (8.1%) may bear the risk of acquiring "Ca. Neoehrlichia mikurensis." Although a fifth of the people (20%) had removed at least one tick infected by "Ca. Neoehrlichia mikurensis," none displayed symptoms described for this pathogen, suggesting that its transmission may not be immediate and/or that immunocompetent individuals may not be affected. Because immunosuppressed patients may be at a particular risk of developing symptoms, it should be considered that "Ca. Neoehrlichia mikurensis" appears to be the second most common pathogen in I. ricinus ticks. In our survey, only Borrelia afzelii appears to infect Central European vector ticks more frequently.     

"Informed altruism" and "partner restriction" in the reduction of HIV infection in injecting drug users entering detoxification treatment in New York City, 1990-2001

OBJECTIVE: To assess recent developments in the HIV epidemic in injecting drug users (IDUs) in New York City. With >50,000 cases of AIDS in IDUs, New York has experienced the largest HIV/AIDS epidemic in IDUs of any city in the world. METHODS: Serial cross-sectional surveys conducted continuously from 1990 to 2001 of IDUs entering the Beth Israel Medical Center (BIMC) drug detoxification program in New York City. HIV serostatus, use of prevention services, and risk behaviors were measured. Individuals were permitted to participate multiple times in the surveys but not more than once in any year. RESULTS: Two thousand eight hundred eighty-seven individuals contributed 3100 observations from 1990 to 2001. There was a substantial and consistent decline in the prevalence of HIV infection among IDUs entering the BIMC detoxification program, from 54% (165/304) in 1991 to 13% (39/303) in 2001 (P < 0.0001). The decline was highly linear, with r2 = 0.92 and a slope of -3.7% in seroprevalence per year. The decline occurred for both males and females, both short and long-term IDUs, and the three largest racial/ethnic subgroups (all P < 0.001 by Cochran-Armitage testing). Use of HIV prevention services increased substantially, particularly syringe exchange and voluntary HIV counseling and testing. General reductions in injection risk behaviors occurred, but substantial numbers of IDUs continued to engage in both receptive and distributive syringe sharing. Two conditional types of risk reduction not currently recommended by health authorities were reported: "informed altruism," in which persons who knew that they were HIV seropositive reduced transmission behavior, and "partner restriction," in which persons who shared needles and syringes primarily confined this sharing within small social networks. CONCLUSIONS: HIV infection continues to decline in this population of IDUs in New York City, suggesting the possibility of bringing very high prevalence epidemics under control. Risk elimination may not be required; rather, multiple forms of risk reduction may be effective in reducing HIV transmission within a local population of IDUs.     

Evidence for a defect in "switch" T cells in patients with immunodeficiency and hyperimmunoglobulinemia M

Immunodeficiency with hyperimmunoglobulinemia M is a syndrome characterized by normal to elevated serum levels of IgM and low levels or absence of IgG and IgA. The defect in this syndrome is thought to reside within the B lymphocyte, which may be unable to undergo a "switch" in immunoglobulin class from IgM to IgG or IgA. To address this question more directly, we cultured B cells from nine patients with this syndrome with pokeweed mitogen and either "switch" T cells or normal control T cells. In cultures with normal T cells, only IgM was secreted, whereas in cultures with switch T cells, IgG as well as IgM, or IgM, IgG, and IgA were secreted. Furthermore, analysis of the immunoglobulin heavy-chain genes in these B cells by means of genetic probes of constant and switch regions revealed normal gene patterns. These data suggest that B cells from patients with hyperimmunoglobulinemia M may not be abnormal, as previously proposed, and that, at least in some patients with this syndrome, a defect in switch T cells may be pathogenic.     

Cellular steady-state levels of "high risk" but not "low risk" human papillomavirus (HPV) E6 proteins are increased by inhibition of proteasome-dependent degradation independent of their p53- and E6AP-binding capabilities

The group of mucosal epithelia-infecting human papillomaviruses (HPV) can be subdivided in "low" and "high risk" HPV types. Both types induce benign neoplasia (condyloma), but only the infection with a "high risk" HPV type is causally associated with an increased risk of developing anogenital tumors. The oncogenic potential of high risk HPVs resides at least partially in the viral E6 protein. The E6 protein targets the cellular p53 protein for proteasome-dependent degradation, which is associated with the immortalizing and transforming functions of these viruses. Recently the E6-dependent proteasome-mediated destabilization of additional cellular proteins (E6TP1, c-myc, Bak, hMCM7, human scribble, E6AP, MAGI-1) has been described, but the cellular mechanisms controlling the viral E6 protein stability itself have been so far not analyzed. In this study, we transiently expressed the E6 genes of the high risk HPV type 16, the low risk HPV types 6a and 11, and the cutaneous epithelia-infecting HPV types 5 and 8 from a eucaryotic expression vector and compared the cellular steady-state levels of the expressed E6 proteins. We demonstrated that the high risk HPV 16 E6 protein possesses the lowest steady-state level in comparison to the low risk HPV type E6 proteins and the cutaneous epithelia-infecting HPV type E6 proteins. Inhibition of cellular proteasome-dependent protein degradation led to an increase in steady-state levels of high risk but not of low risk E6 proteins. Analysis of functionally deficient HPV 16 E6 proteins in p53 null- and p53 wild-type-expressing cell lines revealed that the cellular steady-state level of this protein is influenced neither by its p53- nor its E6AP-binding abilities.     

Mediodorsal thalamic lesions impair "reference" and "working" memory in rats

The present experiment evaluated the ability of rats with lesions in the thalamic mediodorsal nucleus (MD) to perform a task which differentiates between "reference" and "working" memory. In this task, only four of the arms of an 8-arm radial maze were baited, and animals were to restrict their entries to arms which were baited and to avoid never-baited arms. Despite several postoperative acquisition trials, rats with MD lesions did not acquire the task to a degree comparable to control subjects. Subjects with lesions continued to enter never-baited arms (reference memory errors) and to reenter baited arms (working memory errors). Given the lack of specificity in the behavioural impairment, the reference-working memory distinction seems to be an inappropriate one for characterizing the MD lesion deficit in rats. This deficit may involve an inability to use environmental stimuli to distinguish among arms of the maze, or an alteration in motor mechanisms.     

Effect of severity of "risk region" on therapeutic intervention of myocardial infarction size.

Isosorbide dinitrate was tried in 27 patients of acute myocardial infarction (AMI) with the purpose of reduction of infarction size. Overall average effect was not significant. But, it was found that, the small and moderate "predicted infarction size" (PIS) group of patients, were benefitted by the drug therapy. Effectiveness in the therapeutic intervention on ischaemic injury bore an inverse relation with the degree of PIS or the "risk region". Varying "risk region" may be an important factor responsible for the apparent discrepancy between results of different workers regarding therapeutic intervention of infarction size.     

"Near-fatal" deliberate self-harm: characteristics, prevention and implications for the prevention of suicide

BACKGROUND: There have been few studies of the most serious cases of deliberate self-harm (DSH). These cases represent an important clinical problem. They may also be suitable as a "proxy" for suicide in research studies. METHODS: We developed a definition of "near-fatal" deliberate self-harm (NFDSH) and identified all cases attending accident and emergency departments in an urban area during an 18-month period. We compared them to less severe DSH on social and clinical characteristics, and examined their initial clinical management. We compared their age and gender profile with that of completed suicides. NFDSH cases who agreed to be interviewed were asked about their experiences of seeking help and their views on prevention of suicide. RESULTS: 158 cases were identified, 8% of all DSH. The most common method of self-harm was self-poisoning. The most common psychiatric diagnosis was depression. Compared to less severe DSH, near-fatal cases had higher rates of several social and clinical risk factors for suicide and showed evidence of greater suicidal intent. Forty-one percent were allowed home following assessment. Most admissions lasted 2 days or less. The age and gender profile was closer to that of suicide than in DSH generally. Few subjects agreed to be interviewed; those who did described poor previous experiences of services. LIMITATIONS: We did not assess each case of DSH individually but applied a workable definition of NFDSH. Firm conclusions cannot be drawn from the qualitative part of the study because of the low rate of agreement to interview. CONCLUSIONS: NFDSH is an important clinical phenomenon associated with indicators of high suicide risk. This high risk is frequently not reflected in clinical management. Further studies of NFDSH could contribute to what is known about suicide prevention but the reluctance of NFDSH subjects to be interviewed may be a difficulty for future research.     

Diet counseling through "Shoku-dietary Coaching"

"Shoku-dietary Coaching" is a skill under development by Kageyama, who applies "coaching," widely used in the business field, to diet counseling. This counseling aims at improving conventional "nutritional guidance-type diet counseling" and promoting self-motivation so that healthy clients eagerly improve their own health, and clients with obesity or lifestyle-related diseases can learn self-control. In Shoku-dietary Coaching, the basis for the differentiation between healthy and unhealthy conditions is not only the parameters measured by medical devices. In Shoku-dietary Coaching, attention is directed to clients' assessment of their own lifestyle, dietary goals they have, and actions they will take to achieve them. To increase the health level of clients, we are developing techniques to enhance their motivation by showing sympathy with and support for their dietary behavior and health awareness. In addition, we give guidance through both theory and the practice of such things as having three meals a day at regular hours, knowing the kinds and daily amounts of foods appropriate for each client, and clarifying the percentages of seasonings necessary for cooking. The habit of having meals at regular hours alleviates stress, promotes communication with people sitting at the same table, and increases the health level of both the client and the others. These are important elements in the theory of Shoku-dietary Coaching. Putting the above into practice should not be limited to clients, but should include the clinic staff so as to deepen their own understanding and communication. Enhanced communication reinforces team medical care in the clinic. Communication skills which involve respect for others, continuous motivation of individuals, and achievement of purposes that may even require a long time may be useful for all people.     

Confronting "culture" in medicine's "culture of no culture".

The author presents reflections from medical anthropology on the institutional culture of medicine and medical education, which sees itself as a "culture of no culture" and which systematically tends to foster static and essentialist conceptions of "culture" as applied to patients. Even though requirements designed to address cultural competence are increasingly incorporated into medical school curricula, medical students as a group may be forgiven for failing to take these very seriously as long as they perceive that they are quite distinct from the real competence that they need to acquire. To change this situation will require challenging the tendency to assume that "real" and "cultural" must be mutually exclusive terms. Physicians' medical knowledge is no less cultural for being real, just as patients' lived experiences and perspectives are no less real for being cultural. Whether this lesson can be effectively conveyed within existing curricular frameworks remains an open question. Cultural competence curricula will, perhaps, achieve their greatest success if and when they put themselves out of business-if and when, that is, medical competence itself is transformed to such a degree that it is no longer possible to imagine it as not also being "cultural."     

Comments on methods and results in: Sherman et al., "Segregation analysis of balanced pericentric inversions in pedigree data"

The analysis by Sherman et al. (1986), its basis and results have been examined. The analysis relies on general methods, which may give acceptable results under the special conditions considered by the authors, but will usually produce more or less misleading results. The program POINTER (Lalouel & Morton 1981) is shown to be based partly on a chain of irrelevant arguments for the actual context. The so-called "conventional ascertainment rules" (Morton et al. 1983) are shown to produce misleading results in cases where their assumptions are not satisfied. The mean risk for unbalanced offspring is underestimated because of an erroneous ascertainment correction. The segregation frequencies are found to be different in three national samples, contrary to the claim by Sherman et al. Only a small proportion of all information available in the data has been utilized. Alternative and more appropriate models, hypotheses and procedures have been suggested. The frequent use of packages with computer programmes of standard statistical procedures in nonstandard situations with data from collaborative studies in human cytogenetics is discussed.     

Use of elderly tumor-free subjects as a "supercontrol" for cancer epidemiological studies: pros and cons

Search for cancer-predisposing single-nucleotide gene polymorphisms is complicated due to weakness of expected associations. We introduced a novel design for molecular epidemiological study, which relies on selection of highly demonstrative cases and controls. It is assumed that patients with clinical features of hereditary predisposition (e.g., cancer bilaterality, or young onset, or presence of family history, etc.) are more likely to accumulate at-risk alleles than randomly recruited cases. Furthermore, subjects with characteristics of cancer tolerance, e.g., elderly tumor-free smokers, may serve as a "supercontrol" for the rapid assessment of polymorphic candidates. The utility of the "comparison of extremes" design has already been exemplified in a series of reports. However, the use of elderly subjects for cancer case-control studies may possess a bias; for example, factors contributing to cancer predisposition may nevertheless be advantageous for the overall longevity, as they could compensate age-related decline of tissue maintenance and renewal. For example, there is some evidence for a dual role of the apoptosis-deficient Pro/Pro genotype of p53 gene, which may simultaneously increase both cancer risk and survival. Comprehensive studies on distribution of cancer-related gene polymorphisms in elderly population remain to be done.     

Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other"

It is increasingly clear that immunity to "self"-antigens may result in tumor destruction in mouse and man. But which antigens should be targeted with therapeutic cancer vaccines? In the case of melanoma, recognition of melanocyte differentiation antigens (MDA) can be associated with autoimmune depigmentation (vitiligo). We propose that intersection of protein transport to melanosomes and endosomes allows for the loading of MDA-derived peptides on MHC class II molecules, resulting in the activation of MDA-specific CD4+ "helper" T cells that aid the induction of melanoma-specific CD8+ T cells. Thus, the immunogenicity of MDA may be a consequence of their unique cell biology. Studies of MDA-based vaccines can provide new insight into the development of more effective cancer vaccines.     

Aspartate may be an excitatory transmitter mediating visual excitation of "sustained" but not "transient" cells in the cat retina: iontophoretic studies in vivo

Although the excitatory amino acids, aspartate and glutamate are present in large quantities in the layers of the mammalian retina where the bipolar and amacrine cells make contact with the retinal ganglion cells, it was not known whether these amino acids are the actual neurotransmitters which excite the retinal ganglion cells. To answer this L-aspartate, L-glutamate and the recently discovered powerful and selective antagonist for the N-methyl-D-aspartate receptor, 2-amino-5-phosphonovalerate, were applied iontophoretically to the "sustained" and the "transient" classes of retinal ganglion cells in the optically intact eye of anaesthetised cats. The visually-driven excitation of all "sustained" cells was significantly suppressed by 2-amino-5-phosphonovalerate, whereas that of "transient" cells was not. L-aspartate enhanced the visually-driven excitation and increased the spontaneous firing rare of all "sustained" cells but not of "transient" cells and these effects were blocked by 2-amino-5-phosphonovalerate. The results with L-glutamate were inconclusive. It is suggested that L-aspartate may be an excitatory transmitter mediating the visual response at the receptor field centre of "sustained" retinal ganglion cells, but that excitation of "transient" retinal ganglion cells is mediated by a different transmitter.     

Analysis of a previously identified "pain-protective" haplotype and individual polymorphisms in the GCH1 gene in Africans with HIV-associated sensory neuropathy: a genetic association study

We analyzed GTP cyclohydrolase 1 in symptomatic HIV-associated sensory neuropathy in Southern Africans including a "pain-protective" 3-SNP haplotype and 6 SNPs, analyzed individually and in a 6-SNP haplotype. The "pain-protective" 3-SNP haplotype and a 6-SNP haplotype containing these alleles associated with a reduced risk of pain. Another 3-SNP haplotype associated with increased presence of pain. Associations were lost after correction for age, gender, and CD4 T-cell count. Linkage disequilibrium differed between our cohort and Caucasians suggesting that these SNPs may not be ideal markers in Africans. Subsequently, the role of GTP cyclohydrolase 1 in painful HIV-associated sensory neuropathy remains possible.     

"Diabetic rosettes": a cellular immunity marker in subjects at risk for type I diabetes

The authors have previously described a marker of cell-mediated, called "diabetic rosettes", revealed by the increased binding of CD3 CD4 lymphocytes from type I diabetic patients to beta-cell membrane antigens, as compared to lymphocytes from control subjects. In the present study, they have detected such "diabetic rosettes" in some subjects at risk for type I diabetes. The mean value of lymphocytes adhering to beta (RINm5F)-cells (beta-CL) was statistically higher in those subjects at risk than in control blood bank donors (p = 0.003). When a positive test was arbitrarily defined as a value of beta-CL higher than the 95th percentile of controls, 20 p. cent of the subjects at risk were classified as beta-CL+. No difference was observed between two subgroups of subjects at risk: first degree relatives of type I diabetic patients, and non-diabetic subjects with transient hyperglycaemia. "Diabetic rosettes" were associated with HLA DR 3/4 heterozygosity (p less than 0.04) and with a "low" acute insulin release to IV glucose (p = 0.05). They were not associated with islet-cell antibodies, insulin autoantibodies, or "activated" (HLA DR+) T-lymphocytes. The authors suggest that "diabetic rosettes" represent a marker of cellular immunity in some subjects at risk for type I diabetes.     

"Lennert's lymphoma" with transformation to malignant lymphoma, histiocytic type (immunoblastic sarcoma).

Two cases of a recently described lymphoproliferative disorder called "Lennert's lymphoma" are presented. In both cases, the proliferation evolved into a frank malignant lymphoma of large lymphoid cells. This phenomenon has not been previously reported to occur in this disease. Immunohistologic study of the biopsy material in both cases suggest that it may be a T-cell proliferation. The possibility that "Lennert's lymphoma" is not a neoplasm but an abnormal immune reaction with similarities to angioimmunoblastic lymphadenopathy is raised. Whatever its nature, the potential for "Lennert's lymphoma" to transform into a frankly malignant tumor is documented.     

Leukocyte membrane "expansion": a central mechanism for leukocyte extravasation

The infiltration of inflamed tissues by leukocytes is a key event in the development and progression of inflammation. Although individual cytokines, which coordinate extravasation, have become the targets for therapy, a mechanism that is common to white cell extravasation, regardless of the specific molecular mechanism involved, would represent a more attractive therapeutic target. Such a target may be represented by the events underlying the spreading of leukocytes on the endothelium, which is a necessary prelude to extravasation. This leukocyte "spreading" involves an apparent increase in the cell surface area. The aim of this review is to examine whether the mechanism underlying the apparent expansion of plasma membrane surface area during leukocyte extravasation could be an "Achilles' heel," which is amenable to therapeutic intervention. In this short review, we evaluate the models proposed for the mechanism of membrane "expansion" and discuss recent data, which point to a mechanism of membrane "unwrinkling." The molecular pathway for the unwrinkling of the leukocyte plasma membrane may involve Ca2+ activation of mu-calpain and cleavage of cytoskeletal linkage molecules such as talin and ezrin. This route could be common to all extravasation signals and thus, represents a potential target for anti-inflammatory therapy.     

Problems in genetic counseling in a family with an “atypical” centronuclear myopathy

Genetic counseling often deals with a rare disease the inheritance of which is not clearly established or in which genetic heterogeneity is reported. In addition, relevant parameters such as penetrance, gene frequency, and mutation rate may not be available. In this situation, establishing the risk may be very difficult. An example is presented in which Bayesian risk calculation proved to be of great help in providing precise risk estimates in a family in which an “atypical” centronuclear myopathy was segregating.