Confronting Death in Legal Disputes About Treatment-Limitation in Children

Most legal analyses of selective nontreatment of seriously ill children centre on the question of whether it is in a child’s best interests to be kept alive in the face of extreme suffering and/or an intolerable quality of life. Courts have resisted any direct confrontation with the question of whether the child’s death is in his or her best interests. Nevertheless, representations of death may have an important role to play in this field of jurisprudence. The prevailing philosophy is to configure death as a release from a futile or painful existence and/or as a dignified end in an objectively hopeless situation. However, there can be disagreement about the meaning of death in these settings. Some parents object that death would be premature or that it represents a culpable neglect of their child. A closer examination of these discordant interpretations allows for a better comprehension of the cultural understandings that underscore clinical and legal accounts of death following end-of-life decisions.     

The Patient’s View: Issues of Theory and Practice

Almost all the knowledge now produced about psychiatry includes what is called “the patient’s or client’s perspective.” This paper analyzes how this notion has been framed in the discourses on mental health over the last two decades, particularly in mental health research and in anthropology. The very concept of the “patient’s perspective” is a social and historical construct. Despite its remarkable prevalence, the notion remains vague. Mental health research pictures it as a stable attribute of the individual. Anthropologists integrate the contextual nature of the patient view; but they still largely envision the psychiatric patient as a rational actor producing narratives based on common sense. However, in psychiatric practice, the client’s perspective is not something the patient individually produces; it is rather shaped by and in a context. To explore this process, my research investigated interactions between staff and patients in a French community mental health center, and showed that the client’s perspective is the result of a collective process. Further analysis demonstrates that eliciting or producing the patient’s view is sometimes considered a therapeutic goal in itself, since being granted the status of a rational and narrative actor gives access to the most valued model of care, one that is based on partnership. Being an outcome that is negotiated between patients and care providers, the “patient’s view” then becomes a new resource in mental health settings.

Oncogramme,a new individualized tumor response testing method: application to colon cancer

Colon cancer is the second leading cause of cancer-related death in industrialized countries. Many anti-cancer researches are consequently performed and individualized tumor response testing (ITRT) methods are now used to individualize patient chemotherapeutic administrations. Then, a new ITRT method, Oncogramme, was developed for colon cancer. Colon tumor fragments from different patients were dissociated and seeded in a defined culture medium. Cell preparation process as well as culture medium allowed high cell viability and a good primary culture success rate. After treatment of isolated tumoral cells by chemotherapeutics alone or in combination, cytotoxicity was determined by cell death assay allowing the Oncogramme establishment, which was validated by statistical analysis. Indeed, significant results were obtained such as different profile for each patient’s cells with various drugs, and variability between patient’s cells in the response to each drug. Procedure described here to obtain the Oncogramme is a new, fast and technically reliable ITRT method applied to colon cancer. For an individualized cancer treatment use, this test should be further validated by a phase I clinical trial.     

Negotiating A Path To Efficacy At A Clinic Of Traditional Chinese Medicine

Chinese medicine emphasizes the underlying connection of the bodily, emotional, social, and environmental dimensions in illness experience and healing. The therapeutic process, characterized as tiao (attuning, balancing), targets the patient’s overall illness condition and experience including both physical and nonphysical aspects of suffering. This study, incorporating techniques of microanalysis as an ethnographic tool and using an actual recorded clinical interaction as data, analyzes how the path to effective healing is negotiated among multiple clinical realities at a clinic of Chinese medicine in Beijing. A close examination of interactive features of actual face-to-face communication between a doctor and a patient in a specific case of “stagnation of emotions” reveals that, for an illness recognized in Chinese medicine as originating from disordered emotions, adjustment of the patient’s perceptions of reality and social relations is particularly salient in the “attuning” process. Efficacy then should be understood as more than physiological changes produced by herbs, but also as emergent through an interactive event of clinical encounters. This study demonstrates empirically how the clinical process of Chinese medicine works to define and transform the patient’s emotions and experience.     

A novel point mutation in an acceptor splice site of intron 32 (IVS32 A–12→G) but no exon 3 mutations in the glycogen debranching enzyme gene in a homozygous patient with glycogen storage disease type IIIb

Genetic deficiency of the glycogen-debranching enzyme (debrancher) causes glycogen storage disease type III (GSD III), which is divided into two subtypes: IIIa and IIIb. In GSD IIIb, glycogen accumulates only in the liver, whereas both liver and muscles are involved in GSD IIIa. The molecular basis for the differences between the two subtypes has not been fully elucidated. Recently, mutations in exon 3 of the debrancher gene were reported to be specifically associated with GSD IIIb. However, we describe a homozygous GSD IIIb patient without mutations in exon 3. Analysis of the patient’s debrancher cDNA revealed an 11-bp insertion in the normal sequence. An A to G transition at position –12 upstream of the 3′ splice site of intron 32 (IVS 32 A^–12→G) was identified in the patient’s debrancher gene. No mutations were found in exon 3. Mutational analysis of the family showed the patient to be homozygous for this novel mutation as well as three polymorphic markers. Furthermore, the mother was heterozygous and the parents were first cousins. The acceptor splice site mutation created a new 3′ splice site and resulted in insertion of an 11-bp intron sequence between exon 32 and exon 33 in the patient’s debrancher mRNA. The predicted mutant enzyme was truncated by 112 amino acids as a result of premature termination. These findings suggested that a novel IVS 32 A^–12→G mutation caused GSD IIIb in this patient. Received: 1 August 1997 / Accepted: 22 September 1997     

Basic problems of serological laboratory diagnosis

Serological laboratory diagnosis is inflicted with at least two kinds of basic problems. One type relates to the fact that the serological diagnosis of infectious diseases is double indirect: First, to diagnose an infectious disease, the identification of the microbial agent is sought that caused the disease. Second, to identify this infectious agent, the patient’s immune response to potential agents is measured. So, the serological test is neither measuring directly disease nor the cause of the disease, but the patient’s immune system. Another type of problem is based on the fact that each person’s immune system is very individual. The exact physicochemical properties of antibodies are unique for each clone of antibodies. The way an individual’s immune system sees an infectious agent depends not only on the genetic makeup of the person but also on the personal experience from former encounters with infectious agents. Both types of problems lead to complexities in selecting the appropriate test, in interpreting the results, and in standardizing serological tests. Therefore, a close collaboration of the laboratory with the clinic is mandatory to avoid erroneous conclusions from serological test results, which might lead to wrong decisions in patient care.     

Mouth cavity base defect treated with biosynthetic graft

The use of in vitro prepared biosynthetic grafts can considerably improve the patient’s quality of life. This work reports on the use of an autologous graft prepared from a patient’s preputial cells cultivated on biodegradable polymeric membrane. Coladerm membrane is based on the chemically modified polyelectrolyte complex of atelocollagen and hyaluronan. The graft was used to cover a defect in the mouth cavity base and tongue after reconstruction surgery performed at this site in the past. The presented clinical case showed that the autologous biosynthetic graft prepared from foreskin cells can be successfully used for covering of medium-size defects in mouth cavity base resulting in the regeneration of target mouth structures with significant improvement of patient’s quality of life.     

Potential role of Neuregulin 1 and TNF-alpha (−308) polymorphism in schizophrenia patients visiting hospitals in Lahore,Pakistan

Schizophrenia is a chronic and disabling disease of the brain. Schizophrenic patients have auditory hallucinations, delusions and reduced social skills. Recent studies suggest that the genetic polymorphisms are linked with development of schizophrenia. Polymorphisms of schizophrenia susceptibility and different cytokine genes act as the genetic markers. The objective of our study is to examine the association between the neuregulin 1 and tumor necrosis factor-α (−308) gene polymorphism with schizophrenia. This association was performed on the basis of molecular biology to screen the mutations of neuregulin 1 and tumor necrosis factor-α (−308) gene in schizophrenic patients by polymorphism analysis. Statistical analysis of the observed data shows that there was an association (P = 0.003) between patient’s group and controls in terms of genotypes of single-nucleotide polymorphism 1 rather than single-nucleotide polymorphism 2 of neuregulin 1. So, heterozygous (adenine/guanine) allelic pattern can be a higher risk factor of schizophrenic patients. Polymorphism of tumor necrosis factor-α (−308) gene indicated frequent presence of homozygous (adenine/adenine) allelic pattern in patient’s group than in controls (P = 0.015). Statistical analysis indicates that the age distribution has significant difference between patient’s group and controls (P = 0.022) while the gender ratio is not significantly different (P = 0.366) between the two groups. It was concluded that in Pakistani population the neuregulin 1 and tumor necrosis factor-α (−308) genes are strongly associated with schizophrenia.     

Characterization of a novel α-mannosidosis-causing mutation and its use in leukocyte genotyping after bone marrow transplantation

α-Mannosidosis is a lysosomal storage disorder caused by deficiency of lysosomal α-mannosidase (LAMAN). Major symptoms include mental retardation, skeletal changes and recurrent infections. Recently, a successful bone marrow transplantation (BMT) in an α-mannosidosis patient was reported. Here we show that this patient was homozygous for a novel mutation, a 1-bp insertion (1197–1198insA) in exon 9 of the LAMAN gene. By using this mutation as a marker, we demonstrate that 1 year post-BMT, the LAMAN genotype of the patient’s leukocytes was identical to that of the donor. This method of genotyping blood cells is a fast and accurate way to monitor the colonization of donor bone marrow cells. Received: 9 September 1998 / Accepted: 3 November 1998     

Age-related changes of bone mineral density in human calcaneus, talus, and scaphoid bone

To examine whether the bone mineral density (BMD) decreases uniformly with aging in any spongy bones, the authors investigated age-related changes of BMD in the calcaneus, talus, and scaphoid bone. After the ordinary dissection by medical students was finished, calcanei, tali, and scaphoid bones were resected from the subjects, and BMDs were measured by dual-energy X-ray absorptiometry. Their BMDs seemed to decrease gradually with aging in the calcanei, tali, and scaphoid bones. It was found that there were statistically significant relationships between age and BMD in the men’s and women’s scaphoid bones, women’s tali, and women’s calcanei, but not in the men’s tali and calcanei. It should be noted that there were significant relationships between age and BMD in both men’s and women’s scaphoid bones. In regard to relationship in BMD between the bones of the upper and lower limbs in individuals, it was found that the relationship between the calcaneus and talus was higher than that between the calcaneus and scaphoid bone. This suggests that there is a higher relationship in BMD between the two tarsal bones compared with that between the tarsal and carpal bones.     

Characterization of a cytogenetic 17q11.2 deletion in an NF1 patient with a contiguous gene syndrome

We report on a rare patient screened as a putative carrier of a contiguous gene syndrome on the basis of a complex phenotype characterized by sporadic neurofibromatosis type 1 (NF1), dysmorphism, mental retardation and severe skeletal anomalies. A cytogenetically visible 17q11.2 deletion was detected in the patient’s karyotype by high-resolution banding and confirmed by fluorescence in situ hybridization with yeast artificial chromosomes targeting the NF1 region. Analysis of the segregation from parents to proband of 13 polymorphic DNA markers, either contiguous or contained within the NF1 gene, showed that the patient is hemizygous at sites within the NF1 gene – the AAAT-Alu repeat in the 5′ region of intron 27b, the CA/GT microsatellite in the 3′ region of intron 27b, and the CA/GT microsatellite in intron 38 – and at the extragenic D17S798 locus, distal to the 3′ end of NF1. The patient may be an important resource in the identification of genes downstream of NF1 that may contribute to some of his extra-NF1 clinical signs. Received: 8 May 1996 / Revised: 17 June 1996     

Selecting EEG components using time series analysis in brain death diagnosis

In diagnosis of brain death for human organ transplant, EEG (electroencephalogram) must be flat to conclude the patient’s brain death but it has been reported that the flat EEG test is sometimes difficult due to artifacts such as the contamination from the power supply and ECG (electrocardiogram, the signal from the heartbeat). ICA (independent component analysis) is an effective signal processing method that can separate such artifacts from the EEG signals. Applying ICA to EEG channels, we obtain several separated components among which some correspond to the brain activities while others contain artifacts. This paper aims at automatic selection of the separated components based on time series analysis. In the flat EEG test in brain death diagnosis, such automatic component selection is helpful.     

Dealing With Death in the Jewish Legal Tradition

The main theme of the article is the tension between the obligation to preserve life, and the value of timely death. This tension is resolved by distinguishing between precipitating death, which is prohibited, and merely removing an impediment to it, which is permitted. In contemporary Jewish law, a distinction is made between therapy, which may be discontinued, and life-support, which must be maintained until the establishment of death. Another theme is that of “soft” patient autonomy, and its role in dealing with the dying in both traditional Jewish law and Israel’s Terminal Patient Law, 2005. Preventing suffering in relation to a dying person, and praying for his or her death are also discussed in the article.     

A survivor of breast cancer with immunity to MUC-1 mucin, and lactational mastitis

 The human mucin, MUC-1, is a transmembrane glycoprotein that is produced by both normal an malignant epithelium. The MUC-1 produced by malignant epithelium is underglycosylated, which leads to the expression by tumors of novel T and B cell epitopes on the mucin polypeptide core. Similar underglycosylation occurs in the lactating breast. In this report, we describe a long-term survivor of breast cancer whose tumor strongly expressed the T- and B-cell-stimulatory epitopes. Five years after presenting with the tumor, the patient had her first pregnancy, at which time she developed fulminant lymphocytic mastitis. We demonstrate that the lactating breast produced mucin expressing the same “tumor-specific” epitopes as the original cancer. The patient had circulating anti-mucin antibodies of both the IgM and IgG isotypes (these are not found in normal controls), and mucin-specific cytotoxic T lymphocytes in the peripheral blood. Limiting  –  dilution analysis for mucin  –  specific cytotoxic T lymphocytes in three different experiments yielded frequencies of 1 in 3086, 1 in 673, and 1 in 583, compared to approximately 1 in 10⁶ in normal controls. The patient remains clinically free of carcinoma after 5 additional years of follow-up. We propose that the original tumor primed the patient’s immune response against the mucin epitopes, and that the re-expression of these epitopes on the lactating breast evoked a secondary immune response. It is tempting to speculate that the vigor of her anti-mucin immunity may have helped protect this patient against recurrent tumor. Received: 12 February 1996 / Accepted: 5 November 1996     

Selective complement C1s deficiency caused by homozygous four-base deletion in the C1s gene

The complement system plays an important role in defense mechanisms by promoting the adherence of microorganisms to phagocytic cells and lysis of foreign organisms. Deficiencies of the first complement components, C1r/C1s, often cause systemic lupus erythema-tosus-like syndromes and severe pyogenic infections. Up to now no genetic analysis of the C1r/C1s deficiencies has been carried out. In the present work, we report the first genetic analysis of selective C1s deficiency, the patient having a normal amount of C1r. C1s RNA with a normal size was detected in patient’s subcutaneous fibroblasts (YKF) by RNA blot analysis and RT-PCR. The amount of C1s RNA was approximately one-tenth of the RNA from the human chondrosarcoma cell line, HCS2/8. In contrast, the levels of C1r and β-actin RNA of YKF were similar to that of HCS2/8. Sequence analysis of C1s cDNA revealed a deletion at nucleotides 1087–1090 (TTTG), creating a stop codon (TGA) at position 94 downstream of the mutation site. Direct sequencing of the gene between the primers designed on intron 9 and exon 10 indicated the presence of the deletion on exon 10 of the gene. Quantitative Southern blot hybridization suggested the mutation was homozygous. The 4-bp deletion on exon 10 was also found in the patient’s heterozygous mother who had normal hemolytic activity. Received: 6 July 1998 / Accepted: 1 August 1998     

Cellular markers based on DNA repair (BER,MMR) expression of MLH1, MSH2, FasR and death of lymphocytes as predictive parameters for clinical response to chemotherapy of melanoma patients

Melanoma is a highly aggressive tumor of melanocytes. The efficacy of different cytotoxic chemotherapy regimens does not exceed 20%. The search for markers for patient sensitivity to chemotherapy provides a rational basis for the development of cytotoxic chemotherapy. In this study, we evaluated six blood lymphocyte parameters (the efficacy of BER and MMR; the expression of MLH1, MSH2, FasR; and cell death) as prognostic markers for melanoma chemotherapy. We found that chemotherapy induced AP sites and ssDNA breaks in lymphocytes repaired through the BER pathway. However, ssDNA breaks were completely repaired after chemotherapy and, therefore, did not contribute to the toxic effect of chemotherapy. dsDNA breaks produced by a functioning MMR system appeared downstream of methylation adducts, which was confirmed by the linear correlation of these parameters in various patients. The number of dsDNA breaks, but not MMR, MLH1, and MSH2 expression, correlated to the efficacy of chemotherapy. A positive correlation was observed between lymphocyte death induced by chemotherapy and the patient’s clinical response, which may show that the nucleotide excision repair (NER) mechanism is implicated in the generation of double-strand breaks and the cytotoxic effect of chemotherapy.     

Familial genetic risk factors in premature cardiovascular disease: a family study

Cardiovascular disease (CVD) is closely associated with familial predisposition. The aim of the present study was to investigate predisposing risk factors in the family of a young patient who underwent coronary artery bypass graft surgery due to CVD. The father and uncle of the patient died at an early age due to myocardial infarction. Various stages of CVD were identified in both of the patient’s brothers (28 and 32 years of age). Biochemical tests (fasting blood glucose, lipid profile, urea, creatinine and liver enzymes) and a complete blood count (haemoglobin, haematocrit, white blood cell count, and platelet count) were performed. Physiological coagulation inhibitory factors (protein C, protein S, and antithrombin III), prothrombotic genetic risk factors (factor V Leiden, plasminogen activator inhibitor-1, methylenetetrahydrofolate reductase A1C and C6T, angiotensin-converting enzyme, β-fibrinogen, glycoprotein IIIa and factor XIII) and homocysteine levels were evaluated in all cases. Defects were observed in many genetic factors and in the systems regulated by these factors. The results were compatible with those reported in the literature. In conclusion, it is possible to determine a specific family history in young adults with CVD. From this perspective, the emergence of more serious CVD may be prevented by providing disease-related information to the other family members and implementing preventive measures.     

Traumatic Amputation: A Case of Laotian Indignation and Injustice

Culture is an essential variable of diagnosis and treatment. A cultural perspective draws attention to the social context within which symptoms arise, are given meaning, and are managed. Ethno-cultural work on illness narratives suggests that most people can provide culturally-based explanations for their symptoms. While these explanations are inconsistent with biomedical theory, they relieve patient distress by allowing the patient to create meaning for symptoms. Exploring the characteristics, context, and antecedents of the symptoms enables the patient to convey them to the clinician who may have a divergent explanation of sickness. This case study uses the Outline for Cultural Formulation of the DSM-IV created for clinicians to elicit a narrative account of the illness experience from the patient. Our study examines how the patient, a Laotian used social indignation (“Kwam khem keuang”) as an explanatory model for his ailment. He was diagnosed with post-traumatic stress disorder after having undergone a traumatic amputation. In the process of explaining his illness through a cultural idiom, the patient was able to reveal both personal and collective meaning of repressed anger and frustration, expressing them in a context that was acceptable to him. This cultural idiom allowed the patient to reflect upon the structure of the health care system and the specific context in which symptoms and their possible origins are recounted and explored. It also clarified to the treating clinicians some categories of experience and causal explanations that did not fit easily with western biomedical and psychiatric understanding. The case study illustrates how a cultural approach to illness from the patient’s perspective offers a reflexive stance on the clinician–patient interaction that allows for better patient care.     

Dissection and molecular analysis of alloreactive CD8+ T cell responses in allogeneic haematopoietic stem cell transplantation

We applied a cDNA expression screening procedure with cryopreserved non-clonal CD8+ T cell populations (Lennerz et al., Proc. Natl. Acad. Sci. USA 102:16013-8, 2005) to the identification of candidate antigens for graft-versus-host disease (GvHD) and graft-versus-leukaemia (GvL) effects in allogeneic haematopoietic stem cell transplantation (allo-HSCT). In a patient–donor model system with HLA class I disparities, we identified an HLA-B*44 mismatch allele, HLA-B*4405, as the dominant target of alloreactive T cells expanded in vitro from donor peripheral blood mononuclear cells (PBMC). HLA-B*4405-reactive T cells were detectable after multiple in vitro stimulations in the patient’s post-HSCT PBMC. In a patient–donor model with full HLA compatibility, the major target antigen of donor lymphocytes stimulated in vitro with the respective patient’s pre-HSCT PBMC was restricted by HLA-A*0201 and was encoded by TRIM22-442 C, a newly detected polymorphic allele of the tripartite motif family member TRIM22 (synonym: STAF50), preferentially expressed in cells of the haematopoietic system. An arginine(R)-to-cysteine(C) exchange at position 442 generated an immunogenic T cell epitope equivalent to a minor histocompatibility antigen (mHag). TRIM22-442C-specific T cells persisted long-term in the patient’s post-HSCT PBMC. Approximately, 1.3% of Caucasians carry TRIM22.442 C in association with HLA-A*0201. In particular, the knowledge of a large and diverse panel of such mHags may be crucial for further improvement of donor selection and adoptive T cell transfer strategies. The procedure applied herein will help to accelerate and facilitate their identification.     

The role of herbivorous water birds in aquatic systems through interactions with aquatic macrophytes,with special reference to the Bewick’s Swan – Fennel Pondweed system

The role of aquatic macrophytes in stimulating biodiversity and maintaining clear waters is currently undisputed. The management of (eutrophic) shallow waters is therefore often directed at (re-)establishing macrophyte domination. In contrast, the role of water birds has long been considered of minor importance for the functioning of fresh water ecosystems. Indeed, in terms of biomass and production, water birds constitute only a minor part of these systems. However, water birds may graze heavily on water plants under certain circumstances, and the question arises whether herbivorous water birds have an important indirect effect on shallow fresh water systems. Mainly illustrated with the interaction between Bewick’s Swans and Fennel Pondweed, we present data on the role that water plants may play in the life of water birds and how water birds may impact water plants’ fitness in terms of survival, production, dispersal and competitive ability. It appears that water plants may be crucial for water birds during periods of high-energy requirements, such as migration. Despite the plants’ costs associated with water bird grazing, the interaction between water birds and water plants varies in nature from an apparent predator–prey relationship to a mutually beneficial interaction depending on the context and the perspective. For the case of the Bewick’s Swan–Fennel Pondweed interaction, regular bird grazing is sustainable and may actually favour the plant’s dispersal. Thus, Bewick’s Swans themselves may in fact play a crucial role in establishing and maintaining the Fennel Pondweed rich staging sites between the swans’ wintering and breeding grounds, which are vital for the swans’ successful migration.