Primary hyperparathyroidism in childhood and adolescence

Objective : The aim of this study was to determine the nature of the presentation and pathology of primary hyperparathyroidism in children and adolescents and to compare these findings with adults.
Methodology : Data were obtained from the Thyroid Surgery Database at Royal North Shore Hospital on all children and adolescents undergoing parathyroid surgery. These results were then compared to data obtained from the last 100 consecutive adult parathyroidectomies.
Results : A total of eight younger patients underwent parathyroidectomy including three children (0–12 years) and five adolescents (13–18 years). A common presentation in the younger age group was hypercalcaemic crisis (50%) with a serum calcium >3.5 mmol/L and clinical signs of calcium intoxication. This compared to the adult age group where only 8% presented with crisis ( P <0.05). Eighty-eight per cent of the younger patients complained of abdominal symptoms compared to only 1% of adults. Seven of eight young patients had sporadic hyperparathyroidism.
Conclusions : Primary hyperparathyroidism, although uncommon in the younger age group, is still most commonly associated with sporadic tumours. Familial syndromes do not constitute a large percentage of patients. Younger patients are more prone to present late with abdominal symptoms, toxicity and hypercalcaemic crisis, presumably due to delayed diagnosis of an uncommon condition in this age group.     

Evidence for cytochrome P450 2A6 and 3A4 as major catalysts for N'- nitrosonornicotine alpha-hydroxylation by human liver microsomes

The tobacco specific carcinogen N'-nitrosonornicotine (NNN), is believed to be a causative agent for esophageal cancer in smokers. NNN requires metabolic activation to exert its carcinogenic potential. Metabolism occurs through cytochrome P450 (P450) catalyzed 2'- and 5'- hydroxylation, which generates unstable metabolites that decompose to 4- hydroxy-1-(3-pyridyl)-1-butanone ('keto alcohol') and 4-hydroxy-4-(3- pyridyl)butanal, respectively. The latter cyclyzes to 5-(3-pyridyl)-2- hydroxytetrahydrofuran ('lactol'). 2'-Hydroxylation of NNN is believed to be the pathway critical for esophogeal NNN carcinogenesis in the rat. The ability of human liver microsomes and expressed human P450s to metabolize [5-(3)H]NNN to keto alcohol and lactol was determined by reverse phase HPLC with radioflow detection. At low NNN concentrations, 11 human liver microsomes metabolized NNN primarily by 5'-hydroxylation to lactol. This reaction was strongly correlated (r = 0.92) with coumarin 7-hydroxylation, suggesting that NNN 5'-hydroxylation is catalyzed mainly by P450 2A6. 2'-Hydroxylation of NNN by human liver microsomes correlated with 6beta-hydroxylation of testosterone, a P450 3A4-specific activity (r = 0.94). The relative rates of 2'- and 5'- hydroxylation by human P450s 2A6, 2E1, 2D6 and 3A4 expressed in Sf9 cells by the baculovirus-insect cell expression system, and human P450 3A4 produced by stable expression in Chinese hamster ovary cells, were determined. Human P450 2A6 metabolized 1 microM NNN exclusively by 5'- hydroxylation. The rate of lactol formation was 317 pmol/min per nmol P450. Human P450s 2E1 and 2D6 also metabolized NNN only to lactol, but at much lower rates, 0.4 and 0.8 pmol/min per nmol of P450 respectively. In contrast, the metabolism of NNN by expressed human P450 3A4 was specific for keto alcohol formation. The Km for 5'- hydroxylation by baculovirus-expressed P450 2A6 was 2.1 microM, and k(cat) was 953 pmol/min per nmol of P450. The Km for lactol formation by human liver microsomes containing high levels of P450 2A6, was 5 microM . Human liver microsomes exhibited a Km of 312 microM for keto alcohol formation. Coumarin, 8-methoxypsoralen (P450 2A6 inhibitors), and anti-2A6 monoclonal antibody were strong inhibitors of NNN-derived lactol formation in human liver microsomes. Troleandomycin, an inhibitor of P450 3A4, effectively inhibited the metabolism of NNN to keto alcohol by human liver microsomes. These results are consistent with P450 2A6 mediated 5'-hydroxylation and P450 3A4 mediated 2'- hydroxylation of NNN in human liver microsomes.      

Pigmented villonodular synovitis of the knee: a description of two cases treated in arthroscopy

The authors present two cases of pigmented villonodular synovitis of the knee. After a discussion of the aspecificity of clinical findings and difficulties in diagnosis based on radiographic evaluation, they conclude that diagnosis may be possible preoperatively by MRI, and that arthroscopic surgery allows for suitable treatment of localized forms of the disease.     

Human Ig heavy chain CDR3 regions in adult bone marrow pre-B cells display an adult phenotype of diversity: evidence for structural selection of DH amino acid sequences

Ig repertoires generated at various developmental stages differ markedly in diversity. It is well documented that Ig H chain genes in human fetal liver are limited with regard to N-regional diversity and use of diversity elements. It is unclear whether these characteristics persist in pre-B cell H chain genes of adult bone marrow. Using Ig H chain CDR3 fingerprinting and sequence analysis, we analyzed the diversity of Ig H chain third complementarity determining regions (HCDR3) in adult bone marrow pre-B and mature B lymphocytes. Pre-B cell HCDR3 sequences exhibited adult characteristics with respect to HCDR3 size, distribution of N regions and usage of diversity elements. This suggested that pre-B cells in adults are distinct from fetal B cell precursors with regard to Ig H chain diversification mechanisms. At the DNA sequence level, HCDR3 diversity in mature B cells was similar to that in pre-B cells. Pre-B HCDR3s, however, frequently contained a consecutive stretch of hydrophobic amino acids, which were rare in mature B cells. We propose that highly hydrophobic pre-B HCDR3s may be negatively selected on the basis of structural limitations imposed by the antigen binding site. At the same time, usage of hydrophilic HCDR3 sequences (thought to support HCDR3 loop formation) may be promoted by positive selection.      

人胶质母细胞瘤等位基因谱分析的研究

目的 探讨胶质母细胞瘤（glioblastoma,GBM)发病的分子遗传学机理，确定GBM的发生发展主要和哪些染色体或染色体区域有关，哪些染色体区域上可能存在与GBM相关的肿瘤抑制基因（tumor suppressor gene,TSG)。方法 应用聚合酶链反应技术，采用荧光标记的引物和377型DNA序列自动分析仪，对21例GBM的所有22对常染色体上共计382个微卫星位点进行了杂合性丢失（loss of heterozygosity,LOH)分析，相邻2个微卫星位点之间的平均遗传学距离为10cM。结果 在所有被检测的染色体臂上都观察到LOH，其中以染色体10q、10p、9p、17p和13q的LOH率最高（＞50％），这些染色体臂上已知的肿瘤抑制基因PTEN、DMBT1、p16、p53和Rb所在区域LOH率都较高；14q、3q、22q、11p、9q、19q上也存在较高的LOH率（＞40．5％）；首次发现多个共同微小丢失区域：9p22-23、10p12.2-14、10q21.3、13q12.1-14.1、13q14.3-31、17p11.2-12、17p13、3q24-27、11p12-13、14q31-32.3、14q21-24.1、22q13.2-13.3、4q35、4q31.1-31.2、6qtel、6q16.3。结论 GBM存在复杂的遗传学异常，涉及多条染色体臂。以10q、10p、9p、17p和13q的异常与GBM发生发展的关系最为密切。除了已知的肿瘤抑制基因PTEN、DMBT1、p16、p15、p53和Rb外，首次所发现的多个微小共同丢失区域上可能存在GBM相关的多个未知TSG。     

Multilocus linkage identifies two new loci for a mendelian form of stroke, cerebral cavernous malformation, at 7p15-13 and 3q25.2-27

Cerebral cavernous malformation (CCM) is a Mendelian model of stroke, characterized by focal abnormalities in small intracranial blood vessels leading to hemorrhage and consequent strokes and/or seizures. A significant fraction of cases is inherited as an autosomal dominant trait with incomplete penetrance. Among Hispanic Americans, virtually all CCM is attributable to a founder mutation localized to 7q ( CCM1 ). Recent analysis of non-Hispanic Caucasian kindreds, however, has excluded linkage to 7q in some, indicating at least one additional CCM locus. We now report analysis of linkage in 20 non-Hispanic Caucasian kindreds with familial CCM. In addition to linkage to CCM1, analysis of linkage demonstrates linkage to two new loci, CCM2 at 7p13-15 and CCM3 at 3q25.2-27. Multilocus analysis yields a maximum lod score of 14.11, with 40% of kindreds linked to CCM1, 20% linked to CCM2 and 40% linked to CCM3, with highly significant evidence for linkage to three loci (linkage to three loci supported with an odds ratio of 2.6 x 10(5):1 over linkage to two loci and 1.6 x 10(9):1 over linkage to one locus). Multipoint analysis among families with high posterior probabilities of linkage to each locus refines the locations of CCM2 and CCM3 to approximately 22 cM intervals. Linkage to these three loci can account for inheritance of CCM in all kindreds studied. Significant locus- specific differences in penetrance are identified. These findings have implications for genetic testing of this disorder and represent an important step toward identification of the molecular basis of this disease.      

'There but for the grace of God': moral responsibility and mental illness

Abstract Setting the terms of praise‐ and blameworthiness has long dominated philosophers’ discussions of responsibility. Analytic philosophy has most often looked to reason and the abstract relations between individual rational judgements and actions to advance the discourse on moral responsibility. Those whose capacity for reasoned judgement is impaired are deeply problematic. Is it proper to morally appraise ‘the mentally ill’? The philosopher T.M. Scanlon discusses moral responsibility as a precondition of moral appraisal and contends that it is not appropriate to appraise a person as (morally) praise‐ or blameworthy if that person cannot be held responsible for the action(s) for which he is being praised or blamed. What are the conditions, then, under which one can properly be said to be responsible for one's actions? Can one hold ‘the mentally ill’ responsible for their actions? If not, can it in any way be reasonable to expect them to ‘take responsibility’ for their actions and/or characters? The expectation that ‘the mentally ill’ will attempt to control, i.e. take responsibility for their behaviour despite the fact of their mental illness is a pervasive feature of psychiatric approaches to the care and treatment of ‘the mentally ill’. It would seem that such treatment approaches are coherent only to the degree ‘the mentally ill’ can be considered responsible moral agents. This paper explores these issues with regard to that form of mental illness categorized as the personality disorders. It describes the morally and clinically relevant features of personality disorder, explains how they do not fit traditional analytic paradigms of ‘mental illness’ and elaborates the argument that persons with this category of mental illness are fully moral persons who are rightly subject to praise and blame.     

Anti-adhesion molecule therapy in Theiler's murine encephalomyelitis virus-induced demyelinating disease

We examined the role of leukocyte function-associated antigen (LFA)-1 and its counter-receptor intercellular adhesion molecule (ICAM)-1, one of the most important pairs of adhesion molecules, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Immunohistochemical study showed hyper-expression of ICAM-1 on vascular endothelial cells and expression of LFA-1 on mononuclear infiltrating cells in the spinal cords of TMEV-infected mice. Treatment with mAb to ICAM-1 and/or LFA-1 molecules resulted in significant suppression of the development of demyelinating disease, both clinically and histologically, with down-regulation in the CNS of the respective adhesion molecules after treatment. In mice treated with these mAb, the specific delayed-type hypersensitivity and T cell proliferative responses for TMEV were decreased. The production of tumor necrosis factor-alpha and IFN-gamma in spleen cells was also decreased, but IL-4 production remained unchanged. These data suggest that ICAM-1/LFA-1 interaction is critically involved in the pathogenesis of TMEV-IDD and that antibodies to these adhesion molecules could be a novel therapeutic approach to the treatment of demyelinating diseases such as human multiple sclerosis.      

IS CLEAN DISSECTION OF CALOT’S TRIANGLE NECESSARY IN CHOLECYSTECTOMIES?

In this study when patients were followed up for post-operative symptoms, it was seen that the incidence of narrowing of lumen of the common bile duct was more in cases where the operation was done by retrograde cholecystectomy with clean dissection of Calot''s triangle. Though this was a coincidental finding, it raises a doubt whether the narrowing is a result of impairment of blood supply to the common bile duct, which may result from clean dissection and display of Calot''s triangle area. The above dissection removes the fascial layer over the common bile duct and is likely to result in damage to end-arteries piercing through it to the common bile duct. This conjecture requires further study in a larger series.KEY WORDS: Cholecystectomy, Calot''s triangle, Surgical technique, Common bile duct stricture