Geography and genealogy of the human host harbouring a distinctive drug-resistant strain of tuberculosis

For a strain of Mycobacterium tuberculosis mono-resistant to pyrazinamide (PZA), we report the geographic distribution within Quebec of the 77 cases diagnosed during 1990-2000. Known as the Quebec mutation (or the pncA deletion), the strain is rare in urban areas and showed an unexpected concentration in Mauricie, one of the 16 health districts of the province, with a cluster of 10 cases situated in a rural area of 35-km radius. The cases occurred among people >50 (98%), of French Canadian origins (90%), and are understood to have arisen by reactivation. The rarity in Montreal and smaller cities is explained by the youthfulness of massive postwar migrations. To reach back into the history of settlement, we examined genealogies: 92,429 ancestral marriages for 32 of the 77 PZA-resistant isolates and 226,535 for a set of 85 controls with isolates of more diverse mycobacterial strains. Genealogical analysis showed no salient common ancestor for the cases, and kinship among them was no greater than observed in control samples from the same regions. But it identified an unsuspected geographical region as the site of ancestral concentrations prior to 1840, for both resistant strains and controls. The following scenario is proposed for the resistant strain: endemic in a specific geographical region by 1800, it dispersed with families moving into regions opened to settlement in the 1840s and 1850s, among them Mauricie, where dispersion was intensified by seasonal mobility of labour in logging, milling and marketing timber. In high-incidence areas, it is difficult to distinguish cases of reactivation from recent infections, but the low-incidence context allows us to observe a 200-year trajectory of a distinctive drug-resistant strain of M. tuberculosis.     

皱纹下眉头，焦虑上心头

曾经风靡一时的肉毒素，在走到临床之前，其临床前研究开展的要比其他药物更多，因为这是自然界最致命的毒素之一。1989年，FDA批准Allergan公司A型肉毒素，纯化神经毒素复合物（商品名Botox）上市，用于眼睑痉挛及斜视的治疗。直至今天，Allergan仍是全球Botox的唯一生产商。2000年12月，FDA再次批准Botox用于治疗头部偏斜及因颈肌张力障碍引起的颈痛。2001年4月，加拿大批准Botox Cosmetic用于皱眉纹的缓解。2002年4月，FDA对Botox这一化妆品用途也给予了批准。     

Endoglin (CD105): a marker of tumor vasculature and potential target for therapy.

Endoglin (CD105) is an accessory protein of the transforming growth factor-beta receptor system expressed on vascular endothelial cells. Mutation of the endoglin gene is associated with hereditary hemorrhagic telangiectasias, or Osler-Weber-Rendu syndrome, and has been studied extensively in the context of this disease. The expression of endoglin is elevated on the endothelial cells of healing wounds, developing embryos, inflammatory tissues, and solid tumors. Endoglin is a marker of activated endothelium, and its vascular expression is limited to proliferating cells. Recent studies identified endoglin expression in several solid tumor types, with the level of expression correlating with various clinicopathologic factors including decreased survival and presence of metastases. Attempts to target endoglin and the cells that express this protein in tumor-bearing mice have yielded promising results.     

Intermittent intravenous cyclophosphamide therapy for lupus nephritis

We carried out a preliminary study to determine whether intermittent intravenous cyclophosphamide therapy could be safely and effectively used in the treatment of childhood lupus nephritis. Sixteen children (4 to 18 years of age) with lupus nephritis were treated with cyclophosphamide monthly for 6 months and then every 3 months. Eight children were treated because of corticosteroid-unresponsive active lupus nephritis, with a fall in their creatinine clearance to less than 100 ml/min/1.75 m2, and eight children were treated because of corticosteroid-dependent nephrotic syndrome or active lupus nephritis with unacceptable corticosteroid-induced side effects. Cyclophosphamide treatment was associated with significant improvement at 1 year in mean levels of hemoglobin (11.3 +/- 0.5 to 13.1 +/- 0.3 gm/dl), C3 (52 +/- 5.9 to 108 +/- 13.7 mg/dl), and C4 (7.6 +/- 0.9 to 15.9 +/- 2.2 mg/dl) (all p less than 0.005), despite a significant reduction in mean prednisone dosage (31 +/- 5 to 14 +/- 2 mg/day; p less than 0.005). There was a decrease in 24-hour urine protein excretion from 3121 +/- 913 to 1016 +/- 364 mg/24 hours (p less than 0.05). For children whose initial creatinine clearance was less than 100 ml/min/1.75 m2, creatinine clearance also improved significantly (57.5 +/- 11 to 121 +/- 24.5 ml/min/1.75 m2; p less than 0.05). The long-term safety of intravenous cyclophosphamide therapy and its long-term efficacy in comparison with prednisone alone remain to be established. In the interim, intravenous cyclophosphamide therapy should be reserved for children with severe, unacceptable corticosteroid side effects or with corticosteroid-resistant and potentially life-threatening disease.     

Psychologic aspects of childhood reflex neurovascular dystrophy

Psychosocial factors in 21 families with children affected by reflex neurovascular dystrophy were studied. Each family was interviewed and given a battery of standardized psychologic tests. Two distinct types of families were identified. Fifteen families showed high internal cohesion, expressiveness, and organization and low levels of conflict. Six families showed high overt conflict with low levels of family cohesion, expressiveness, and organization. In all families parental enmeshment with the patient was present. Marital discord was present in 12 families. Thirteen patients had significant school problems (ten had learning disabilities). Although most of the children were described as especially bright, only four had above average intelligence test scores. Four had a history of sexual abuse. The patients and their mothers perceived the health problem as significantly worse than did children with arthritis from whom similar scores had been obtained. Possible role models with similar symptoms were reported by ten patients. These data support the concept that childhood reflex neurovascular dystrophy is frequently a stress-related disease; the therapeutic approach to treating these children and their families must take these psychosocial factors into account.     

GABA(A) receptor binding and localization in the tiger salamander retina

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the retina and also appears to act as a trophic factor regulating photoreceptor development and regeneration. Although the tiger salamander is a major model system for the study of retinal circuitry and regeneration, our understanding of GABA receptors in this species is almost exclusively based on the results of physiological studies. Therefore, we have examined the pharmacological binding properties of GABA(A) receptors and their anatomical localization in the tiger salamander retina. Radioligand-binding studies showed that specific 3H-GABA binding to GABA(A) receptors was dominated by a single high-affinity binding site (Kd = 15.6+/-6.9 nM). Specific binding of 3H-GABA was almost completely eliminated by muscimol (Ki = 105+/-62 nM) and bicuculline (Ki = 14.3+/-2.2 microM); however, SR-95531 only displaced about 40% of specific 3H-GABA binding (Ki = 35.0+/-3.8 nM). These data indicate that there are at least two subtypes of GABA(A) receptors present in the salamander retina that can be distinguished by their antagonist binding properties: one sensitive to both bicuculline and SR-95531, and one sensitive to bicuculline but insensitive to SR-95531. Because localization of GABA receptors in the salamander retina by immunocytochemistry is problematic, GABA(A) receptors were localized by fluorescent ligand binding combined with immunocytochemical labeling for cell specific markers. Binding of fluorescently labeled muscimol to GABA(A) receptors was present in both plexiform layers and on photoreceptor cell bodies. GABA(A) receptors in the outer plexiform layer were localized to both photoreceptor terminals and horizontal cell processes.     

Osteoporosis prevention project: a model multidisciplinary educational intervention

Osteoporosis is a systemic metabolic disease resulting in low bone mass, which increases the risk for fracture. Evidence suggests that lifestyle changes to prevent or delay development of osteoporosis should be implemented throughout the life span. The purpose of this study was to evaluate the effectiveness of a multidisciplinary primary osteoporosis prevention program for community-dwelling women aged 25 to 75 years to determine if osteoporosis prevention program participants (treatment group) increased their knowledge of osteoporosis, calcium intake, and exercise compared with a control group. Other outcomes included participants' willingness to adopt lifestyle changes and ability to view themselves as able to make behavioral changes. Subjects in the treatment group versus control subjects increased their knowledge of osteoporosis over time. At posttest, subjects in the treatment group were more likely to be planning to change calcium intake, and at follow-up, they were more likely to be changing their calcium intake. No other group differences were found between the two groups. These findings suggest that a multidisciplinary education program may have an impact on knowledge and behaviors that may help to delay the development of osteoporosis.     

Prevalence and location of teeth marks observed on painted surfaces in an evaluation of the HUD lead hazard control grant program

Data from an evaluation of the HUD Lead Hazard Control Grant Program were used to evaluate the prevalence and location of teeth marks on painted surfaces in residential housing. The results of these analyses will be useful in the development of more effective pediatric lead poisoning prevention programs. These programs have historically placed considerable emphasis on surfaces accessible to children for mouthing activities. This study analyzes the largest set of data ever assembled on the prevalence of teeth marks in housing. Data from 308,851 observations in 3,454 housing units were analyzed to determine the prevalence of teeth mark observations per surface, dwelling unit, and building component, and by housing age, inspector, and grantee. An average of 4.0 teeth marks per 10,000 surfaces with paint-lead greater than or equal to 1.0 mg/cm2 were observed. For surfaces with less than 1.0 mg/cm2 lead the rate was 1.5 teeth marks/10,000 surfaces. The number of teeth marks per 10,000 surfaces increased with age of housing for surfaces with 1.0 mg/cm2 or higher lead but not for surfaces with less than 1.0 mg/cm2 lead. Teeth mark observation rates were 36 times higher for windowsills than for other components and ranged up to 11 per 10,000 surfaces and 9 dwellings per 100 dwelling units for 2 grantees with the highest rates. Blood lead levels in children exhibiting moderate to high mouthing behavior were higher than in children without such behavior, especially in housing where teeth marks were observed. Special priority should be given to windowsills when making decisions on lead hazard control for "accessible," "chewable," or "mouthable" surfaces.