Synaptology of trigemino- and spinothalamic lamina I terminations in the posterior ventral medial nucleus of the macaque

We used the electron microscope to examine lamina I trigemino- and spinothalamic (TSTT) terminations in the posterior part of the ventral medial nucleus (VMpo) of the macaque thalamus. Lamina I terminations were identified by anterograde labeling with biotinylated dextran, and 109 boutons on 38 terminal fibers were closely studied in series of ultrathin sections. Five unlabeled terminal boutons of similar appearance were also examined in detail. Three-dimensional, volume-rendered computer models were reconstructed from complete series of serial sections for 29 boutons on 10 labeled terminal fibers and one unlabeled terminal fiber. In addition, postembedding immunogold staining for GABA was obtained in alternate sections through 23 boutons. Lamina I TSTT terminations in VMpo generally have several large boutons (mean length = 2.16 microm, mean width = 1.29 microm) that are densely packed with vesicles and make asymmetric synaptic contacts on low-order dendrites of VMpo neurons (mean diameter 1.45 microm). They are closely associated with GABAergic presynaptic dendrites (PSDs), and nearly all form classic triadic arrangements (28 of 29 reconstructed boutons). Consecutive boutons on individual terminal fibers make multiple contacts with a single postsynaptic dendrite and can show evidence of progressive complexity. Dendritic appendages that enwrap and invaginate the terminal bouton constitute additional anatomic evidence for secure, high-fidelity synaptic transfer. These observations provide direct ultrastructural evidence supporting the hypothesis that VMpo is a lamina I TSTT thalamocortical relay nucleus in primates that subserves pain, temperature, itch, and other sensations related to the physiological condition of the body.     

Mutations of the slow muscle alpha-tropomyosin gene,TPM3, are a rare cause of nemaline myopathy

The alpha-tropomyosin-3 (TPM3) gene was screened in 40 unrelated patients with nemaline myopathy (NM). A single compound heterozygous patient was identified carrying one mutation that converts the stop codon to a serine and a second splicing mutation that is predicted to prevent inclusion of skeletal muscle exon IX. TPM3 mutations are a rare cause of NM, probably accounting for less than 3% of cases. The severity of cases with TPM3 mutations may vary from severe infantile to late childhood onset, slowly progressive forms.     

Is the global rise of asthma an early impact of anthropogenic climate change?

The increase in asthma incidence, prevalence, and morbidity over recent decades presents a significant challenge to public health. Pollen is an important trigger of some types of asthma, and both pollen quantity and season depend on climatic and meteorologic variables. Over the same period as the global rise in asthma, there have been considerable increases in atmospheric carbon dioxide concentration and global average surface temperature. We hypothesize anthropogenic climate change as a plausible contributor to the rise in asthma. Greater concentrations of carbon dioxide and higher temperatures may increase pollen quantity and induce longer pollen seasons. Pollen allergenicity can also increase as a result of these changes in climate. Exposure in early life to a more allergenic environment may also provoke the development of other atopic conditions, such as eczema and allergic rhinitis. Although the etiology of asthma is complex, the recent global rise in asthma could be an early health effect of anthropogenic climate change.     

Oesophagectomy for squamous cell carcinoma: lessons from a decade of consecutive resections

The aim of this study was to analyse the outcome following oesophageal resection for squamous cell carcinoma (SCC) in a large volume unit. Between 1987 and 1997, 166 patients with SCC underwent oesophagectomy. The outcomes and pathological characteristics of this cohort were then analysed. Operative mortality was 6% (10 patients). Anastomotic leak occurred in 11 (6.6%). A history of previous respiratory disease and anastomotic leak were independent predictors of early mortality (P=0.02). Pathological examination demonstrated the presence of stage I disease in 8, stage IIa in 58, stage IIb in 14 and stage III in 87 patients. Kaplan-Meier survival at 1, 3 and 5 years for all patients was 71.6%, 44.6% and 33.5%. Five-year survival was 87.5% for stage I, 47.1% for stage IIa, 27.4% for stage IIb and 14.5% for stage III. On multivariate analysis, pathological stage (P=0.001) and presence of involved lymph nodes were independent adverse predictors of survival (P<0.0001). In conclusion, oesophagectomy for SCC carries an acceptable risk, which is higher for those having a respiratory disease and those developing an anastomotic leak. The good survival observed in early pathological stages and the presence of long-term survivors amongst those with locally advanced disease are encouraging.     

Predictors of operative death after oesophagectomy for carcinoma

BACKGROUND: Oesophagectomy for carcinoma provides a chance of cure but carries significant risk. This study defined risk factors for death after oesophageal resection for malignant disease. METHODS: Between 1990 and 2003, 773 oesophagectomies for oesophageal cancer were performed. Continuous variables were categorized into quartiles for analysis. Predictors of operative mortality were identified by univariate and multiple logistic regression analysis. RESULTS: The operative mortality rate was 4.8 per cent (37 of 773). In univariate analysis, advanced age, reduced forced expiratory volume in 1 s (FEV1), reduced forced vital capacity, presence of diabetes and tumour located in the upper third of the oesophagus were associated with a higher mortality rate. Multivariate analysis identified age (highest relative to lowest quartile, odds ratio (OR) 4.87 (95 per cent confidence interval (c.i.) 1.35 to 17.55); P = 0.009), tumour position (upper third relative to other locations, OR 4.23 (95 per cent c.i. 1.06 to 16.86); P = 0.041) and FEV1 (lowest relative to highest quartile, OR 4.72 (95 per cent c.i. 1.01 to 21.99); P = 0.018) as independent predictors of death. CONCLUSION: Advanced age, impaired preoperative respiratory function and a tumour high in the oesophagus are associated with a significantly increased risk of death after oesophagectomy for carcinoma.     

Improving drug use for children in the developing world

Children differ significantly from adults in the way they absorb, metabolise, and excrete drugs. These parameters also vary as children grow from neonates through to adolescence. The practical implications and challenges that this presents are well know to anyone who is involved in the medical management of sick children. The importance of paediatric medication safety and efficacy has been gaining increasing attention in the developed world over the past decade. The United States has introduced a carrot and stick approach to increase research into medications for children with the "paediatric exclusivity provision" and the "paediatric rule". The European Union is also investigating ways of improving the availability of medications for children. Unfortunately, this increased focus on appropriate medicines for children, which has occurred in the developed world, has not been mirrored in developing nations. Currently more than 10 million children under the age of 5 years die each year, with only six countries accounting for 50% of these deaths. The majority of these deaths are from treatable or preventable diseases. The developed world has a moral and ethical obligation to share its gains with the children of the world.     

X-linked myotubular and centronuclear myopathies

Recent work has significantly enhanced our understanding of the centronuclear myopathies and, in particular, myotubular myopathy. These myopathies share similar morphologic appearances with other diseases, namely the presence of hypotrophic myofibers with prominent internalized or centrally placed nuclei. Early workers suggested that this alteration represented an arrest in myofiber maturation, while other hypotheses implicated either failure in myofiber maturation or neurogenic causes. Despite similarities in morphology, distinct patterns of inheritance and some differences in clinical features have been recognized among cases. A severe form, known as X-linked myotubular myopathy (XLMTM), presents at or near birth. Affected males have profound global hypotonia and weakness, accompanied by respiratory difficulties that often require ventilation. Most of these patients die in infancy or early childhood, but some survive into later childhood or even adulthood. The responsible gene (MTM1) has been cloned; it encodes a phosphoinositide lipid phosphatase known as myotubularin that appears to be important in muscle maintenance. In autosomal recessive centronuclear myopathy (AR CNM), the onset of weakness typically occurs in infancy or early childhood. Some investigators have divided AR CNM into 3 subgroups: 1) an early-onset form with ophthalmoparesis, 2) an early-onset form without ophthalmoparesis, and 3) a late-onset form without ophthalmoparesis. Clinically, autosomal dominant CNM (AD CNM) is relatively mild and usually presents in adults with a diffuse weakness that is slowly progressive and may be accompanied by muscle hypertrophy. Overall, the autosomal disorders are not as clinically uniform as XLMTM, which has made their genetic characterization more difficult. Currently the responsible gene(s) remain unknown. This review will explore the historical evolution in understanding of these myopathies and give an update on their histopathologic features, genetics and pathogenesis.