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INTRODUCTION Only 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear. Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans. RATIONALE To determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals. RESULTS Previously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between the location of heteroplasmic sites and known D-loop polymorphisms, including the absence of variants in critical sites required for mtDNA transcription and replication. We defined 206 unrelated individuals for which the nuclear and mitochondrial genomes were from different human populations. In these individuals, new population-specific heteroplasmies were more likely to match the nuclear genetic ancestry than the mitochondrial genome on which the mutations occurred. These findings were independently replicated in 654 additional unrelated individuals. CONCLUSION The characteristics of mtDNA in the human population are shaped by selective forces acting on heteroplasmy within the female germ line and are influenced by the nuclear genetic background. The signature of selection can be seen over one generation, ensuring consistency between these two independent genetic systems.

Kitchen-area 22-h gravimetric PM2.5 and passive diffusion stain-tube carbon monoxide (CO) concentrations were measured in homes with open fire and improved wood cookstoves in two studies. In the first study (Guat-2), which also studied homes with gas cookstoves, three samples were collected per stove condition from each of three test houses. In the second study (Guat-3), one sample was collected per house from 15 open fire and 25 improved-stove houses. CO personal samples were also taken for mother and child in both studies. Spearman correlation coefficients (R) between kitchen-area CO and PM2.5 levels in homes using open fires or impoved wood cookstoves were high ranging from 0.92 (Guat-2) to 0.94 (Guat-3), as were those between the personal samples for mother and child ranging from 0.85 (Guat-3) to 0.96 (Guat-2). In general, the correlations were lower for less-polluted conditions. The study found that CO is a good proxy for PM2.5 in homes using open fires or planchas (improved wood cookstove with chimney) but not under gas stove use conditions. It also determined that mother personal CO is a good proxy for child's (under 2 years of age) personal CO and that area CO measurements are not strongly representative of personal CO measurements. These results generally support the use of Draeger CO passive diffusion tubes as a proxy for PM2.5 in such cases where a single type of emission source is the predominant source for CO and PM2.5.

Within three weeks of definitive surgical intervention, 467 patients with histologically proved malignant glioma were randomized to receive one of four treatment regimens: semustine (MeCCNU), radiotherapy, carmustine (BCNU) plus radiotherapy, or semustine plus radiotherapy. We analyzed the data for the total randomized population and for the 358 patients in whom the initial protocol specifications were met (the valid study group). Observed toxicity included acceptable skin reactions secondary to radiotherapy and reversible leukopenia and thrombocytopenia due to chemotherapy. Radiotherapy used alone or in combination with a nitrosourea significantly improved survival in comparison with semustine alone. The group receiving carmustine plus radiotherapy had the best survival, but the difference in survival between the groups receiving carmustine plus radiotherapy and semustine plus radiotherapy was not statistically significant. The combination of carmustine plus radiotherapy produced a modest benefit in long-term (18-month) survival as compared with radiotherapy alone, although the difference between survival curves was not significiant at the 0.05 level. This study suggests that it is best to use radiotherapy in the post-surgical treatment of malignant glioma and to continue the search for an effective chemotherapeutic regimen to use in addition to radiotherapy.

A series of nonionic x-ray contrast media containing novel linkages between the triiodobenzene and polyhydroxy moieties have been prepared and screened against established criteria. Of the coupler groups examined (amide including dipeptide, carbamate, ureido, and ester), amide showed the greatest overall utility in terms of safety, solubility, stability, and ease of synthesis. Acute toxicity, solubility and stability data are summarized for each series. In the CNS, certain compounds were well tolerated and some were devoid of any excitatory effects. Intrathecal tissue irritant effects were also unremarkable. Most agents exhibited relatively high osmolalities, raising questions as to the influence of this factor on the safety of myelographic agents. Intravascularly, nonionic media appear also to offer advantages over classical ionic media. However, nonionic media can exert positive inotropic effects and exhibit high viscosity at higher iodine concentrations. Nevertheless, overall results continue to demonstrate the radiographic potential of nonionic contrast media.

Eighty-seven children with histologically confirmed brain tumors were reviewed. Fifty-nine of the tumors were in the posterior fossa, 19 were cerebral gliomas, and nine were miscellaneous supratentorial tumors, including five craniopharyngiomas and two papillomas of the choroid plexus. In the posterior fossa there were 22 astrocytomas, 11 medulloblastomas, and ten ependymomas, indicating that half of the cerebellar tumors are benign. Of the patients with cerebellar astrocytomas, 15 are alive and 10 are probably cured. The cerebellar ependymomas have a very poor prognosis with only one long-term survivor and an average survival time of 14 months. The medulloblastoma group has only four survivors, and some of these are less than two years postoperative. Of 11 patients having cerebral astrocytoma, only three are leading satisfactory lives, three are dead, and five are handicapped to a significant degree. Of the eight patients with supratentorial ependymoma, all are dead with the longest survival being six years. It is emphasized that a benign cerebellar astrocytoma is the single most likely tumor in childhood, and many of these patients can be cured and survive without significant neurologic deficit.

This study analyzes the potential impact of physician extenders on the productivity of primary care practices and considers the consequent implication for future health manpower requirements. A number of previous investigations have evaluated a variety of extenders in experimental settings. This study, in contrast, constructs and operates a simulation model of the representative practice permitting one to synthesize the experiences and insights of earlier demonstration projects. The model requires the practice to delegate tasks to paramedical personnel including the physician extender in such a way as to minimize the total cost of delivering a list of required medical services. The alternative acceptable techniques for delivering care are defined by the number of minutes of each type of medical personnel that must be employed in producing each service. Primary care is characterized by distinct medical services. The model reveals that physician extenders could increase the productivity of a representative primary care practice by up to 74 per cent. Alternatively, the commitment of physician time required to serve a patient load of 100 visits a week might be reduced by 14.2 hours through effective use of an extender. The article concludes with observations on the implications of physician extenders for future health manpower requirements.

A recent review of the surgical management of diverticular disease of the colon included 73 patients. One-stage resections were accomplished in 67%, primarily in patients operated on electively for recurrent diverticulitis or fistula, and in the group of patients with cecal diverticulitis operated on for presumed appendicitis. Single-stage resection with ileorectal anastomosis is also preferred in patients with massive diverticular bleeding. For patients with large abscesses or diffuse peritonitis a two-stage procedure which removes the site of disease in the initial operation is recommended. There were no deaths and a lower incidence of complications in the group of patients who had elective operations for recurrent diverticulitis and fistula.

Decompressive craniotomy has a place in acute hemispheric infarctions. Patient selection should be guided by CT to exclude those with huge dominant hemispheric lesions that make reasonable neurologic recovery unattainable. Intracranial pressure monitoring should reduce the severity of neurologic sequelae by providing earlier, more timely operative intervention.

(1964). Los Angeles Air Pollution and Respiratory Disease. Archives of Environmental Health: An International Journal: Vol. 8, No. 1, pp. 182-183.