Untangling “NETosis” from NETs

Neutrophil extracellular trap (NET) formation is a cellular function of neutrophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form NETs, neutrophils release a DNA scaffold consisting of mitochondrial DNA binding granule proteins. This process does not depend on cell death, but requires glycolytic ATP production for rearrangements in the microtubule network and F‐actin. Such cytoskeletal rearrangements are essential for both mitochondrial DNA release and degranulation. However, the formation of NETs has also been described as a distinct form of programed, necrotic cell death, a process designated “NETosis.” Necrotic cell death of neutrophils is associated with the permeabilization of both plasma and nuclear membranes resulting in a kind of extracellular cloud of nuclear DNA. The molecular mechanisms eliciting necrotic neutrophil death have been investigated and appear to be different from those responsible for NET formation following mitochondrial DNA release. Here, we discriminate between the mechanisms responsible for the release of mitochondrial versus nuclear DNA and address their respective functions. Our aim is to clarify existing differences of opinion in the fields of NET formation and neutrophil death.     

Bone “mass” and the “mechanostat”: A proposal

The observed fit of bone mass to a healthy animal's typical mechanical usage indicates some mechanism or mechanisms monitor that usage and control the three longitudinal growth, bone modeling, and BMU-based remodeling activities that directly determine bone mass. That mechanism could be named a mechanostat. Accumulated evidence suggests it includes the bone itself, plus mechanisms that transform its mechanical usage into appropriate signals, plus other mechanisms that detect those signals and then direct the above three biologic activities. In vivo studies have shown that bone strains in or above the 1500–3000 microstrain range cause bone modelling to increase cortical bone mass, while strains below the 100–300 microstrain range release BMU-based remodeling which then removes existing cortical-endosteal and trabecular bone. That arrangement provides a dual system in which bone modeling would adapt bone mass to gross overloading, while BMU-based remodeling would adapt bone mass to gross underloading, and the above strain ranges would be the approximate “setpoints” of those responses. The anatomical distribution of those mechanical usage effects are well known. If circulating agents or disease changed the effective setpoints of those responses their bone mass effects should copy the anatomical distribution of the mechanical usage effects. That seems to be the case for many agents and diseases, and several examples are discussed, including postmenopausal osteoporosis, fluoride effects, bone loss in orbit, and osteogenesis imperfecta. The mechanostat proposal is a seminal idea which fits diverse evidence but it requires critique and experimental study.     

Psychiatric “Co-occurrence”? I'll Stick with “Comorbidlty”

Lilienfeld et al's critique of the use of the term comorbid in psychopathological research is critically examined. They are incorrect in asserting that the original use of the term in medical epidemiology was intended to restrict it to disease entities. Furthermore, the ways in which medical comorbidity can be understood apply equally well to understanding the comorbidity of psychiatric or psychological disorders. Just as it has been useful to use the general term psychiatric disorders to include symptom patterns and syndromes and few If any true diseases, so to it is useful to apply the generic term of comorbidity to the joint occurrence of psychiatric disorders. Because methodological factors can sometimes contribute to artifactual comorbidity which is uninformative about the disorders being studied is no reason to abandon the term comorbidity in psycho-pathological research.     

Smith-Lemli-Opitz syndrome: Thirty-year follow-up of “S” of “RSH” syndrome

We have reassessed patient “S,” one of the first 3 individuals recognized to have Smith-Lemli-Opitz (or RSH) syndrome, at age 34 years, and we describe his physical, developmental, and behavioral manifestations. This reassessment provides formal evidence that this individual has the cholesterol biosynthetic defect which is thought to be the cause of Smith-Lemli-Opitz syndrome. Dietary manipulation appears to have had a beneficial effect on the patient's behavior and suggests that even in adults with this condition, dietary cholesterol supplementation may be indicated. Am. J. Med. Genet. 68:260–262, 1997. © 1997 Wiley-Liss, Inc.     

Apnoea and Bradycardia from Submersion in “Chronically” Decerebrated Cats

In “chronically” but not in acutely decerebrated cats, submersion of the head caused apnoea and marked bradycardia, associated with a maintained or slightly raised arterial pressure. Since these reflex adjustments, though very reproducible, occurred with a varying latency and could be induced also by nasal injection of water, they appeared to be, at least in part, elicited from the upper respiratory passages. Thus, a terrestrial mammal, reputed to shun any form of immersion, can exhibit adjustments during head submersion, similar to those in habitually diving species. This response pattern is basically organized at the lower brainstem level.     

“Primary” leptomeningeal medulloblastoma

We report the case of an 8-year-old boy who presented with a 2-month history of headaches and mild visual impairment and was found to have a medulloblastoma with primary leptomeningeal involvement. No mass lesion was found on imaging studies, during subsequent intraoperative surgical inspection or at autopsy. The pathologic findings were first documented on cerebrospinal fluid cytologic examination and biopsy of the cerebellum and were later confirmed at necropsy. To our knowledge, this is the third reported case of medulloblastoma identified with primary leptomeningeal involvement without a cerebellar mass and the first such case with documented autopsy findings.     

“Hypotyrosinemia” in Phenylketonuria

It has been postulated that the significant incidence of learning disabilities in well-treated patients with phenylketonuria (PKU) may be due, in part, to reduced production of neurotransmitters as a result of deficient tyrosine transport across the neuronal cell membrane. Hypotyrosinemia has been reported in treated and untreated PKU but virtually no data are available. We decided to examine this in our patient population and to compare it with the published norms, patient data from our hospital clinical biochemical laboratory database, and a group of normal children and adolescents in a private pediatric practice. We found that the mean nonfasting plasma tyrosine in 99 classical PKU patients was 41.1 μmol/L, in 26 mild (atypical) PKU patients 53.3 μmol/L, and in 35 non-PKU mild hyperphenylalaninemia patients 66.6 μmol/L. This compared to nonfasting plasma tyrosine levels in 102 non-PKU subjects of 64.0 μmol/L in our hospital biochemistry database, 69.1 μmol/L in 58 volunteers in the private office practice, and 64–78.8 μmol/L in infants, children, and adolescents in the literature review. Our data support the previously undocumented statements in the literature that plasma tyrosine levels are low in PKU.