Molecular clock-like evolution of human immunodeficiency virus type 1

AbstractThe molecular clock hypothesis states that the rate of nucleotide substitution per generation is constant across lineages. If generation times were equal across lineages, samples obtained at the same calendar time would have experienced the same number of generations since their common ancestor. However, if sequences are not derived from contemporaneous samples, differences in the number of generations may be misinterpreted as variation in substitution rates and hence may lead to false rejection of the molecular clock hypothesis. A recent study has called into doubt the validity of clock-like evolution for HIV-1, using molecular sequences derived from noncontemporaneous samples. However, after separating their within-individual data according to sampling time, we found that what appeared to be nonclock-like behavior could be attributed, in most cases, to noncontemporaneous sampling, with contributions also likely to derive from recombination. Natural selection alone did not appear to obscure the clock-like evolution of HIV-1

NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth

Mitochondria are emerging as important players in the transformation process of cells, maintaining the biosynthetic and energetic capacities of cancer cells and serving as one of the primary sites of apoptosis and autophagy regulation. Although several avenues of cancer therapy have focused on mitochondria, progress in developing mitochondria-targeting anticancer drugs nonetheless has been slow, owing to the limited number of known mitochondrial target proteins that link metabolism with autophagy or cell death. Recent studies have demonstrated that two members of the newly discovered family of NEET proteins, NAF-1 (CISD2) and mitoNEET (mNT; CISD1), could play such a role in cancer cells. NAF-1 was shown to be a key player in regulating autophagy, and mNT was proposed to mediate iron and reactive oxygen homeostasis in mitochondria. Here we show that the protein levels of NAF-1 and mNT are elevated in human epithelial breast cancer cells, and that suppressing the level of these proteins using shRNA results in significantly reduced cell proliferation and tumor growth, decreased mitochondrial performance, uncontrolled accumulation of iron and reactive oxygen in mitochondria, and activation of autophagy. Our findings highlight NEET proteins as promising mitochondrial targets for cancer therapy

HbSC Disease and Spontaneous Epidural Hematoma with Kernohan’s Notch Phenomena

Spontaneous (nontraumatic) acute epidural hematoma is a rare and poorly understood complication of sickle cell disease. A 19-year-old African American male with hemoglobin SC disease (HbSC) presented with generalized body aches and was managed for acute painful crisis. During his hospital stay he developed rapid deterioration of his mental status and computed topography revealed a spontaneous massive epidural hematoma with mass effect and midline shift with Kernohan’s notch phenomena for which urgent craniotomy and evacuation was done. We report the first case of HbSC disease associated with catastrophic epidural hematoma progressing to transtentorial herniation and Kernohan’s notch phenomena within few hours with rapid clinical deterioration. The etiopathogenesis and the rare presentation are discussed in detail in this case report

Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

To examine the role of striatal mechanisms in cocaine-induced stereotyped licking, we investigated the acute effects of cocaine on striatal neurons in awake, freely moving rats before and after cocaine administration (0, 5, 10, or 20 mg/kg). Stereotyped licking was induced only by the high dose. Relative to control (saline), cocaine reduced lick duration and concurrently increased interlick interval, particularly at the high dose, but it did not affect licking rhythm. Firing rates of striatal neurons phasically related to licking movements were compared between matched licks before and after injection, minimizing any influence of sensorimotor variables on changes in firing. Both increases and decreases in average firing rate of striatal neurons were observed after cocaine injection,and these changes exhibited a dose-dependent pattern that strongly depended on predrug firing rate. At the middle and high doses relative to the saline group, the average firing rates of slow firing neurons were increased by cocaine, resulting from a general elevation of movement-related firing rates. In contrast, fast firing neurons showed decreased average firing rates only in the high-dose group, with reduced firing rates across the entire range for these neurons. Our findings suggest that at the high dose, increased phasic activity of slow firing striatal neurons and simultaneously reduced phasic activity of fast firing striatal neurons may contribute, respectively, to the continual initiation of stereotypic movements and the absence of longer movements

Dose- and Rate-Dependent Effects of Cocaine on Striatal Firing Related to Licking

To examine the role of striatal mechanisms in cocaine-induced stereotyped licking, we investigated the acute effects of cocaine on striatal neurons in awake, freely moving rats before and after cocaine administration (0, 5, 10, or 20 mg/kg). Stereotyped licking was induced only by the high dose. Relative to control (saline), cocaine reduced lick duration and concurrently increased interlick interval, particularly at the high dose, but it did not affect licking rhythm. Firing rates of striatal neurons phasically related to licking movements were compared between matched licks before and after injection, minimizing any influence of sensorimotor variables on changes in firing. Both increases and decreases in average firing rate of striatal neurons were observed after cocaine injection,and these changes exhibited a dose-dependent pattern that strongly depended on predrug firing rate. At the middle and high doses relative to the saline group, the average firing rates of slow firing neurons were increased by cocaine, resulting from a general elevation of movement-related firing rates. In contrast, fast firing neurons showed decreased average firing rates only in the high-dose group, with reduced firing rates across the entire range for these neurons. Our findings suggest that at the high dose, increased phasic activity of slow firing striatal neurons and simultaneously reduced phasic activity of fast firing striatal neurons may contribute, respectively, to the continual initiation of stereotypic movements and the absence of longer movements

Hydrocephalus associated with childhood nonaccidental head trauma

OBJECTIVE The incidence of posttraumatic ventriculomegaly (PTV) and shunt-dependent hydrocephalus after nonaccidental head trauma (NAHT) is unknown. In the present study, the authors assessed the timing of PTV development, the relationship between PTV and decompressive craniectomy (DC), and whether PTV necessitated placement of a permanent shunt. Also, NAHT/PTV cases were categorized into a temporal profile of delay in admission and evaluated for association with outcomes at discharge. METHODS The authors retrospectively reviewed the cases of patients diagnosed with NAHT throughout a 10-year period. Cases in which sequential CT scans had been obtained (n = 28) were evaluated for Evans\u27 index to determine the earliest time ventricular dilation was observed. Discharge outcomes were assessed using the King\u27s Outcome Scale for Childhood Head Injury score. RESULTS Thirty-nine percent (11 of 28) of the patients developed PTV. A low admission Glasgow Coma Scale (GCS) score predicted early PTV presentation (within \u3c 3 days) versus a high GCS score (\u3e 1 week). A majority of PTV/NAHT patients presented with a subdural hematoma (both convexity and interhemispheric) and ischemic stroke, but subarachnoid hemorrhage was significantly associated with PTV/NAHT (p = 0.011). Of 6 patients undergoing a DC for intractable intracranial pressure, 4 (67%) developed PTV (p = 0.0366). These patients tended to present with lower GCS scores and develop ventriculomegaly early. Only 2 patients developed hydrocephalus requiring shunt placement. CONCLUSIONS PTV presents early after NAHT, particularly after a DC has been performed. However, the authors found that only a few PTV/NAHT patients developed shunt-dependent hydrocephalus

Hydrocephalus associated with childhood nonaccidental head trauma.

OBJECTIVE The incidence of posttraumatic ventriculomegaly (PTV) and shunt-dependent hydrocephalus after nonaccidental head trauma (NAHT) is unknown. In the present study, the authors assessed the timing of PTV development, the relationship between PTV and decompressive craniectomy (DC), and whether PTV necessitated placement of a permanent shunt. Also, NAHT/PTV cases were categorized into a temporal profile of delay in admission and evaluated for association with outcomes at discharge. METHODS The authors retrospectively reviewed the cases of patients diagnosed with NAHT throughout a 10-year period. Cases in which sequential CT scans had been obtained (n = 28) were evaluated for Evans\u27 index to determine the earliest time ventricular dilation was observed. Discharge outcomes were assessed using the King\u27s Outcome Scale for Childhood Head Injury score. RESULTS Thirty-nine percent (11 of 28) of the patients developed PTV. A low admission Glasgow Coma Scale (GCS) score predicted early PTV presentation (within \u3c 3 days) versus a high GCS score (\u3e 1 week). A majority of PTV/NAHT patients presented with a subdural hematoma (both convexity and interhemispheric) and ischemic stroke, but subarachnoid hemorrhage was significantly associated with PTV/NAHT (p = 0.011). Of 6 patients undergoing a DC for intractable intracranial pressure, 4 (67%) developed PTV (p = 0.0366). These patients tended to present with lower GCS scores and develop ventriculomegaly early. Only 2 patients developed hydrocephalus requiring shunt placement. CONCLUSIONS PTV presents early after NAHT, particularly after a DC has been performed. However, the authors found that only a few PTV/NAHT patients developed shunt-dependent hydrocephalus