MRI Shrimp Sign in Cerebellar Progressive Multifocal Leukoencephalopathy: Description and Validation of a Novel Observation.

BACKGROUND AND PURPOSE: There are no validated imaging criteria for the diagnosis of progressive multifocal leukoencephalopathy in the cerebellum. Here we introduce the MR imaging shrimp sign, a cerebellar white matter lesion identifiable in patients with cerebellar progressive multifocal leukoencephalopathy, and we evaluate its sensitivity and specificity. MATERIALS AND METHODS: We first identified patients with progressive multifocal leukoencephalopathy seen at Massachusetts General Hospital between 1998 and 2019 whose radiology reports included the term "cerebellum." Drawing on a priori knowledge, 2 investigators developed preliminary diagnostic criteria for the shrimp sign. These criteria were revised and validated in 2 successive stages by 4 additional blinded investigators. After defining the MR imaging shrimp sign, we assessed its sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We identified 20 patients with cerebellar progressive multifocal leukoencephalopathy: 16 with definite progressive multifocal leukoencephalopathy (mean, 46.4 [SD, 9.2] years of age; 5 women), and 4 with possible progressive multifocal leukoencephalopathy (mean, 45.8 [SD, 8.5] years of age; 1 woman). We studied 40 disease controls (mean, 43.6 [SD, 21.0] years of age; 16 women) with conditions known to affect the cerebellar white matter. We defined the MR imaging shrimp sign as a T2- and FLAIR-hyperintense, T1-hypointense, discrete cerebellar white matter lesion abutting-but-sparing the dentate nucleus. MR imaging shrimp sign sensitivity was 0.85; specificity, 1; positive predictive value, 1; and negative predictive value, 0.93. The shrimp sign was also seen in fragile X-associated tremor ataxia syndrome, but radiographic and clinical features distinguished it from progressive multifocal leukoencephalopathy. CONCLUSIONS: In the right clinical context, the MR imaging shrimp sign has excellent sensitivity and specificity for cerebellar progressive multifocal leukoencephalopathy, providing a new radiologic marker of the disease.

Clinical, Imaging, and Lab Correlates of Severe COVID-19 Leukoencephalopathy.

BACKGROUND AND PURPOSE: Patients infected with the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) can develop a spectrum of neurological disorders, including a leukoencephalopathy of variable severity. Our aim was to characterize imaging, lab, and clinical correlates of severe coronavirus disease 2019 (COVID-19) leukoencephalopathy, which may provide insight into the SARS-CoV-2 pathophysiology. MATERIALS AND METHODS: Twenty-seven consecutive patients positive for SARS-CoV-2 who had brain MR imaging following intensive care unit admission were included. Seven (7/27, 26%) developed an unusual pattern of "leukoencephalopathy with reduced diffusivity" on diffusion-weighted MR imaging. The remaining patients did not exhibit this pattern. Clinical and laboratory indices, as well as neuroimaging findings, were compared between groups. RESULTS: The reduced-diffusivity group had a significantly higher body mass index (36 versus 28 kg/m2, P < .01). Patients with reduced diffusivity trended toward more frequent acute renal failure (7/7, 100% versus 9/20, 45%; P = .06) and lower estimated glomerular filtration rate values (49 versus 85 mL/min; P = .06) at the time of MRI. Patients with reduced diffusivity also showed lesser mean values of the lowest hemoglobin levels (8.1 versus 10.2 g/dL, P < .05) and higher serum sodium levels (147 versus 139 mmol/L, P = .04) within 24 hours before MR imaging. The reduced-diffusivity group showed a striking and highly reproducible distribution of confluent, predominantly symmetric, supratentorial, and middle cerebellar peduncular white matter lesions (P < .001). CONCLUSIONS: Our findings highlight notable correlations between severe COVID-19 leukoencephalopathy with reduced diffusivity and obesity, acute renal failure, mild hypernatremia, anemia, and an unusual brain MR imaging white matter lesion distribution pattern. Together, these observations may shed light on possible SARS-CoV-2 pathophysiologic mechanisms associated with leukoencephalopathy, including borderzone ischemic changes, electrolyte transport disturbances, and silent hypoxia in the setting of the known cytokine storm syndrome that accompanies severe COVID-19.

Brain MR Spectroscopic Findings in 3 Consecutive Patients with COVID-19: Preliminary Observations.

Brain multivoxel MR spectroscopic imaging was performed in 3 consecutive patients with coronavirus disease 2019 (COVID-19). These included 1 patient with COVID-19-associated necrotizing leukoencephalopathy, another patient who had a recent pulseless electrical activity cardiac arrest with subtle white matter changes, and a patient without frank encephalopathy or a recent severe hypoxic episode. The MR spectroscopic imaging findings were compared with those of 2 patients with white matter pathology not related to Severe Acute Respiratory Syndrome coronavirus 2 infection and a healthy control subject. The NAA reduction, choline elevation, and glutamate/glutamine elevation found in the patient with COVID-19-associated necrotizing leukoencephalopathy and, to a lesser degree, the patient with COVID-19 postcardiac arrest, follow a similar pattern as seen with the patient with delayed posthypoxic leukoencephalopathy. Lactate elevation was most pronounced in the patient with COVID-19 necrotizing leukoencephalopathy.

Perineal trauma in women undergoing vaginal delivery following intra-uterine fetal demise: a case-control analysis.

INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate any differences in the incidence of perineal trauma in women undergoing vaginal delivery following intrauterine fetal death (IUFD) versus live-births. This information would be of interest in evaluating the possible effect of fetal demise on the mechanism of labour in the second stage and thus may provide invaluable insights to contribute to our understanding of the impact of fetal tone on the mechanics of labour and delivery. METHODS: 323 women who delivered vaginally following IUFD were matched with 1,000 women with a live-birth for age, parity, gestation and birth weight. Women undergoing assisted vaginal delivery and/or episiotomy were excluded. RESULTS: Women with an IUFD had a significantly lower risk of perineal trauma overall (relative risk 0.16) as well as a lower risk of obstetric anal sphincter injury specifically (RR 0.12). CONCLUSIONS: Women delivering vaginally after IUFD have a lower incidence of perineal trauma compared with women delivering a live infant. This may be due to differences in biomechanics following an IUFD.

Urinomas protect renal function in posterior urethral valves--a population based study.

BACKGROUND/PURPOSE: Urinomas have been thought to protect renal function in boys with posterior urethral valves (PUVs), although recent reports have disputed this. This study tested the hypothesis that urinomas protect global renal function in boys with PUV. METHODS: A retrospective analysis of all boys with PUV presenting to a tertiary unit derived from a region with an estimated population of 5.5 million was performed. Comparisons of the initial nadir creatinine, current creatinine, and renal status score (RSS) were made between those with and without urinomas. The RSS was derived from nephrology assessment of current renal status (0 = normal to 4 = end-stage renal failure or transplantation). Results were given as median (range), except for RSS, which was given as mean +/- SEM. P < or = .05 was regarded as significant. RESULTS: During 1989-2009, 9 of 89 PUV boys were diagnosed with urinomas. Initial nadir creatinine was statistically lower in boys with urinomas (31 [18-44] vs 45 [20-574] mumol/L, P < .01). Length of follow-up was similar (5.1 [2.2-17.3] vs 5.9 [1.8-19.7] years, P = .59). Follow-up creatinine was significantly lower in urinoma boys (44 [25-77] vs 61 [29-1227] micromol/L, P < .05), as was the RSS (0.14 +/- 0.14 vs 0.91 +/- 0.14, P < .01). No urinoma boys progressed to end-stage renal failure or required transplant. CONCLUSION: This population-based study of PUV boys demonstrates that urinomas reduce nadir creatinine and significantly protect long-term global renal function.

Plastic surgery and the teenage patient.

Over the past year, the media have reported an increase in the number of teenagers undergoing plastic surgery, and with a tone of faint alarm have suggested that this merits some cultural self-scrutiny. This paper presents the statistics on the number and types of plastic surgery operations done in teenagers over the last eight years and discusses these in the context of cultural influences and societal concepts of beauty. The reason to have plastic surgery is psychological and involves body image, which is defined as the subjective perception of the body as it is seen through the mind's eye. To explain why changing the external appearance affects personality and behavior, the complex psychological reactions that occur after an operation that alters the size or shape of a body part are reviewed. Body image development occurs in stages, and puberty stands out as a particularly sensitive time as the teenager undergoes major changes in his or her physical appearance and does this at a time of heightened vulnerability to the opinion of others. Plastic surgery to correct a truly unattractive feature is enormously successful and remarkably free of conflict in this population. Teenagers undergo a rapid reorganization of their self-image after plastic surgery with subsequent positive changes in behavior and interpersonal interactions. The key to achieving success with plastic surgery is patient selection. The core value of the surgery lies not in the objective beauty of the visible result, but in the patient's opinion of and response to the change. Good patient management includes selecting candidates with clear and realistic expectations who are free of psychopathology. There must be true informed consent and attention to psychological issues must continue into the postoperative period. It is the responsibility of the patient's physician and plastic surgeon to recognize a need for psychiatric evaluation and to help the patient get this as needed. The eight operations most commonly done in the teenage population are rhinoplasty, ear surgery, reduction mammoplasty, surgery for asymmetric breasts, excision of gynecomastia, augmentation mammoplasty, chin augmentation, and suction assisted lipoplasty. Each of these is reviewed with regard to techniques, expectations, risks, and logistics. Guidelines for timing the referral of teenage patients for plastic surgery evaluation are given.

Haem biosynthesis and human porphyria cutanea tarda: effects of alcohol intake.

The review describes the structural and biochemical properties of the haem biosynthetic enzyme, uroporphyrinogen decarboxylase (UROD), which sequentially catalyzes the removal of the four carboxyl groups from the acetate side chains of octacarboxylic uroporphyrinogen to form coproporphyrinogen, and the possible biochemical mechanism of the genesis of porphyria cutanea tarda (PCT). The disease is caused when the activity of UROD is significantly reduced. PCT is a multifactorial disease where both inherent and environmental factors such as alcohol, estrogens, halogenated aromatic hydrocarbons and viral infection (mainly hepatitis C) are involved in biochemical and clinical expression. In PCT, hepatic iron plays a key role. Alcohol intake could induce mobilization of iron from protein-bound ferritin. PCT should be managed by avoidance of these toxins and removal of iron by vigorous phlebotomy. Such iron-reduction therapy would provide additional benefit for hepatitis C patients by interferon therapy.

Psychological impact of the Antarctic winter on Indian expeditioners.

The authors studied the psychological variables of 25 men who participated in the winter-over team of an Indian expedition to Antarctica for possible associations with seasonality and isolation. It was found that increased cigarette smoking was associated with the stress of the beginning of isolation (March), sleep difficulty was associated with midwinter (June), rapport was at a minimum at the point of maximum isolation in temporal terms (September), and decreased satisfaction with work and life situations was associated with continued isolation (December, January). The study suggested that variables postulated to affect performance undergo changes during the course of wintering over in Antarctica.

Management of penetrating laryngotracheal injuries.

BACKGROUND: Penetrating laryngotracheal injuries are uncommon; however, these injuries are associated with significant morbidity and mortality. In an attempt to define the management of penetrating laryngotracheal injuries, we reviewed our experience with these injuries. METHODS: We retrospectively analyzed the records of all patients admitted to a Level I trauma center who required operative management for penetrating laryngotracheal injuries. During the period of this study all patients with penetrating neck injuries were managed according to a protocol of selective exploration. RESULTS: Of fifty-seven patients with penetrating laryngotracheal injury 32 patients sustained gunshot wounds and 25 had stab wounds. The injuries were to the larynx in 24 (42%) and trachea in 33 (58%). Forty-six (81%) had isolated airway injuries and 11 (19%) had combined airway and digestive-tract injuries. Emergent airway management in 32 (56%) patients included: tracheostomy (15), endotracheal intubation (14), and cricothyroidotomy (3). Respiratory distress and subcutaneous crepitus were the commonest clinical findings. Diagnostic evaluation included: laryngoscopy/ tracheoscopy (17), esophagoscopy (12), contrast esophagography (9), angiography (8), and bronchoscopy (3). Repair of laryngotracheal and esophageal injury was performed in the majority of patients. Selected patients with milder laryngotracheal injury did not have tracheostomy performed, with no increase in morbidity or mortality. There were 2 (3.5%) early deaths from associated major vascular injury. CONCLUSION: Mortality can be minimized by aggressive airway control. Endotracheal intubation can be accomplished safely in selected patients with penetrating laryngotracheal injuries. Digestive-tract injuries can often clinically occult and contribute significantly to morbidity and mortality; therefore, early evaluation of the esophagus is vital. Simple repair of laryngotracheal and digestive-tract injuries can be performed safely with good results. In patients with minor injuries, tracheostomy does not appear to be mandatory.

Uroporphyrinogen decarboxylases from human erythrocytes: purification, complete separation and partial characterization of two isoenzymes.

1. Two distinct molecular forms of uroporphyrinogen decarboxylase have been completely separated and highly purified from human erythrocytes. 2. Each protein, with molecular masses of about 52-54 kDa and 35 kDa, are apparently composed of a single polypeptide chain. 3. They may form a functional decarboxylating complex for heme biosynthesis.

Free radical mechanism of oxidation of uroporphyrinogen in the presence of ferrous iron.

Human porphyria cutanea tarda is an unusual consequence of common hepatic disorders such as alcoholic liver disease. Hepatic iron plays a key role in the expression of the metabolic lesions, i.e., defective hepatic decarboxylation of porphyrinogens, catalyzed by uroporphyrinogen decarboxylase. This prompted the present study to determine the in vitro effects of iron on the uroporphyrinogen substrate in the absence and presence of atmospheric oxygen. We observed that (i) unless oxygen is the limiting reactant, autoxidation of ferrous iron and iron-catalyzed oxidation of uroporphyrinogen occurred soon after initiating the reaction at pH 7.4 and 30 degrees C in buffers which are non- or poor chelators of iron; (ii) the rates of uroporphyrinogen oxidation were proportional to the initial concentration of ferrous ion; (iii) about 70% of the oxidations of uroporphyrinogen were accountable due to a free-radical chain reaction pathway involving superoxide radical and hence inhibitable by superoxide dismutase; (iv) uroporphyrinogen could be further oxidized to completion by the hydroxyl radical since the reaction was partially inhibited by both mannitol and catalase which prevent hydroxyl radical production; (v) the oxidizing effects of ferric ion on uroporphyrinogen were none or negligible as compared to those of ferrous ion. Ferric was reduced to ferrous ion in the presence of dithiothreitol. When the ferrous ion thus formed was reoxidized in the presence of atmospheric oxygen, minor but definite oxidations of both uroporphyrinogen and dithiothreitol were observed. The oxidations of Fe2+ and uroporphyrinogen could be blocked by 1,10-phenanthroline, a ferrous iron chelator. The data suggest that ferrous is the reactive form of iron that may contribute to pathogenic development of the disease by irreversibly oxidizing the porphyrinogen substrates to nonmetabolizable porphyrins, which accumulate in porphyric liver.

Simulation of aspects of ischemia in cell culture: changes in lactate compartmentation.

Aspects of hyperglycemic ischemia were simulated in cultures of astrocytes and of neurons by high glucose and dinitrophenol exposure. Lactate release increased almost sevenfold and it was found that astrocytes were responsible for 92% of the release. There was no significant increase in internal lactate content. Experiments involving loading of astrocytes with lactate at different external pH values showed that lactate accumulation was increased by an increased inward proton gradient. This inward transport of lactate probably consists of two transport components, a passive diffusion of its neutral form and transport via a recently described monocarboxylic acid carrier. It was found that lactate did not get trapped in astrocytes, despite the fact that loading of astrocytes with lactic acid by exposure to 30 mM lactic acid increased the membrane input resistance dramatically. We conclude that lactate is released as lactic acid from astrocytes and equilibrates quickly with all CNS compartments. Thus we argue against a role of lactate accumulation in cytotoxic swelling.

Defective human erythrocyte uroporphyrinogen decarboxylase in familial porphyria cutanea tarda: the metabolic lesion or the result of endogenous porphyrinemia?

We have demonstrated that oral charcoal therapy is as effective as therapeutic phlebotomy in reducing porphyrinemia in porphyria cutanea tarda. The effects of immediate and sustained reduction of porphyrinemia on the catalytic properties of partially purified (approximately 200-fold) preparations of red cell uroporphyrinogen decarboxylase of a patient with familial porphyria cutanea tarda were studied. All populations of the patient's red cells exhibited defective enzyme activity, and the apparent Michaelis constants (Km) determined with penta-, hepta-, and octa-carboxylic I porphyrinogen substrates were approximately 3-4 times higher as compared to the normal controls. Mixing experiments (normal and defective enzyme), and preincubation of the normal enzyme with porphyric plasma prior to purification, yielded data supporting the concept that the catalytic defects of red cell uroporphyrinogen decarboxylase in familial porphyria cutanea tarda are independent of interactions between circulating endogenous porphyrins and the enzyme.

Lactate production and release in cultured astrocytes.

Intracellular lactate content and release of lactate into the surrounding medium of mouse astrocytes in primary culture was measured using the lactate dehydrogenase method. During culturing the cellular content of astrocytes decreased from 400 to 200 nmol/mg protein. The total lactate released into the extracellular space, however, amounted to 75,000 nmol/mg within 98 h, corresponding to a lactate concentration of 10 mM in the cell culture dish. In another set of experiments, cytotoxic swelling was evoked by exposure of the cells to 60 mM K+, this situation caused a 40% increase in cellular volume and an increase in the KCl content of astrocytes. Within 3 h of a change to 60 mM K+ the intracellular lactate content was increased by 100 nmol/mg (one third) and the lactate release in the extracellular space by about 2000 nmol/mg (twice as high as during exposure to 3 mM K+). However, due to the increased intracellular water content, the lactate concentration inside the cells remained unchanged. It is concluded that astrocytes produce substantial amounts of additional lactate during cytotoxic swelling. This lactate, however, is not increasing the intracellular osmolarity and most of the lactate is released into the extracellular space. Depending on the transmembrane transport mechanism it could have the capability to decrease the strong ion difference and contribute to acid shifts in the extracellular space.

Lactate release from cultured astrocytes and neurons: a comparison.

Lactate released into the surrounding salt solution as well as the cellular lactate content were measured in cerebral primary cultures of mouse astrocytes and of mouse neurons. Any newly produced lactate was immediately released as lactic acid into the extracellular compartment via a lactate/proton cotransport. The astrocytic release was about 2,000 nmol x mg-1 x hr-1; the neuronal release was about 300 nmol x mg-1 x hr-1. However, if election transport was blocked with dinitrophenol, the neuronal lactate release was as high as the astrocytic one under normal conditions. High glucose (30 mM) and K+ (60 mM) increased lactate release of astrocytes but not of neurons. In contrast it was found that insulin (1 microM) exposure mainly stimulated neuronal lactate release rather than glial release. Adenosine stimulated both neuronal and glial release. Neither intracellular lactate content nor concentration changed significantly in either cell type under any conditions tested. The pathophysiological implications of these measurements are discussed.

Mouse placental receptor for basic somatomedin following maternal ethanol administration.

We have previously reported a reduction in the basic somatomedin (B-SM) binding activity of day-15 mouse placental membranes following 3 days of acute maternal ethanol administration. In the present experiments, we have investigated the effects of acute maternal ethanol administration early in gestation on the subsequent development of the placental B-SM receptor, and its relationship to alcohol-related embryofetal growth deficits. Following administration of aqueous ethanol (0.0, 3.6, 5.5 or 7.1 ml/kg) by gavage on days 7, 8 and 9 of gestation, there was no evidence of reproductive impairment in alcohol-treated dams, but there was a significant reduction in day-15 embryonic body weight. Crown-rump length was unaffected. There was no treatment-related difference in the percentage specific binding of [125I]-B-SM by day-15 placental membranes, or in maternal serum B-SM concentrations. These observations suggest that embryofetal growth restriction following maternal ethanol administration is not mediated directly by peripheral unresponsiveness of the B-SM receptor, at least when the exposure occurs early in or prior to placental receptor ontogeny.

KCl movements during potassium-induced cytotoxic swelling of cultured astrocytes.

Astrocytes in primary cultures from mouse cortex were used to investigate the ionic mechanism of cytotoxic swelling which develops after exposure of the cells to 60 mM K+ under isosmotic conditions. Radiotracer analysis combined with a washing efflux method were used to analyze ion changes. We found that both the K+ and the Cl- content increased by about 100% within 1 min after increasing the external K+, and remained constant for 30 min thereafter. The mechanisms, i.e., Na+,K+-ATPase-mediated transport and NaCl/KCl contransport, that are involved in glial ion homeostasis in physiologic situations (extracellular K+ increase to 12 mM) are disturbed in this system and do not contribute to the cytotoxic swelling induced by pathologic K+ concentrations. The Na+,K+-ATPase-mediated K+ uptake is not additionally stimulated by the pathologic K+ increase. The NaCl/KCl cotransport was minimal, presumably due to a severe reduction of the Na+ driving force by the depolarization. The mechanisms of this pathological swelling were found to consist mainly of a passive KCl influx. This influx is mediated by a disturbance of the Donnan equilibrium. It probably involves an increase of the Cl- permeability by activation of a previously described voltage-dependent Cl- channel, which is closed under physiological conditions. However, it was found that the intracellular Cl- accumulation did not completely match the corresponding K+ accumulation. Possible reasons for this anion deficit are discussed.

Evidence for two uroporphyrinogen decarboxylase isoenzymes in human erythrocytes.

In animals and plants, uroporphyrinogen decarboxylase catalyzes the stepwise decarboxylations of uroporphyrinogen, the precursor of heme and chlorophyll. To better understand its metabolic roles, we characterized the enzyme purified to electrophoretic homogeneity (about 11,000-fold) from human erythrocytes by a novel uroporphyrin-sepharose affinity chromatographic method. Native polyacrylamide disc gel electrophoresis of the purified enzyme preparation showed two bands detected by staining either for protein or with uroporphyrin-I. Each individual protein eluted from the gel when subjected to re-electrophoresis on SDS-polyacrylamide gel, appeared as a single protein band with molecular masses of approximately 54,000 and approximately 35,000 daltons respectively. Both proteins were able to catalyze all four decarboxylation steps, though the ratios of enzyme activity using octa-, hepta-, hexa- to pentacarboxylic porphyrinogen substrates were distinctly different. Also, their kinetic analysis with heptacarboxylic porphyrinogen-I substrate provided distinctly different apparent Michaelis constants. This provides the first evidence that decarboxylations of uroporphyrinogen to coproporphyrinogen are catalyzed by two isoenzymes.