Migraine Mimics

The symptoms of migraine are non‐specific and can be present in many other primary and secondary headache disorders, which are reviewed. Even experienced headache specialists may be challenged at times when diagnosing what appears to be first or worst, new type, migraine status, and chronic migraine.     

Trajectory Clustering of Estradiol and Follicle-Stimulating Hormone during the Menopausal Transition among Women in the Study of Women's Health across the Nation (SWAN)

Context: Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. Objective: The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. Design: The Study of Women's Health Across the Nation is a longitudinal observational study of the menopausal transition. Setting: Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. Participants: Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. Main Outcome Measures: Annual serum E2 and FSH levels anchored to final menstrual period were measured. Results: Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. Conclusions: E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition.     

Prolonged early G1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4

Dysregulation of cyclin-dependent kinase 4 (CDK4) and CDK6 by gain of function or loss of inhibition is common in human cancer, including multiple myeloma, but success in targeting CDK with broad-spectrum inhibitors has been modest. By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. We show that induction of prolonged early-G(1) arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G(1) and prevents expression of genes programmed for other cell-cycle phases. Removal of the early-G(1) block leads to S-phase synchronization (pG1-S) but fails to completely restore scheduled gene expression. Consequently, the IRF4 protein required to protect myeloma cells from apoptosis is markedly reduced in pG1 and further in pG1-S in response to cytotoxic agents, such as the proteasome inhibitor bortezomib. The coordinated loss of IRF4 and gain of Bim sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 in the absence of Noxa and more profoundly in pG1-S in cooperation with Noxa in vitro. Induction of pG1 and pG1-S by reversible CDK4/CDK6 inhibition further augments tumor-specific bortezomib killing in myeloma xenografts. Reversible inhibition of CDK4/CDK6 in sequential combination therapy thus represents a novel mechanism-based cancer therapy.     

Estimating memory function: Disparity of wechsler memory scale-revised and California verbal learning test indices in clinical and normal samples

Although a high degree of convergence has been reported between the California Verbal Learning Test (CVLT) and the Wechsler Memory Scale-Revised (WMS-R), standard scores from these tests may not provide commensurate global estimations of memory function. Data were reviewed from 161 subjects who had taken both tests, including schizophrenic (n = 33) and temporal-lobe epilepsy (n = 31) patients and 97 normal volunteers. The patient group performed approximately one standard deviation below the normal mean on the WMS-R indexes, but three standard deviations below the normal mean on CVLT indices. The normal volunteers, who were well-educated as a group, performed approximately one standard deviation above the population-based mean on the WMS-R (commensurate with their IQ level), but at the mean of the CVLT reference sample. These findings suggest that the standardization samples for these two tests are not representative of the same population. The CVLT normative reference sample appears to have been higher functioning than the WMS-R sample, and may also have been characterized by a narrower range of memory function. The implications of these findings with respect to the clinical evaluation of memory are discussed.     

Cyclodextrin Protects Podocytes in Diabetic Kidney Disease

Diabetic kidney disease (DKD) remains the most common cause of end-stage kidney disease despite multifactorial intervention. We demonstrated that increased cholesterol in association with downregulation of ATP-binding cassette transporter ABCA1 occurs in normal human podocytes exposed to the sera of patients with type 1 diabetes and albuminuria (DKD⁺) when compared with diabetic patients with normoalbuminuria (DKD⁻) and similar duration of diabetes and lipid profile. Glomerular downregulation of ABCA1 was confirmed in biopsies from patients with early DKD (n = 70) when compared with normal living donors (n = 32). Induction of cholesterol efflux with cyclodextrin (CD) but not inhibition of cholesterol synthesis with simvastatin prevented podocyte injury observed in vitro after exposure to patient sera. Subcutaneous administration of CD to diabetic BTBR (black and tan, brachiuric) ob/ob mice was safe and reduced albuminuria, mesangial expansion, kidney weight, and cortical cholesterol content. This was followed by an improvement of fasting insulin, blood glucose, body weight, and glucose tolerance in vivo and improved glucose-stimulated insulin release in human islets in vitro. Our data suggest that impaired reverse cholesterol transport characterizes clinical and experimental DKD and negatively influences podocyte function. Treatment with CD is safe and effective in preserving podocyte function in vitro and in vivo and may improve the metabolic control of diabetes.Diabetic kidney disease (DKD) is responsible for nearly half of the incidents of end-stage kidney disease in the U.S. (1), yet our current understanding of the pathophysiological processes responsible for DKD has led to limited improvements in patient outcomes. Multifactorial intervention reduces the rate of progression of DKD but does not prevent end-stage kidney disease in type 1 (T1D) or type 2 diabetes (T2D) (2,3). A key factor for this translation gap is the current lack of adequate mechanistic insight into DKD in humans.The kidney glomerulus is a highly specialized structure that ensures the selective ultrafiltration of plasma so that essential proteins are retained in the blood (4). Podocytes are glomerular epithelial cells that contribute to the glomerular filtration barrier through a tight regulation of actin cytoskeleton remodeling (4). Currently, the diagnosis of DKD relies on the detection of microalbuminuria (5). However, a growing body of evidence suggests that key histological lesions precede the development of albuminuria (6,7); among them, decreased podocyte number (podocytopenia) has been described as an independent predictor of DKD progression (8–12). Although we have previously shown that podocyte insulin resistance and susceptibility to apoptosis is already present at the time of onset of microalbuminuria in experimental models of DKD, the cause of podocyte injury in early DKD remains unknown (13).We used a previously established cell-based assay in which differentiated human podocytes are exposed to 4% patient sera for 24 h (14) to identify new pathways and targets in DKD. Podocytes exposed to the sera of patients with DKD showed increased cholesterol accumulation in association with downregulation of ATP-binding cassette transporter 1 (ABCA1) expression that was independent of circulating cholesterol.ABCA1 is a major regulator of cellular cholesterol homeostasis by mediating efflux to lipid-poor apolipoprotein acceptors in the bloodstream (15). ABCA1 genetic variants are strongly associated with the risk of coronary artery disease (16). Furthermore, the capacity of patient sera to induce ABCA1-mediated cholesterol efflux in macrophages is impaired in patients with T2D and incipient or overt nephropathy (17). Excessive cholesterol accumulation has been described in glomeruli of rodent models of T1D and T2D (18–20) and may contribute to DKD development and progression. Finally, inactivating mutations of ABCA1 result in Tangier disease, which causes premature atherosclerosis and proteinuria (21).Although interventions that increase ABCA1 expression (such as liver X receptor agonists) may be beneficial in DKD, they have a relatively high incidence of adverse events (22) as well as intrinsic lipogenic effects (23). We used β-cyclodextrins, cyclic oligosaccharides consisting of seven β(1-4)-glucopyranose rings, to remove cholesterol from differentiated human podocytes in vitro and from diabetic animals in vivo. The exact mechanism by which cyclodextrins (CDs) remove cholesterol from cells is not completely understood, but the formation of cholesterol/CD inclusion complexes at the membrane surface plays an important role in this process (24).We hypothesized that 2-hydroxypropyl-β-cyclodextrin, which was recently approved by the U.S. Food and Drug Administration (FDA) for the cure of Niemann-Pick disorder (25,26), would be an effective way to sequester cholesterol and to protect podocytes from cholesterol-dependent damage in DKD in vivo and in vitro.     

Operative treatment of chance injuries in the paediatric population

Purpose

Chance fractures are an uncommon spine injury in the paediatric population. As such there is a relative paucity of evidence in the literature to guide management decisions. We present our single centre experience in the operative management of these injuries.

Methods

All patients presenting to a tertiary paediatric trauma centre between 2000 and 2008 were included. Retrospective analysis of clinical (SRS-22 and Oswestry) and radiological outcomes was undertaken.

Results

Twelve patients underwent operative stabilization of a Chance type injury. Radiological and clinical outcome measures demonstrated excellent outcomes in the majority of patients with no significant complications.

Conclusions

Operative management of paediatric chance injuries with instrumentation results in excellent clinical and radiological outcomes.     

Prospective validation study of Cernea classification for predicting EMG alterations of the external branch of the superior laryngeal nerve

Purposes

Cernea classification is applied to describe the external branch of the superior laryngeal nerve (EBSLN). Using intraoperative neural monitoring we evaluated whether or not this classification is useful for predicting which EBSLN subtype has an increased risk of injury.

Methods

An analysis of 400 EBSLN. The identification of EBSLN was achieved with both cricothyroid muscle twitch and the glottis evoked electromyography response. We defined S1 initial EBSLN stimulation at identification and S2 final nerve stimulation achieved in the most cranial aspect of the nerve exposed above the area of surgical dissection after superior artery ligation.

Results

The mean S1 amplitude acquired was 259+/67 (180–421), 321 +/79 (192–391), 371 +/38 (200–551) μV, respectively, for type 1, 2A, 2B (p = 0.08). The S1 and S2 amplitudes were similar in type 1 (p = 0.3). The S1 and S2 determinations changed significantly in type 2A and 2B (p = 0.04 and 0.03). EBSLN which demonstrated a >25 % decreased amplitude in S2 increased significantly from Type 1 (4.9 %) to Type 2A (11.2 %) and 2B (18 %) (p = 0.01). None of type 1, 2.8 % type 2A and 3 % type 2B showed a loss of EBSLN conductivity. The latency determinations did not vary significantly for any parameter compared.

Conclusions

The Cernea classification was, therefore, found to predict the risk of EBSLN stress. We identified amplitude differences between S1 and S2 determinations in type 2A and 2B, thus confirming that surgical dissection in these subtypes is, therefore, extremely difficult to perform.