Multimodality Imaging in Primary Progressive Aphasia.

Primary progressive aphasia is a clinically and neuropathologically heterogeneous group of progressive neurodegenerative disorders, characterized by language-predominant impairment and commonly associated with atrophy of the dominant language hemisphere. While this clinical entity has been recognized dating back to the 19th century, important advances have been made in defining our current understanding of primary progressive aphasia, with 3 recognized subtypes to date: logopenic variant, semantic variant, and nonfluent/agrammatic variant. Given the ongoing progress in our understanding of the neurobiology and genomics of these rare neurodegenerative conditions, accurate imaging diagnoses are of the utmost importance and carry implications for future therapeutic triaging. This review covers the diverse spectrum of primary progressive aphasia and its multimodal imaging features, including structural, functional, and molecular neuroimaging findings; it also highlights currently recognized diagnostic criteria, clinical presentations, histopathologic biomarkers, and treatment options of these 3 primary progressive aphasia subtypes.

Increased retention of tau PET ligand [18F]-AV1451 in Alzheimer's Disease Psychosis.

Psychosis in Alzheimer's disease (AD) represents a distinct disease subtype with a more rapid progression of illness evidenced by an increased velocity of cognitive decline and a hastened mortality. Previous biomarker and post-mortem studies have implicated tau neuropathology as a possible mediator of the accelerated decline in AD psychosis. Tau positron emission tomography (PET) neuroimaging provides the opportunity to evaluate tau pathology in-vivo, so that clinical symptomatology can be correlated with disease pathology. [18F]-AV1451 (Flortaucipir) is a PET ligand with high affinity for insoluble paired-helical filaments (PHFs) of hyperphosphorylated tau. In order to determine whether the development of psychosis and worsened prognosis in AD is associated with an increased burden of tau pathology that can be identified with tau imaging, we identified subjects within the Alzheimer's disease neuroimaging initiative (ADNI) who had [18F]-AV1451 imaging at baseline and became psychotic over the course of the study (N = 17) and matched them 1:3 for gender, age, and education to subjects who had [18F]-AV1451 imaging at baseline and did not become psychotic (N = 50). We compared baseline [18F]-AV1451 retention, in addition to cognitive and functional baseline and longitudinal change, in those who became psychotic over the course of participation in ADNI with those who did not. Results suggest that increases in tau pathology in frontal, medial temporal, and occipital cortices, visualized with [18F]-AV1451 binding, are associated with psychosis and a more rapid cognitive and functional decline.

Patients with prior vertebral or hip fractures treated with teriparatide in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study.

SUMMARY: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months. INTRODUCTION: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period). METHODS: We performed a post hoc analysis to assess the effect of teriparatide 20 µg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period. RESULTS: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events. CONCLUSION: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.

Atypical mycobacterial spondylitis in HIV-negative patients identified by genotyping.

Non-tuberculous mycobacterial infections pose a significant diagnostic and therapeutic challenge. We report two cases of such infection of the spine in HIV-negative patients who presented with deformity and neurological deficit. The histopathological features in both specimens were diagnostic of tuberculosis. The isolates were identified as Mycobacterium intracellulare and M. fortuitum by genotyping (MicroSeq 16S rDNA Full Gene assay) and as M. tuberculosis and a mycobacterium other than tuberculosis, respectively, by culture. There is a growing need for molecular diagnostic tools that can differentiate accurately between M. tuberculosis and atypical mycobacteria, especially in regions of the developing world which are experiencing an increase in non-tuberculous mycobacterial infections.

Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1.

The mitogen-activated protein kinases (MAPKs) are integral to the mechanisms by which cells respond to physiological stimuli, such as growth factors, hormones, and cytokines, and to a wide variety of environmental stresses. The MAPKs, which are stimulated by phosphorylation of a TXY motif in their activation loop, are components of signal transduction cascades in which sequential activation of protein kinases culminates in their activation and their subsequent phosphorylation of various effector proteins that mediate the physiological response. MAPKs are also subject to dephosphorylation and inactivation, both by enzymes that recognize the residues of the TXY motif independently and by dual specificity phosphatases, which dephosphroylate both Tyr and Ser/Thr residues. We report the identification and characterization of a novel dual specificity phosphatase. Contrary to expectation, this broadly expressed enzyme did not inactivate MAPKs in transient cotransfection assays but instead displayed the capacity to function as a selective activator of the MAPK Jnk, hence the name, Jnk Stimulatory Phosphatase-1 (JSP-1). This study illustrates a new aspect of the regulation of MAPK-dependent signal transduction and raises the possibility that JSP-1 may offer a different perspective to the study of various inflammatory and proliferative disorders associated with dysfunctional Jnk signaling.

p53 mutations in basal cell carcinomas arising in routine users of sunscreens.

Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients.

The role of clobetasol propionate emollient 0.05% in the treatment of patients with dry, scaly, corticosteroid-responsive dermatoses.

The use of topical corticosteroids has significantly enhanced the treatment of patients with dermatoses such as psoriasis and eczema. In particular, group I high-potency corticosteroids such as clobetasol propionate have proved safe and effective for limited-course treatment of inflammatory and pruritic manifestations of moderate-to-severe corticosteroid-responsive dermatoses. At the same time, much effort has gone into devising more effective strategies for addressing the dry skin conditions associated with various dermatologic disorders. An emollient added to a steroid, although not itself an active ingredient, can help restore the normal moisturizing process of the skin; this may be particularly important in soothing the discomfort of the dry skin conditions often encountered in moderate-to-severe dermatoses. In addition, the degree of epidermal hydration can affect the penetration of steroids into the skin. Therefore, successful outcomes in the treatment of patients with corticosteroid-responsive dermatoses may involve more than use of an effective topical steroid. This article examines a currently available cream formulation of 0.05% clobetasol propionate containing moisturizers--emollients, dimethicone, and a humectant--that may contribute to improved moisture content in treated skin. A review of recent studies shows that clobetasol propionate emollient cream is well tolerated and effective in courses of up to 4 weeks for the treatment of patients with psoriasis or atopic dermatitis.

Care of the skin at midlife: diagnosis of pigmented lesions.

Intrinsic skin changes with advancing years include dryness, decreasing elasticity, increasing skin fragility, and more prominent vasculature. Extrinsic skin aging, caused primarily by cigarette smoking and exposure to sunlight, includes mottled pigmentation and yellow discoloration, rough leathery textural changes, and wrinkling. Major premalignant and malignant neoplasms in photodamaged skin are actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma. Nonmalignant lesions include solar lentigines and seborrheic keratoses. The A, B, C, D criteria can assist in the evaluation of pigmented nevi. Physicians play an important role in educating patients about the health risks associated with excessive sun exposure and about sun protection to prevent further skin damage.

Pustular and erythrodermic psoriasis complicated by acute respiratory distress syndrome.

BACKGROUND: The pustular and erythrodermic types of psoriasis have been associated with a number of systemic complications, including congestive heart failure and pneumonia. Acute respiratory distress syndrome (ARDS) refers to acute noncardiogenic pulmonary edema with hypoxemia of various causes and has been attributed to pulmonary capillary leak. Recently, 4 cases of generalized pustular or erythrodermic psoriasis have been described associated with a pulmonary capillary leak syndrome. OBSERVATIONS: We describe 2 additional patients, 1 with pustular and erythrodermic psoriasis and 1 with erythrodermic psoriasis; who developed ARDS. Radiographic findings, pulmonary capillary wedge pressures, echocardiograms, and, in one case, an open lung biopsy specimen, were consistent with the diagnosis of ARDS. In neither case could we document any of the common causes of acute respiratory failure. CONCLUSIONS: Generalized pustular and erythrodermic psoriasis may be complicated by ARDS. The pathogenesis of this complication is unclear, but proinflammatory cytokines may be involved.

Agonistic activity of a CD40-specific single-chain Fv constructed from the variable regions of mAb G28-5.

A single-chain Fv (sFv) was expressed from the variable regions of the CD40-specific mAb G28-5. The molecule bound CD40 with a high affinity (2.2 nM) and was a monomer in solution. Surprisingly, G28-5 sFv was a potent CD40 agonist that rapidly crosslinked CD40 on the cell surface but did not crosslink CD40-Ig in solution. G28-5 sFv was a more potent agonist than G28-5 IgG and was able to stimulate CD40 responses by B cells and monocytes. G28-5 IgG partially blocked, whereas G28-5 sFv augmented CD40 responses during stimulation with natural ligand (gp39-CD8 fusion protein). These results indicate that the functional activity of ligands built from the binding site of G28-5 is highly dependent upon the size and physical properties of the molecule both in solution and on the cell surfaces.

Efficacy of auditory brainstem response as a screening test for small acoustic neuromas.

Auditory brainstem response (ABR) has been advocated as a high sensitivity screening test for acoustic neuroma. With the advent of magnetic resonance imaging (MRI), smaller size acoustic neuromas are now detectable. A prospective trial was performed to determine the sensitivity of ABR in diagnosing small acoustic neuromas. One hundred five randomly selected patients with surgically proved acoustic neuromas underwent preoperative ABR tests within 2 months of their surgery. Patients with a histologic diagnosis other than acoustic neuroma were excluded from this study. A test was considered abnormal when the interaural wave I-V latency difference was greater than 0.2 ms, the absolute wave V latency was abnormally prolonged, or there was abnormal or absent waveform morphology. Of the 105 patients tested 92 (87.6%) had abnormal ABR test, and 13 (12.4%) had completely normal waveforms and wave latencies. Eighteen patients had tumors over 2 cm in total diameter. Of these, 12 were 2.5 cm or larger and 6 were between 2.1 and 2.4 cm. All of these 18 patients had abnormal ABR tests. Of the 29 patients with tumors 1.6-2.0 cm in size, 25 (86%) had abnormal ABRs. In the 1.0-1.5 cm diameter range there were 45 patients who underwent a preoperative ABR. Of these, 40 (89%) had abnormal ABRs. Of 13 patients with tumors 9 mm or smaller, only 9 (69%) had abnormal ABR test (p < .05). Thus, it appears that ABR sensitivity decreases with tumor size and is particularly inadequate for tumors of less than 1 cm in diameter. The authors conclude that ABR is not a good screening test for smaller acoustic neuromas and recommend MRI for patients with suspected acoustic neuroma.

The neuroendocrine challenge paradigm in headache research.

The neuroendocrine challenge paradigm provides a "window" on central neurotransmitter function in vivo. This strategy is based on the premise that the sensitivity of certain central receptors can be inferred from the magnitude of the hormonal response to specific pharmacologic probes. For example, the serotonin (5HT) receptor agonist m-chlorophenylpiperazine (m-CPP) stimulates the release of cortisol and prolactin and induces migraine-like headaches. We have previously reported that the headache and cortisol responses to m-CPP are highly correlated, which may implicate a disturbance in central serotonergic neurotransmission in the pathogenesis of migraine. As pharmacologic probes with greater specificity for 5HT receptor subtypes become available, we may be able to elucidate these mechanisms with greater precision. The neuroendocrine challenge methodology is also applicable to the study of other neurotransmitter systems and other headache disorders.

Nonoperative management of upper thoracic spine fractures.

We attempted to determine if nonsurgical treatment could be successful in treating instability of upper thoracic spine fractures, which may receive some stabilization and splinting from the ribs. From 1966 to 1989, the records of all patients treated at Rancho Los Amigos Medical Center for fractures from T-1 to T-8 were reviewed. Penetrating injuries and malignant lesions were excluded. A total of 118 patients were admitted during this period; 49 patients had nonsurgical treatment. Complications included 1 patient with neurologic worsening, brace-related skin necrosis in 8 cases, and deep venous thrombosis in 12 patients. No failure of arthrodesis was noted. Rib fractures did not adversely affect late stability. We conclude that orthotic treatment of thoracic spine instability from T-1 to T-8 can be successful, especially in cases where early surgery is not possible.

Headache and cortisol responses to m-chlorophenylpiperazine are highly correlated.

The serotonin receptor agonist m-chlorophenylpiperazine (m-CPP) stimulates the release of cortisol and prolactin, and induces migraine-like headaches. We have studied the neuroendocrine and headache responses to m-CPP in 8 subjects with migraine and 10 normal subjects. Each subject underwent two challenge tests, one with 0.25 mg/kg PO of m-CPP and the other with placebo, administered in a double-blind crossover format. Serial measurements of serum cortisol, prolactin, and m-CPP levels were made at 30-min intervals for 210 min following ingestion of the medication. The incidence and severity of headache was assessed by a structured telephone interview after each test. We confirmed that m-CPP stimulates the release of cortisol and prolactin, and may induce headache, in both migraine subjects and normal controls. The cortisol response as well as ratings of headache severity and duration directly correlated with plasma levels of m-CPP. There were highly significant associations between the cortisol response and both headache severity and duration, independent of m-CPP plasma levels. We did not find statistically significant differences between the migraine and normal subjects in terms of their neuroendocrine or headache responses to m-CPP.

Outsourcing data processing: planning for the disentanglement.

Outsourcing data processing operations may be considered a conventional acquisition transaction between a customer and supplier. The most distinctive feature of a DP outsourcing contract is that it involves complex issues relating to computer software and technology and, frequently, intense issues relating to employees. But, one must do more in order to provide for preservation of the integrity (and, therefore, the value) of the data center. The contract must include not just the sale of a facility to a supplier who will take over the operations, but also terms for reconveying the facility at a future date. Getting out of the arrangement can be very complex. Disentanglement can be made less complex however, if the customer and the supplier negotiate all or part of the disentanglement procedures during the original contract proposal. Know ahead of time the possible scenarios for when disentanglement may take place and know what to do during the contract negotiations and during the length of the agreement to keep track of each other's properties. Know also the risks involved in outsourcing DP operations, such as what happens when the supplier's business fails. Having the supplier set up a separate profit entity for your contracted business or using a lien on the data center properties may help avoid loss if such failure occurs.

Identification of a program of contractile protein gene expression initiated upon skeletal muscle differentiation.

The functional diversity of skeletal muscle is largely determined by the combinations of contractile protein isoforms that are expressed in different fibers. Just how the developmental expression of this large array of genes is regulated to give functional phenotypes is thus of great interest. In the present study, we performed a comprehensive analysis of contractile protein isoform mRNA profiles in skeletal muscle systems representing each generation of fiber formed: primary, secondary, and regenerating fibers. We find that in each system examined there is a common pattern of isoform gene expression during early differentiation for 5 of the 6 gene families we have investigated: myosin light chain (MLC)1, MLC2, tropomyosin, troponin (Tn)C, and TnI. We suggest that the common isoform patterns observed together represent a genetic program of skeletal muscle differentiation that is independent of the mature fiber phenotype and is found in all newly formed myotubes. Within each of these contractile protein gene families the program is independent of the isoforms of myosin heavy chain (MHC) expressed. The maintenance of such a program may reflect a specific requirement of the initial differentiation process.

Episodic paroxysmal hemicrania: two new cases and a literature review.

Episodic paroxysmal hemicrania (EPH) is a rare disorder characterized by discrete bouts of hemicranial headache separated by headache-free remissions. Although EPH resembles episodic cluster headache in the location and quality of pain as well as the pattern of associated autonomic features, it is distinguished by the greater frequency and shorter duration of individual headaches. Differentiation of these disorders is important because EPH almost invariably responds to treatment with indomethacin but not to standard cluster headache therapy.