The Comparative Prognostic Value of Directional Preference and Centralization: A Useful Tool for Front-Line Clinicians?

A large number of prognostic factors have been associated with recovery from an episode of back pain, and much emphasis has been placed on psychosocial prognostic factors. The large number of prognostic factors and the lack of comparative analysis of different factors make use of these difficult in clinical practice. The aim of this study was to evaluate the comparative usefulness of a range of factors to predict outcome using data from a randomized controlled trial (RCT) in which 312 patients with sub-acute to chronic back pain received a mechanical evaluation and were sub-grouped based on the presence or absence of directional preference (DP). Patients were then randomized to treatment that was matched or unmatched to that DP. Patients with a minimal reduction of 30% in Roland-Morris Disability Questionnaire (RMDQ) score were defined as the good outcome group. Seventeen baseline variables were entered into a step-wise logistic regression analysis for the ability to predict a good outcome. Of the patients, 84 met the good outcome criteria and had a mean RMDQ decrease of 58.2% (9.8 points) in 4 visits. Leg pain, work status, depression, pain location, chronicity, and treatment assignment were significant predictors of outcome in univariate analysis. Only leg bothersomeness rating and treatment assignment survived multivariate analysis. Subjects with DP/centralization who received matched treatment had a 7.8 times greater likelihood of a good outcome. Matching patients to their DP is a stronger predictor of outcome than a range of other biopsychosocial factors.KEYWORDS: Centralization, McKenzie Method, Mechanical Low Back Pain, Multivariate Regression Analysis, PrognosisLow back pain (LBP) is extremely common both in the general population and in those seeking healthcare^1–8. Point prevalence estimates for LBP are at least 20% of the general population^2,5,6; yearly prevalence estimates are at least 40%^1–4,8; and lifetime prevalence is around 60%^2,3,6,8. In contrast to earlier claims⁹ of a relatively benign natural history for acute back pain, it is now clear that LBP is commonly both highly recurrent and frequently persistent^10,11. These systematic reviews on the topic noted that after initial improvements, there is little further improvement after 3 months, at which point approximately 50% are still experiencing activity limitation; in addition, 66–75% of patients have at least one recurrence within 12 months^10,11. Not surprisingly, the direct and indirect costs associated with such a common, activity limiting, persistent, and episodic problem are vast in many developed countries^12–14. Treatments seem to have been largely ineffective at altering this “20^th-century medical disaster”¹⁵.Given the now documented high prevalence rate, and the persistent and recurrent nature of LBP, there has been considerable recent interest in determining prognostic factors that might affect the outcome of an episode of LBP. Understanding prognostic factors would help to shape relevant management strategies and assist with early identification of individuals at high risk of developing chronic pain and disability. Ultimately, the goal would be to refine treatment approaches and permit the wiser allocation of scarce health care resources and the prevention of chronic problems¹⁶. Equally, identification of patients likely to have an uncomplicated recovery would help prevent overuse of healthcare resources by those who least need it¹⁶.For these reasons, a substantial volume of literature has been published on prognostic factors for LBP and sciatica. The 2004 European Guidelines for the Management of Acute Nonspecific Low Back Pain in Primary Care cited 74 articles on the topic¹⁷. This systematic review and numerous recent studies share a dominant theme: the prominence of psychosocial variables in the prediction models^18–24. However, the quantity of prognostic variables that have been identified as possible effectors of prognosis form a cumbersome and unrealistic list for clinicians to assess and address (Table ​(Table11).

TABLE 1

Examples of prognostic factors for LBP/sciatica^16–26.

Positional Stretching of the Coracohumeral Ligament on a Patient with Adhesive Capsulitis: A Case Report

Idiopathic frozen shoulder is a common medical diagnosis for patients seeking physical therapy. Radiographic and surgical evidence exists that describes the coracohumeral ligament (CHL) as a major contributor to lack of external rotation in patients diagnosed with frozen shoulder. No stretching techniques targeting the anatomical fiber orientation of the CHL have been reported in the literature. This single-patient case-report describes the use of a positional stretching technique of the CHL on a 51-year-old female diagnosed with phase I frozen shoulder. The patient completed 8 in-office visits and 17 home exercise program sessions of positional CHL stretching combined with a simple volitional rotator cuff exercise program in a 4-week period. The patient''s Disabilities of the Arm Shoulder and hand (DASH) scores improved from 65 to 36 and Shoulder Pain and Disability Index (SPADI) scores improved from 72 to 8 and passive external rotation from 20° to 71°. While a cause-and-effect relationship cannot be inferred from a single case, this report may foster further investigation regarding the role of the CHL in patients with stage-I and stage-II frozen shoulder as well as therapeutic strategies to help reduce loss of mobility and function.KEYWORDS: Coracohumeral Ligament, Frozen Shoulder, Positional StretchingIdiopathic frozen shoulder, commonly known as adhesive capsulitis, is a condition of uncertain etiology characterized by a progressive loss of both active and passive shoulder motion¹. The complete loss of external rotation is the single most important factor in differential diagnosis². Three stages of frozen shoulder have been identified: painful freezing, adhesion, and resolution². Table ​Table11 depicts the clinical presentations of each stage². Cyriax³ described the typical capsular pattern seen in frozen shoulder as external rotation being the most limited. Pain, particularly in the first phase of adhesive capsulitis, often keeps patients from performing activities of daily living⁴.

TABLE 1

The three stages of adhesive capsulitis also known as frozen shoulder

Non-invasive mechanical ventilation in hematology patients: let's agree on several things first

Acute respiratory failure is a dreaded and life-threatening event that represents the main reason for ICU admission. Respiratory events occur in up to 50% of hematology patients, including one-half of those admitted to the ICU. Mortality from acute respiratory failure in hematology patients depends on the patient''s general status, acute respiratory failure etiology, need for mechanical ventilation and associated organ dysfunction. Non-invasive mechanical ventilation is clearly beneficial for chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema. These benefits are based mainly on the avoidance of invasive mechanical ventilation complications. Non-invasive mechanical has also been recommended in hematology patients with acute respiratory failure but its real benefits remain unclear in these settings. There is growing concern about the safety of non-invasive mechanical ventilation to treat hypoxemic acute respiratory failure overall, but also in hematology patients. Prophylactic non-invasive mechanical ventilation in patients with acute respiratory failure but not respiratory distress seems to be effective in hematology patients with a reduced rate of intubation. However, curative non-invasive mechanical ventilation should be restricted to those patients with isolated respiratory failure, with fast improvement of respiratory distress under non-invasive mechanical ventilation, and with rapid switch to intubation to avoid deleterious delays in optimal invasive mechanical ventilation.In a previous issue of Critical Care, Molina and colleagues provide the results of a large multicenter Spanish observational cohort study of hematology patients with acute respiratory failure (ARF) [1]. Their main findings are that non-invasive mechanical ventilation (NIV) failure is an independent risk factor for ICU mortality. Indeed, NIV patients exhibited higher mortality rates compared with patients who were intubated early. Not surprisingly, cardiogenic pulmonary edema was associated with reduced proportion of NIV failure.The observational design does not actually allow any firm conclusion about NIV efficacy in hematology patients. The poorer prognosis associated with NIV failure could simply result from patient selection, clinicians being less keen to intubate patients without lifespan-expanding therapy or those who were older or sickest. Late intubation would thus only be a surrogate marker of poor prognosis. Nevertheless, this study is along the line of other studies in the literature that show early intubation to be associated with lower mortality [2,3]. In hematology patients with hypoxemic ARF, therefore, the questionable benefit from NIV supports the dilemma of intubation timing faced by clinicians managing these patients.ARF occurs in up to 50% of hematology patients and is the leading reason for ICU admission in this population. Despite significant improvement in the last years [4,5], ARF still carries a high mortality rate of 50% overall, with even higher rates in patients needing mechanical ventilation [4,6,7]. The high incidence of cancer together with the use of a highly intensive curative regimen will increase the number of patients at risk of respiratory complications, and physicians will be asked to manage these patients more and more.NIV is now recognized as the first-line therapy for patients with ARF due to chronic obstructive pulmonary disease exacerbation or cardiogenic pulmonary edema [8]. The clear benefit of NIV in these patients relies on the reduced rate of complications from invasive mechanical ventilation. NIV has also been recommended for hypoxemic ARF in immunocompromised patients [9]. In the subgroup of hematology patients, invasive mechanical ventilation has been associated with the worse prognosis of ARF [4,6,7] and NIV may therefore be particularly beneficial to these patients. However, published studies have inconsistently found a benefit from NIV in these patients [1,4,6,10-12].Several factors may explain these discordant results. First, studies did not control the timing of NIV implementation and evaluated together prophylactic NIV (in patients with hypoxemia but no respiratory distress) and curative NIV (in patients with established respiratory distress) [10,13]. Second, the unit where NIV was performed - the hematology ward or the ICU - differed between studies [11,12]. Early ICU admission and the opportunity for tight monitoring probably positively impacted the results, whereas delayed ICU admission for patients treated in the hematology ward may have worsened prognosis with delayed intubation and treatment of associated organ failures [13]. Third, studies included patients with ARF from various etiologies, some of which may better respond to NIV. Finally, studies did not take into account associated organ dysfunctions that may have hampered NIV efficacy.The overall lack of actually proven benefit from NIV in hypoxemic ARF of hematology patients therefore raises safety concerns for its use in patients who may benefit from early intubation and mechanical ventilation [14]. The recent advances in life-sustaining therapies and the better outcome of hematology patients admitted to the ICU in the last years strengthen these concerns [4,5].Taken together, studies evaluating NIV in hematology patients highlight the deleterious effects of NIV failure and late intubation, as does the study by Molina and colleagues [1,10,13]. Improving NIV results in these patients will probably derive from tailor-made management based on the lessons we have learned from these studies (Figure ​(Figure11 and Table ​Table1).1). In our belief, this relies on the three following points: improved patient selection, careful identification of ARF etiology [7], and early assessment of NIV efficacy. Available evidence supports the use of prophylactic NIV performed in the ICU in hematology patients [10]. These benefits may result from improved oxygenation and reduced work of breathing that alleviate respiratory load. Prophylactic NIV may also help to secure diagnostic procedures such as fiberoptic bronchoscopy and bronchoalveolar lavage [15]. In opposition, we believe the reason why NIV may be effective for hypoxemic ARF in hematology patients and not in other settings is highly questionable. We therefore recommend the cautious use of curative NIV only in patients with isolated ARF and with an early assessment of its efficacy. Curative NIV should be discouraged in patients with an associated extra-respiratory organ failure and should be contraindicated in those with two or more extra-respiratory failures.Open in a separate windowFigure 1Propositions for the use of non-invasive mechanical ventilation in hematology patients with acute respiratory failure. ARF, acute respiratory failure; NIV, non-invasive mechanical ventilation; RRT, renal replacement therapy.

Table 1

Situations in which NIV should be encouraged or avoided in hematology patients

Antipneumococcal Activities of a Ketolide (HMR 3647), a Streptogramin (Quinupristin-Dalfopristin), a Macrolide (Erythromycin), and a Lincosamide (Clindamycin)

Four different compounds belonging to the macrolide-lincosamide-streptogramin B (MLS_b) class of antimicrobial agents were tested against 611 Streptococcus pneumoniae strains. The ketolide (HMR 3647, previously RU66647) and the streptogramin (quinupristin-dalfopristin) were both active against pneumococci with high-level MLS_b resistance (clindamycin-resistant strains) as well as those with low-level macrolide resistance (clindamycin-susceptible strains).Macrolide-resistant strains of Streptococcus pneumoniae are increasing in prevalence (1, 2, 4). Consequently, there is a need for alternative agents that might include macrolide-resistant pneumococci in their spectrum of activity. The ketolide HMR 3647 (previously RU66647) is a new addition to the macrolide-lincosamide-streptogramin B (MLS_b) class of antimicrobial agents; it is a ketolide derivative which is a semi-synthetic 14-member-ring macrolide, harboring a 3-keto group instead of an α-l-cladinose on the aglycone A (6). The purpose of this report is to compare the antipneumococcal activities of HMR 3647 and a streptogramin (quinupristin-dalfopristin) to that of erythromycin and clindamycin. Specifically, the data were examined to determine the extent of cross-resistance to the different agents among the pneumococci.Macrolide-resistant strains of S. pneumoniae have been studied by other investigators in recent years (7, 10, 11). Three common phenotypes have been defined according to their resistance or susceptibility to erythromycin and clindamycin (10, 11). Pneumococci may be Ery^s Clin^s, Ery^r Clin^s, or Ery^r Clin^r; Ery^s Clin^r strains have not been reported. Ery^r Clin^s strains tend to be resistant to other 14- and 15-member-ring macrolides but susceptible to clindamycin and streptogramin B. This low-level macrolide resistance has been shown to be associated with an altered macrolide efflux system, which results in cross-resistance to other macrolide and azalide compounds (11) but not to clindamycin or streptogramin B. To date, macrolide-inactivating enzymes have not been described for pneumococci. The Ery^r Clin^r phenotype presents as high-level macrolide resistance that is presumably the result of altered rRNA, which blocks binding of the macrolides to their target site. The altered target sites result in high-level resistance to the macrolides, clindamycin, and streptogramin B (8, 10, 11).We performed in vitro studies with 611 isolates of S. pneumoniae using the broth microdilution procedure recommended by the National Committee for Clinical Laboratory Standards (9). The study drugs were serially diluted in cation-adjusted Mueller-Hinton broth supplemented with 2 to 3% lysed horse blood. The inocula were adjusted to provide ca. 5 × 10⁵ CFU/ml in each well, as confirmed by periodic colony counts performed throughout the study. Microdilution trays were incubated 20 to 24 h at 35°C without added CO₂. HMR 3647 was provided by Roussel Uclaf, Romainville, France, and quinupristin-dalfopristin was obtained from Rhone-Poulenc Rorer, Collegeville, Pa. Erythromycin and clindamycin were obtained from their respective U.S. manufacturers.The 611 isolates of S. pneumoniae were selected from stock cultures that originated from medical centers distributed throughout the continental United States. This included 396 penicillin-susceptible (MIC, ≤0.06 μg/ml), 138 penicillin-intermediate (MIC, 0.12 to 1.0 μg/ml), and 77 penicillin-resistant (MIC, ≥2.0 μg/ml) strains. Most (73%) of the 74 erythromycin-intermediate or -resistant strains were also resistant or intermediate in susceptibility to penicillin (1). Each isolate was categorized as being susceptible (MIC, ≤0.25 μg/ml) or resistant (MIC, ≥1.0 μg/ml) to erythromycin and/or clindamycin. For three strains, the MIC of erythromycin was intermediate (0.5 μg/ml), and those three strains were considered resistant to erythromycin for the purposes of this analysis. There were no clindamycin-intermediate strains. The 611 isolates were divided into three phenotypes: i.e., Ery^s Clin^s, Ery^r Clin^s, and Ery^r Clin^r. Table ​Table11 describes the results of microdilution tests with isolates within each phenotype. Fasola et al. (5) reported a few false-susceptible test results with the National Committee for Clinical Laboratory Standards broth microdilution procedure. Those methodologic concerns were not addressed in this study. Furthermore, the possibility that inducible resistance may be overlooked was not considered since others have found it to be very uncommon among pneumococci (5, 7).

TABLE 1

In vitro activity of a ketolide (HMR 3647) and a streptogramin (quinupristin-dalfopristin) against S. pneumoniae

SIRPα polymorphisms,but not the prion protein,control phagocytosis of apoptotic cells

Prnp^−/− mice lack the prion protein PrP^C and are resistant to prion infections, but variable phenotypes have been reported in Prnp^−/− mice and the physiological function of PrP^C remains poorly understood. Here we examined a cell-autonomous phenotype, inhibition of macrophage phagocytosis of apoptotic cells, previously reported in Prnp^−/− mice. Using formal genetic, genomic, and immunological analyses, we found that the regulation of phagocytosis previously ascribed to PrP^C is instead controlled by a linked locus encoding the signal regulatory protein α (Sirpa). These findings indicate that control of phagocytosis was previously misattributed to the prion protein and illustrate the requirement for stringent approaches to eliminate confounding effects of flanking genes in studies modeling human disease in gene-targeted mice. The plethora of seemingly unrelated functions attributed to PrP^C suggests that additional phenotypes reported in Prnp^−/− mice may actually relate to Sirpa or other genetic confounders.The cellular prion protein PrP^C, encoded by the Prnp gene, is tethered to the membrane of most mammalian cells by a glycosylphosphatidylinositol anchor. Conversion and aggregation of PrP^C into a misfolded conformer (termed PrP^Sc) triggers transmissible spongiform encephalopathies, also termed prion diseases (Aguzzi and Calella, 2009). Disparate functions have been ascribed to PrP^C on the basis of phenotypes described in Prnp^−/− mice (Steele et al., 2007; Linden et al., 2008), yet none of these functions has been clarified mechanistically, and their validity was frequently challenged.All currently available Prnp^−/− lines were generated using embryonic stem (ES) cells derived from the 129 strain of Mus musculus. Typically, chimeric founder mice were crossed with WT (Prnp^wt/wt) mice of the C57BL/6 strain (B6; Sparkes et al., 1986). Consequently, congenic Prnp^wt/wt and Prnp^−/− mice may differ at additional polymorphic loci (Smithies and Maeda, 1995; Gerlai, 1996). We hypothesized that co-segregation of linked genes may have confounded the attribution of functions to PrP^C based on phenotypes observed in Prnp^−/− mice (Collinge et al., 1994; Lledo et al., 1996; Walz et al., 1999; Rangel et al., 2007; Laurén et al., 2009; Calella et al., 2010; Gimbel et al., 2010; Ratté et al., 2011; Striebel et al., 2013).

Table 1.

Prnp KO mouse lines analyzed in this study

Azithromycin Alters Macrophage Phenotype and Pulmonary Compartmentalization during Lung Infection with Pseudomonas

Infection with mucoid strains of Pseudomonas aeruginosa in chronic inflammatory diseases of the airway is difficult to eradicate and can cause excessive inflammation. The roles of alternatively activated and regulatory subsets of macrophages in this pathophysiological process are not well characterized. We previously demonstrated that azithromycin induces an alternatively activated macrophage-like phenotype in vitro. In the present study, we tested whether azithromycin affects the macrophage activation status and migration in the lungs of P. aeruginosa-infected mice. C57BL/6 mice received daily doses of oral azithromycin and were infected intratracheally with a mucoid strain of P. aeruginosa. The properties of macrophage activation, immune cell infiltration, and markers of pulmonary inflammation in the lung interstitial and alveolar compartments were evaluated postinfection. Markers of alternative macrophage activation were induced by azithromycin treatment, including the surface expression of the mannose receptor, the upregulation of arginase 1, and a decrease in the production of proinflammatory cytokines. Additionally, azithromycin increased the number of CD11b⁺ monocytes and CD4⁺ T cells that infiltrated the alveolar compartment. A predominant subset of CD11b⁺ cells was Gr-1 positive (Gr-1⁺), indicative of a subset of cells that has been shown to be immunoregulatory. These differences corresponded to decreases in neutrophil influx into the lung parenchyma and alteration of the characteristics of peribronchiolar inflammation without any change in the clearance of the organism. These results suggest that the immunomodulatory effects of azithromycin are associated with the induction of alternative and regulatory macrophage activation characteristics and alteration of cellular compartmentalization during infection.Chronic inflammation of the airways is observed in asthma, cystic fibrosis (CF), interstitial lung diseases, and chronic obstructive pulmonary disease (COPD). The lungs of patients with pulmonary disorders are often colonized by Pseudomonas aeruginosa, which induces a cycle of inflammation, airway damage, remodeling, and functional decline (3, 34, 49). Pseudomonas subacutely infects the lungs of up to 80 to 90% of patients in the end stages of CF and through periodic exacerbations accelerates the pulmonary disease pathology (16, 34). The repeated activation of immune cells in this setting contributes to progressive lung destruction, increased exacerbations of disease, and increased mortality (28, 33, 44). The continuous influx of neutrophils into the airways is primarily responsible (43), with cytokines and chemokines secreted by both epithelial cells and macrophages driving the response (5, 9).Macrophage activity has been defined along a spectrum of functional activity (18). While the function of classically activated macrophages (CAMs) is well-defined, alternatively activated macrophages (AAMs) also play a distinct role in both host defense and the maintenance of homeostasis within the lung. In response to infection, CAMs phagocytose and kill bacteria, initiate inflammation through cytokine and chemokine release, and are induced to full function in Th1 types of responses by T-cell secretion of gamma interferon (IFN-γ). Conversely, alternative activation occurs through the induction of a distinct set of genes upon the binding of interleukin-4 (IL-4) and/or IL-13, primarily produced by Th2-type CD4⁺ T lymphocytes. These cells express high levels of mannose receptor (MR) and produce a distinct cytokine pattern (29, 37, 47). The main roles of AAMs are to scavenge debris, phagocytose apoptotic cells after inflammatory injury, and orchestrate tissue remodeling and repair through the production of extracellular matrix proteins. The function of AAMs has mainly been evaluated in disease processes that illicit Th2-type immune responses, including asthma and a variety of infectious etiologies (23, 48, 55). These studies demonstrate the ability of AAMs to suppress effector functions of CAMs, which include inducible nitric oxide synthetase (iNOS) upregulation, inflammatory cytokine and chemokine secretion, and the induction of neutrophil infiltration (26, 27, 58, 61). AAMs inhibit CAM-driven inflammatory processes in part through the upregulation of arginase 1, which competes with iNOS for l-arginine, thereby decreasing reactive oxygen species formation and increasing extracellular matrix protein production (36, 38). The properties of classical macrophage activation in response to bacterial infection have been shown to potentially contribute to the pathophysiology of CF, including increased proinflammatory cytokine secretion (6, 7), decreased IL-10 production (52), and altered phagosome acidification (11). Whether the induction of alternative macrophage activation during a Gram-negative bacterial infection could beneficially alter the immune response is the focus of our work. In addition, various groups have identified a third population of macrophages that has a more regulatory phenotype. This subset is anti-inflammatory and is hallmarked by high levels of IL-10 production and high levels of expression of antigen presentation molecules (41, 51). A comparison of these macrophage subsets is given in Table ​Table11.

TABLE 1.

Properties of macrophage activation states^a

Characterization of the 6′-N-Aminoglycoside Acetyltransferase Gene aac(6′)-Iq from the Integron of a Natural Multiresistance Plasmid

The nucleotide sequence of a newly identified amikacin resistance gene, aac(6′)-Iq (551 bp), is reported. It has 68.4 and 94.4% homology with the aac(6′)-Ia gene and the recently described aac(6′)-Ip gene, respectively. Analysis of its flanking sequences indicated that it is in the first cassette of a class I integron and has an attC site (59-base element) 108 bp in length.Resistance to amikacin in Klebsiella pneumoniae is widespread and to date has been found to depend exclusively upon production of enzymes which modify the antibiotic (15). Different genes designated aac(6′)-Ib, aac(6′)-Id, aac(6′)-Il, aac(6′)-Ip, ant(4′)-IIa, and aph(3′)-VIb, encoding the production of enzymes that modify amikacin, have been characterized for this species (6, 16). The aac(6′)-Ib gene, which was the most frequently identified gene in several multicenter studies, is located in integrons (8) or in Tn1331 (2, 18, 19). The other genes are extremely rare (16). All aac(6′)-I genes thus far described for gram-negative bacteria are within cassettes, except for aac(6′)-Ic, which is located in chromosomal DNA (15, 16). Cassettes are mobile elements, each of which usually includes a single structural gene, which covers most of the cassette length, and a recombination site known as a 59-base element or attC site. Despite differences in sequence and length, members of the 59-base-element family are active as sites for site-specific recombination events catalyzed by the integron DNA integrase. When the cassettes are integrated, they become part of the integron and, since they usually do not have their own promoters, are expressed from a common promoter region upstream of the attachment site (5, 7). Integrons are usually located on plasmids or on transposons (pVS1, Tn21, and Tn402, etc.) (1, 10, 14); this location allows the rapid spread of cassettes among a wide variety of bacterial species. In the present communication we describe the aac(6′)-Iq gene cassette of a multiresistant strain, the K. pneumoniae K1 isolate from the Clínica Santa Rosa in Buenos Aires, Argentina. This gene is carried in a 50-kb conjugative plasmid that also codes for resistance to cefotaxime, gentamicin, and sulfonamides.The aminoglycoside resistance profile (16) of K. pneumoniae K1, determined by using aminoglycoside disks from Schering-Plough, Kenilworth, N.J. (16), on Mueller-Hinton agar, suggested the presence of AAC(3)-II and AAC(6′)-I enzymes. By colony hybridization (8) with a labeled oligonucleotide probe (5′-CCT CCG TTA TTG CCT TC), it was shown that the AAC(3)-II activity was due to the aac(3)-IIa (aacC2) gene, which is usually flanked by IS140s and is not part of integrons. By using PCR amplification with primers specific for the integron 5′ conserved sequence (5′-CS) (5′-GGC ATC CAA GCA GCA AG) and 3′ conserved sequence (3′-CS) (5′-AAG CAG ACT TGA CCT GA) (8), we determined that the variable region of the integron was 1,600 bp in length, suggesting the presence of two cassettes. PCR amplification revealed that the ant(3")-Ia (aadA1) gene cassette was the second and last cassette in the integron based on the sizes of the bands obtained: 850 bp with the 5′-CS and ant(3")-Ia (5′-TCG ATG ACG CCA ACT AC) primers and 170 bp with the ant(3")-Ia-3′ (5′-CGC AGA TCA CTT GGA AG) and 3′-CS primers. Its location was confirmed by sequencing the beginning of the gene encoding resistance to both streptomycin and spectinomycin (see below).The PCR amplification product of the 5′-CS2 (5′-GCC TGA CGA TGC GTG GA) and ant(3")-Ia primers (1,150 bp), made by using cloned Pfu polymerase (Stratagene, La Jolla, Calif.) was cloned into the pCR^TM2.1 cloning vector (original TA cloning kit; Invitrogen Corporation, San Diego, Calif.) in the Escherichia coli NM522 host strain (laboratory collection). This plasmid was named pLQ1001. Since the pCR^TM2.1 vector contains a kanamycin resistance gene, the 1,200-bp EcoRI fragment from pLQ1001 was subcloned into the EcoRI site of the ampicillin resistance-carrying plasmid pTZ19 (Pharmacia-LKB Biotechnology, Uppsala, Sweden), resulting in the plasmid pLQ1002. The disk susceptibility testing of E. coli NM522(pLQ1002) produced a typical AAC(6′)-I profile (Table ​(Table1),1), with low-level expression of enzyme activity. All other molecular procedures were carried out by using previously published protocols (13).

TABLE 1

Disk susceptibilities of the host strain E. coli NM522(pTZ19), E. coli NM522(pLQ1002), and the parent K. pneumoniae K1 strain

Influential Variables Associated with Outcomes in Patients with Cervicogenic Headache

Cervicogenic headache (CGH) is a common sequela of upper cervical dysfunction with a significant impact on patients. Diagnosis and treatment have been well validated; however, few studies have described characteristics of patients that are associated with outcomes of physical therapy treatment of this disorder. A retrospective chart review of patient data was performed on a cohort of 44 patients with CGH. Patients had undergone a standardized physical therapy treatment approach that included spinal mobilization/manipulation and therapeutic exercise, and outcomes of treatment were determined by quantification of changes in headache pain intensity, headache frequency, and self-reported function. Multiple regression analysis was utilized to determine the relationship between a variety of patient-specific variables and these outcome measures. Increased patient age, provocation or relief of headache with movement, and being gainfully employed were all patient factors that were found to be significantly (P<0.05) related to improved outcomes.Key Words: Cervicogenic Headache, Physical Therapy, Treatment Characteristics, Manual TherapyAlthough cervicogenic headache (CGH) has been described as a “final common pathway” of cervical spine dysfunction¹, its true prevalence is difficult to determine due to inconsistent use of diagnostic criteria in the literature. Incidence of cervicogenic headache has been reported to range from 0.7% to as high as 13.8% in populations of patients suffering from headache disorders². Others have reported cervicogenic origins of higher values (14% to 18%) in all chronic headaches³.gThe anatomical basis for CGH is the convergence of the afferent input of the upper cervical spine nerve roots (C1-C3) with the afferent tracts of the trigeminal nerve in the trigeminocervical nucleus. This convergence results in cervical spine nociceptive input being expressed in the sensory distribution of the trigeminal nerve, most commonly the ophthalmic branch of the trigeminal nerve, which innervates the forehead, temple, and orbit and has its greatest topographic representation near the dorsal horns of spinal nerves C1-C3^4,5. Therefore, any structure innervated by C1, C2, or C3 spinal nerves can be implicated in the etiology of CGH. This includes the atlanto-occipital, median atlanto-axial, lateral atlanto-axial, and C2-3 zygapophyseal joints as well as the C2-3 intervertebral disc, suboccipital, upper posterior cervical, and upper paravertebral musculature, the trapezius and sternocleidomastoid muscles, upper cervical spinal dura mater, and the vertebral arteries^4–6. Because of the ability of afferent nerves to travel up to three segments cephalically or caudally in the cervical spinal cord, bony and soft tissue structures of the middle and lower cervical spine cannot be excluded from contributing to CGH^4,5.The diagnosis of CGH has been a source of contention in the literature ever since the inception of the term by Sjaastad et al in 19837-9. Currently, two major sets of diagnostic criteria exist for CGH (Table ​(Table1).1). The International Headache Society (IHS) accepted the diagnosis of CGH in 1988 as a type of secondary headache and, at that time, included criteria for its diagnosis in the International Classification of Headache Disorders, which was most recently updated in 2004¹⁰. However, the criteria established in 1990 by Sjaastad and the Cervicogenic Headache International Study Group (CHISG) and revised in 1998¹ are the most utilized clinically. The exception of the clinical utility of Sjaastad''s criteria is Point II, which stipulates the use of a nerve block to diagnose CGH in scientific works. The use of a nerve block may be impractical for daily clinical practice, despite being the only means by which a structure in the cervical spine can truly be isolated as the pain generator^5,11,12. Furthermore, although Point III of Sjaastad''s criteria specifies unilaterality of symptoms, the presence of bilateral symptoms or “unilaterality on two sides” has been documented^1,13. Differential diagnosis includes hemicrania continua, occipital neuralgia, migraine, and tension-type headache, with the differentiation of CGH from migraine and tension-type headache being the most challenging due to the overlap of many symptoms among these three disorders^2,14.

TABLE 1

Diagnostic criteria for cervicogenic headache

The dysfunctional host response to influenza A H7N9: a potential treatment option?

The newly emerging human pathogen influenza A H7N9 represents a potentially major threat to human health. The virus was first shown to be pathogenic in humans in 2013, and outbreaks continue to occur in China to the present time. The current incident mortality rate is disturbingly high despite the frequent use of antiviral therapy and intensive care management. If the virus gains the capacity for efficient person-to-person transmission, a global influenza pandemic could ensue with devastating consequences. In the absence of an effective vaccine, targeted regulation of the host immune response by immune modulators might be considered. Readily available, approved drugs with immune-modulating activities might prove to be a treatment option in combination with existing antiviral agents and supportive care.In this issue of Critical Care Wu and colleagues provide a tantalizing glimpse into the immune dysfunction and possible immunopathogenesis of infection due to the novel H7N9 avian strain of influenza A virus [1]. Human cases of H7N9 influenza have thus far occurred only in China and surrounding regions [2-4], but there is disturbing evidence that this virus could easily evolve and create a pandemic of immense proportions. The observed case fatality rate in H7N9 influenza is much higher (about 25%) than that seen in patients infected with pandemic H1N1 virus in 2009 [5,6]. The H7N9 virus is derived from an avian influenza A virus that has crossed species barriers to infect humans, primarily those who have had exposure to live poultry markets. The virus spreads by respiratory aerosols, and limited human-to-human transmission probably occurs, although there is no evidence of continued spread thus far [2,3]. The virus causes essentially asymptomatic infection in chickens, but when transmitted to humans it leads to a highly symptomatic and potentially lethal illness. Severe H7N9 illness affects predominantly older patients (mean age ≥60 years), unlike pandemic H1N1 or avian influenza A H5H1 virus infections that affect younger individuals [1].Wu and colleagues studied 27 H7N9 patients who were hospitalized at one center in Zhejiang Province in China and compared their immune responses with 30 healthy controls. All of the patients were severely ill (mean Acute Physiology and Chronic Health Evaluation II score 22) and all were treated with oseltamivir. Diffuse lymphopenia was seen in two-thirds of patients. More than 70% of patients developed acute respiratory distress syndrome and almost 50% acquired secondary bacterial pneumonia.On the day of admission, the investigators performed multiplex cytokine analyses and flow cytometry to survey circulating peripheral blood mononuclear cells for activation or markers of T-cell anergy or exhaustion. Compared with healthy controls, cytokine analyses revealed elevated IL-6, IL-8 and IL-10 levels, but no increase in tumor necrosis factor, gamma-interferon or other proinflammatory cytokines. Flow cytometry showed increases in CD38, a marker of T-cell activation, and T-cell immunoglobulin and mucin protein-3 (TIM3), a surface marker for T-cell anergy/exhaustion. Conversely, human leukocyte antigen DR expression and TIM3-expressing monocytes were significantly lower. TIM3 is a well-characterized indicator of T-cell exhaustion in the mice, but this may not be true in humans [7]. Regrettably, the investigators did not measure programmed cell death-1 on T cells, which is a reliable marker of lymphocyte exhaustion in both mice and humans [1]. They were also unable to perform serial determinations of inflammatory markers to document the course of immune dysfunction over time.The clinical and immunologic findings in H7N9 influenza differ substantially from those seen in younger patients infected by the pandemic H1N1 influenza virus or the more pathogenic avian influenza A H5N1 viruses [1]. H5N1 patients often have significant elevations of tumor necrosis factor and gamma-interferon, neither of which was seen with H7N9 influenza. Instead, a mixed pattern of proinflammatory (IL-6 and IL-8) and anti-inflammatory (IL-10) cytokines was observed, along with simultaneous expressions of T-cell activation (CD38) and de-activation (TIM3). These differences might reflect the unique virulence properties of the H7N9 virus or differences in the host response of older H7N9 patients.A major question is whether patients with severe H7N9 influenza could benefit from immune modulator therapy in addition to antiviral agents and supportive care [8,9]. Many fundamental questions need to be answered. It is unclear whether the immune profile described by Wu and colleagues is a manifestation of the host response to the virus or whether immune dysregulation is actually contributing to the pathogenesis of the disease. Could the immune response be specifically targeted to aid patient recovery? Optimal treatment may not simply be a question of giving proinflammatory or anti-inflammatory agents. It may depend upon patient age, the specific virus, the presence of co-morbid illness, the extent of disease and the timing of the intervention [10-12].Several commonly prescribed therapeutic agents that have immunomodulatory effects have been shown to be effective in treating influenza in experimental settings and in observational studies of patients with pneumonia and influenza (and even one randomized controlled trial in sepsis; Table 9,13]. Statins are the agents best studied, but several other drug classes might also have clinical utility [13,14]. Many of these drugs are produced as inexpensive generics and are widely distributed in low-income and middle-income countries [9,13].

Table 1

Low-cost, readily available drugs with immunomodulatory activities that could benefit patients with severe influenza

Moving beyond the 'pancreatic rest' in severe and critical acute pancreatitis

Nasojejunal tube feeding is considered the current standard of care in patients with severe and critical acute pancreatitis. However, it is not known whether enteral nutrition is best delivered into the jejunum. This Commentary discusses recent clinical studies that have shown that tube feeding into the stomach is safe and well tolerated in the vast majority of patients with acute pancreatitis, thus overthrowing the notion of putting the pancreas at rest. Development of a new conceptual framework is warranted to further advance nutritional management of patients with acute pancreatitis.Enteral nutrition is a rapidly evolving frontier in the management of acute pancreatitis (AP). In the previous issue of Critical Care, Chang and colleagues investigate whether nasojejunal tube feeding confers any tangible benefit compared with nasogastric tube feeding in patients with AP [1]. It has been 5 years since publication of the previous systematic review on the topic [2] and it is timely to review the progress. Further, the recent international multidisciplinary classification of AP has redefined the ''severe'' category of severity and introduced the new ''critical'' category of severity (Table ​(Table1),1), thus putting a high emphasis on the need to optimise management of these most challenging patients [3-6].

Table 1

Definitions of the four severity categories according to the 2012 international multidisciplinary classification of acute pancreatitis [4]

Synergism between Poly-(1-6)-β-d-Glucopyranosyl-(1-3)-βd-Glucopyranose Glucan and Cefazolin in Prophylaxis of Staphylococcal Wound Infection in a Guinea Pig Model

To determine whether the infection-preventing capability of the neutrophil-activating agent poly-(1-6)-β-d-glucopyranosyl-(1-3)-β-d-glucopyranose glucan (PGG-glucan) can be enhanced with antibiotic prophylaxis, we administered PGG-glucan and cefazolin, alone and in combination, to guinea pigs inoculated with isolates of staphylococci. Guinea pigs receiving both PGG-glucan and cefazolin had 50% infective doses that were 8- to 20-fold higher than those obtained with cefazolin alone and 100- to 200-fold higher than those obtained with PGG-glucan alone. PGG-glucan and cefazolin are synergistic in their ability to prevent staphylococcal wound infection.Antibiotics have proven to be dramatically effective in preventing and treating bacterial infections. Nevertheless, these agents only provide support for the essential immunological functions of phagocytosis and intracellular killing. The enhancements provided by combining phagocyte-stimulating agents with antibiotics have only recently been explored (12, 18, 19). PGG-glucan (poly-[1-6]-β-d-glucopyranosyl-[1-3]-β-d-glucopyranose glucan) (Betafectin; Alpha-Beta Technology, Inc., Worcester, Mass.) is a complex carbohydrate derived from Saccharomyces cerevisiae (6). PGG-glucan primes neutrophils to exhibit greater phagocytosis and a stronger oxidative burst in response to subsequent stimulation (2, 17). While this agent has no innate antibacterial activities, it has been demonstrated to have both prophylactic and therapeutic activity in in vivo models (3, 11, 14, 17), presumably through its stimulation of polymorphonuclear activity. The present study was designed to evaluate whether the prophylactic properties of PGG-glucan could be enhanced with antibiotic prophylaxis in a guinea pig model of staphylococcal wound infection.Staphylococcus aureus 3094, S. aureus 5030, and Staphylococcus epidermidis 9021 were recovered from wound infections complicating cardiac surgery. Previous in vitro studies have found the MICs of methicillin for S. aureus 3094 and 5030 and S. epidermidis 9021 to be 4, 32, and 16 μg/ml, respectively (11). None of these isolates are inhibited in vitro by PGG-glucan at concentrations as high as 500 μg/ml (11).Details of the low-inoculum guinea pig model and the methods of administering PGG-glucan (Betafectin) (Alpha-Beta Technology, Inc.) and cefazolin (Eli Lilly & Company, Indianapolis, Ind.) in this model have been described previously (7–11). All in vivo experiments were approved by the institutional committee for animal care at the Nashville Veterans Affairs Medical Center. Five days prior to inoculation, after surgical and anesthetic preparation, the internal jugular veins of albino Hartley guinea pigs, 500 ± 50 g, of either sex (Kingstar, Kingston, N.H.) were cannulated with saline-filled polyethylene catheters (PE-50; Becton Dickinson and Company, Sparks, Md.). The distal end of the jugular cannula was tunneled through the subcutaneous tissue to exit the skin of the dorsal neck and clamped. After placement of the catheter, each guinea pig was housed separately.On the day of in vivo experimentation, bacteria and sterile dextran microbeads (Cytodex; Sigma Chemical Co., St. Louis, Mo.) were mixed to prepare a range of inocula that produced abscesses from 0 to 100% at the time. When the guinea pigs were prepared for inoculation, the dorsal hair was removed and a grid designating 12 sites was drawn. The experimental design required that on the day of bacterium-microbead inoculation (experimental day 0), prepared guinea pigs first received either PGG-glucan (Betafectin lot no. 2610054), 1 mg/kg of body weight, or placebo intravenously over 2 min, followed by cefazolin, 100 mg/kg, or placebo given subcutaneously. Previous investigations have demonstrated that this dose of cefazolin produced levels in serum comparable to those achieved with a 1-g parenteral dose administered in the clinical setting (7). Immediately thereafter, the potential space between the fascia surrounding skin-related muscle groups and truncal muscle groups underlying each site was inoculated with 0.2 ml of one of the bacterium-microbead suspensions. After inoculation the guinea pigs were returned to their cages. Based on our previous report that PGG-glucan administered 1 day postinoculation is effective in preventing infection (11) and subsequent work showing an enhancement of in vivo prophylaxis related to additional postinoculation administration of PGG-glucan (data not shown), PGG-glucan was administered again at the same dose on postinoculation days 1, 2, and 3.On day 6 following inoculation of the bacterium-microbead suspensions, the guinea pigs were sacrificed and the lesions were harvested by a sterile technique and cultured as previously described (7). Bacterial growth in samples from each site was recorded. Binary logistic regression was used to calculate inoculum-response (dose-response) curves for each staphylococcal isolate-and-prophylactic regimen combination and statistical differences by using JMP, version 3.1.6. (SAS Institute, Cary, N.C.) (13). The mean infective dose (ID₅₀) was determined as exp(−intercept/slope of log back count). A total of 1,081 lesions among 101 animals, divided almost evenly among the 12 staphylococcal isolate-prophylactic regimen combinations, provided the data for analysis.The in vivo prophylaxis studies revealed a significant association between inoculum size and subsequent infection rate after prophylaxis with placebo, PGG-glucan, cefazolin, and PGG-glucan–cefazolin for all three isolates (P < 0.01) (Fig. ​(Fig.1).1). For a given isolate the number of bacteria required to cause infection differed significantly among the four prophylactic regimens (P < 0.0001). An ID₅₀ for each strain-prophylactic regimen combination was calculated from the logistic regression curves (Table ​(Table1).1). For the three strains, the ID₅₀ was approximately a log higher for PGG-glucan than for placebo, for cefazolin than for PGG-glucan, and for PGG-glucan–cefazolin than for cefazolin. These findings were particularly impressive as all three organisms exhibit borderline or full resistance to methicillin. Importantly, the combination of cefazolin and PGG-glucan yielded an ID₅₀ which far exceeded the ID₅₀ of either agent used alone against the respective strains. Although standardized definitions of antibacterial synergy have yet to be fully established for in vivo studies (16), we believe that the highly significant improvements in efficacy of the PGG-glucan–cefazolin combinations, as demonstrated by the logistic regression analysis as well as by the higher-than-additive MIC results, reflect clear synergy against all three bacterial isolates used in this model (4). Open in a separate windowFIG. 1Semilog graph of infection rate versus inoculum size (in CFU) for animals inoculated with strains 3094 (A), 5030 (B), and 9021 (C). The curves are idealized constructs derived from the logistic model. The ID₅₀s were determined from the regression equation and correspond to the points at which each curve intersects a horizontal line extending from the 50% infection mark on the y axis. The ID₅₀s are reported in Table ​Table11.

TABLE 1

ID₅₀s for staphylococcal strains in guinea pigs receiving different prophylactic regimens

Inclusion of Mechanical Diagnosis and Therapy (MDT) in the Management of Cervical Radiculopathy: A Case Report

Various interventions are used by physical therapists to treat neck conditions. Treatments may include exercises based on a direction of preference, cervical spine stabilization, neuromobilization, or traction. The purpose of this case study was to describe the use of mechanical diagnosis and therapy (MDT) in the management of a patient diagnosed with cervical radiculopathy. The case study involved a 39-year-old male (subject), classified with cervical derangement, hypermobility, and adverse neural tension. The subject''s intervention included MDT, deep neck flexor muscle strengthening, and neuromobilization. This subject''s scores on the Neck Disability Index, Numerical Pain Rating Scale (NPRS), and range of motion were assessed at initial examination, discharge, and 3-month follow-up. The subject improved on all outcome measures and was discharged after four visits with a NPRS of 0/10. Percent improvement per visit was 17.5%. This case describes a positive outcome for a patient diagnosed with cervical radiculopathy in which MDT, deep neck flexor strengthening, and neuromobilization were used as an alternative to cervical traction.Key Words: Cervical Spine Stabilization, Direction of Preference, Exercise, TractionNeck or cervical pain has a prevalence of 67% among young adults and comprises approximately 1% of costs of total health care expenditures¹. Of the total patients seen in outpatient physical therapy, 25% are referred for treatment for cervical pain². In terms of mechanism of injury, motor vehicle accidents often result in a chronic cervical dysfunction known as whiplash associated disorder³.Physical therapists may recommend patient-specific treatments for cervical spine pain, or may use a more generalized protocol for management. Treatments may include physical agents, isometric exercises, stretching, and traction⁴. A derangement of the intervertebral disc may lead to a cervical radiculopathy, a condition that can negatively affect mental and physical function⁵.Although the anatomical source of cervical spine pain can be difficult to determine, classification of the condition may give direction to intervention. An approach based on responses to repeated end range movements to determine a direction of preference is mechanical diagnosis and therapy (MDT). MDT was previously referred to as the McKenzie approach, which was developed by Robin McKenzie, and involves classifying the patient''s condition into postural, dysfunction, or derangement categories based on the patient''s responses to repeated end range movements^6,7. The derangement classification is characterized by the determination that certain repeated movements cause symptoms to become magnified, centralized, reduced, or abolished (Table ​(Table1).1). Those movements that produce or intensify the pain are avoided until the derangement has stabilized. The treatment for the derangement classification involves postural correction and the performance of those repeated movements that improve symptoms. The direction of movement and exercises that produce a favorable response are referred to as the patient''s direction of preference⁸. A treatment protocol for cervical derangement based on determining a direction of preference has been shown to positively effect the impairments associated with this condition in six weeks⁹. The operational definition of direction of preference used in this study is an immediate, lasting improvement in pain from performing either repeated flexion, extension, or sideglide/rotation tests⁸.

TABLE 1

Mechanical Diagnosis and Therapy (MDT) Classifcation Model.^6,7