Spousal concordance for substance use and anxiety disorders

Assortative mating -- the tendency for mate selection to occur on the basis of similar traits -- plays an essential role in understanding the genetic contribution to psychiatric illness. It also carries significant impact on clinical prognosis and is an important mechanism explaining spousal concordance. This study uses a family study design ascertaining 225 probands with substance abuse/dependence, anxiety disorders, and controls to address: (1) Is there spousal concordance or cross-concordance for substance use and/or anxiety disorders? (2) Is the spousal concordance or cross-concordance associated with worse clinical outcomes? (3) What is the mechanism of the concordance or cross-concordance? Results show a high magnitude of spousal concordance for substance use disorders with a third of the substance probands' spouses also substance dependent. In contrast, there was no spousal concordance for anxiety disorders. Couples were also concordant for having "no disorders." Both substance use and anxiety disorder concordance were associated with poorer global functioning and persistent illness. Assortative mating is a likely mechanism for spousal concordance given the elevated rate of substance use disorders among the relatives of spouses' of substance probands. Implications for family/genetic studies and the transmission of substance use disorders and "no disorders" include: (1) at the individual level, spousal concordance influences probands' course of illness, couples' marital functioning, and offspring's genetic and environmental context; and (2) at the population level, it shifts the general distribution of substance use disorders and "no disorders" by reducing the "average" couple concordance and increasing the number concordant and discordant couples at extremes of the distribution.     

Loss of A5 noradrenergic neurons in multiple system atrophy

The A5 noradrenergic group of the pons projects on the medulla and spinal cord and contributes to control of sympathetic activity and respiration. Because these functions are affected in multiple system atrophy (MSA), we sought to determine whether there was involvement of A5 neurons in this disorder. We counted tyrosine-hydroxylase (TH) immunoreactive neurons in the A5 area and locus ceruleus in the pons obtained from six patients with clinical and neuropathological diagnoses of MSA and six age-matched controls using stereological methods. There was a severe loss of A5 neurons in MSA (total cell number 3,215 +/- 258 in controls and 321 +/- 62 in MSA, P < 0.001). The severity of cell loss was comparable to that of locus ceruleus neurons in these cases. Our results indicate that A5 neurons are severely affected in MSA and this may contribute to some of the manifestations of this synucleinopathy.     

Lymph Node Status Influences Follow-Up Thyroglobulin Levels in Papillary Thyroid Cancer

Background  Elevated thyroglobulin (Tg) levels post surgery are associated with disease recurrence in papillary thyroid carcinoma (PTC). The aim of this study is to determine which clinicopathological factors influence Tg elevation following surgery and radio-iodine ablation (RAI) for PTC. Methods  A retrospective study of consecutive patients undergoing total thyroidectomy and RAI for PTC was carried out. Prophylactic central neck dissection (CND) was performed if the diagnosis of PTC was made preoperatively. Lateral neck dissection (LND) was guided by ultrasound findings. RAI was administered 6 weeks postoperatively. Stimulated Tg levels were measured at 12 months. Results  One hundred patients with PTC were studied. Forty patients had routine CND. The median tumour size was 15 mm. Median stimulated Tg level at 12 months was 0.3 μg/L. On multivariate analysis the number of metastatic lymph nodes removed had a significant positive association with serum Tg levels (P = 0.003). The total number of lymph nodes resected had a significant inverse relationship with serum Tg levels (P = 0.04). Tumour size, multifocality, vascular and capsular invasion did not appear to have significant correlation with Tg levels. Conclusion  Lymph node metastases are associated with increased postablative Tg levels in PTC. More complete lymphadenectomy is associated with lowering of Tg levels.     

Diagnosis and treatment of low back pain: a joint clinical practice guideline from the American College of Physicians and the American Pain Society

RECOMMENDATION 1: Clinicians should conduct a focused history and physical examination to help place patients with low back pain into 1 of 3 broad categories: nonspecific low back pain, back pain potentially associated with radiculopathy or spinal stenosis, or back pain potentially associated with another specific spinal cause. The history should include assessment of psychosocial risk factors, which predict risk for chronic disabling back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 2: Clinicians should not routinely obtain imaging or other diagnostic tests in patients with nonspecific low back pain (strong recommendation, moderate-quality evidence). RECOMMENDATION 3: Clinicians should perform diagnostic imaging and testing for patients with low back pain when severe or progressive neurologic deficits are present or when serious underlying conditions are suspected on the basis of history and physical examination (strong recommendation, moderate-quality evidence). RECOMMENDATION 4: Clinicians should evaluate patients with persistent low back pain and signs or symptoms of radiculopathy or spinal stenosis with magnetic resonance imaging (preferred) or computed tomography only if they are potential candidates for surgery or epidural steroid injection (for suspected radiculopathy) (strong recommendation, moderate-quality evidence). RECOMMENDATION 5: Clinicians should provide patients with evidence-based information on low back pain with regard to their expected course, advise patients to remain active, and provide information about effective self-care options (strong recommendation, moderate-quality evidence). RECOMMENDATION 6: For patients with low back pain, clinicians should consider the use of medications with proven benefits in conjunction with back care information and self-care. Clinicians should assess severity of baseline pain and functional deficits, potential benefits, risks, and relative lack of long-term efficacy and safety data before initiating therapy (strong recommendation, moderate-quality evidence). For most patients, first-line medication options are acetaminophen or nonsteroidal anti-inflammatory drugs. RECOMMENDATION 7: For patients who do not improve with self-care options, clinicians should consider the addition of nonpharmacologic therapy with proven benefits-for acute low back pain, spinal manipulation; for chronic or subacute low back pain, intensive interdisciplinary rehabilitation, exercise therapy, acupuncture, massage therapy, spinal manipulation, yoga, cognitive-behavioral therapy, or progressive relaxation (weak recommendation, moderate-quality evidence).     

Angiotensin II directly triggers endothelial exocytosis via protein kinase C-dependent protein kinase D2 activation

Angiotensin II (AII) has been reported to induce leukocyte adhesion to endothelium through up-regulation of P-selectin surface expression. However, the underlying molecular and cellular mechanisms remain unknown. P-selectin is stored in Weibel-Palade bodies (WPBs), large secretory granules, in endothelial cells. In this study, we examined the role of protein kinase D (PKD), a newly identified regulator of protein transport, in AII-induced WPB exocytosis and the resultant P-selectin surface expression. We demonstrated that PKD2 was rapidly activated by AII in endothelial cells through phosphorylation of the activation loop at Ser744/748. AII-induced PKD2 activation correlated with increased P-selectin surface expression. Furthermore, AII-regulated PKD2 activation is protein kinase C (PKC) alpha-dependent. Importantly, knock-down of either PKD2 or PKCalpha expression inhibited AII-mediated P-selectin surface expression and monocyte adhesion. Our findings provide the first evidence that stimulation of P-selectin surface expression via PKCalpha-dependent PKD2 activation could be an important mechanism in the early onset of AII-initiated endothelial adhesiveness.     

Folate-targeted dinitrophenyl hapten immunotherapy: effect of linker chemistry on antitumor activity and allergic potential

Targeting of malignancies with folate-linked therapeutics has proven to be a promising endeavor due to the preferential expression of folate receptors (FR) on human tumors. We have shown that folic acid (pteroyl-glutamate) can be used to deliver an antigenic hapten, fluorescein, to the surface of tumor cells to promote their opsonization within a fluorescein-immunized host. Here, we investigate structure-activity relationships among members of another class of folate-hapten conjugates ( EC57, EC63, EC0293, and EC0294), namely, those containing the dinitrophenyl (DNP) group as the antigenic hapten. We report that despite exhibiting similar affinities for the FR, the antitumor activity and allergic potential of these DNP conjugates varied depending on their linker chemistries and abilities to bind anti-DNP IgG/IgE antibodies. Unlike EC57 and EC63, both EC0293 and EC0294 (i) share the identical DNP bridging chemistry to that found in keyhole limpet hemocyanin (KLH)-DNP (i.e., the immunogen), (ii) efficiently recognize DNP-specific IgG, and (iii) mediate more pronounced antitumor responses. However, EC0293 and EC0294 were also found to recognize DNP-specific IgE, and they displayed a greater risk of allergy when evaluated in a passive cutaneous anaphylaxis assay. Nonetheless, upon co-stimulation with the appropriate cytokines (IL-2/IFN-alpha), the folate-targeted "haptenization" process allowed for tumor rejection and protective antitumor immunity without causing any visible allergy in immunized mice. Our data further support the concept that folate-hapten-targeted immunotherapy may offer an effective therapeutic option for treatment of FR-positive cancers, but such treatment should proceed with caution given the risk of a potential allergic reaction.     

Respiratory Infection in Institutions during Early Stages of Pandemic (H1N1) 2009, Canada

Outbreaks of respiratory infection in institutions in Ontario, Canada were studied from April 20 to June 12, 2009, during the early stages of the emergence of influenza A pandemic (H1N1) 2009. Despite widespread presence of influenza in the general population, only 2 of 83 outbreaks evaluated by molecular methods were associated with pandemic (H1N1) 2009.     

Aligned and random nanofibrous substrate for the in vitro culture of Schwann cells for neural tissue engineering

The current challenge in peripheral nerve tissue engineering is to produce an implantable scaffold capable of bridging long nerve gaps that will produce results similar to autograft without requiring the harvest of autologous donor tissue. Aligned and random polycaprolactone/gelatin (PCL/gelatin) nanofibrous scaffolds were fabricated for the in vitro culture of Schwann cells that assist in directing the growth of regenerating axons in nerve tissue engineering. The average fiber diameter attained by electrospinning of polymer blend (PCL/gelatin) ranged from 232 ± 194 to 160 ± 86 nm with high porosity (90%). Blending PCL with gelatin resulted in increased hydrophilicity of nanofibrous scaffolds and yielded better mechanical properties, approaching those of PCL nanofibers. The biocompatibility of fabricated nanofibers was assessed for culturing and proliferation of Schwann cells by MTS assay. The results of the MTS assay and scanning electron microscopy confirmed that aligned and random PCL/gelatin nanofibrous scaffolds are suitable substrates for Schwann cell growth as compared to PCL nanofibrous scaffolds for neural tissue engineering.