Contractile dysfunction in hypertrophied hearts with deficient insulin receptor signaling: possible role of reduced capillary density

Diabetics have worse outcomes than nondiabetics after a variety of cardiac insults. We tested the hypothesis that impaired insulin receptor signaling in myocytes worsens cardiac remodeling and function following injury, even in the absence of hyperglycemia. Mice with cardiomyocyte-restricted knock out of the insulin receptor (CIRKO) and wild type (WT) mice were treated with isoproterenol (ISO) for 2 or 5 days. Heart rates and cardiac mass increased comparably following ISO in WT and CIRKO mice. After 5 days, WT hearts were hyperdynamic by echocardiographic and left ventricular pressure measurements. However, CIRKO hearts had a blunted increase in contractility and relaxation following ISO. Interestingly, single myocytes isolated from both CIRKO ISO and WT ISO hearts had increased cellular shortening with prolonged time to peak shortening vs. respective shams. Thus, loss of myocytes or extramyocyte factors, rather than intrinsic dysfunction of surviving myocytes, caused the blunted inotropic response in ISO treated CIRKO hearts. Indeed, CIRKO ISO mice had increased troponin release after 2 days and greater interstitial and sub-endocardial fibrosis at 5 days than did ISO WT. Apoptosis assessed by TUNEL and caspase staining was increased in CIRKO ISO compared to WT ISO hearts; however, very few of the apoptotic nuclei were clearly in cardiac myocytes. After 5 days of ISO treatment, VEGF expression was increased in WT but not in CIRKO hearts. In keeping with this finding, capillary density was reduced in CIRKO ISO relative to WT ISO. Basal expression of hypoxia-inducible factor-1alpha was lower in CIRKO vs. WT hearts and may explain the blunted VEGF response. Thus, absence of insulin receptor signaling in the cardiac myocyte worsens catecholamine-mediated myocardial injury, at least in part, via mechanisms that tend to impair myocardial blood flow and increase ischemic injury.     

A Short Review of the Treatment of Headaches Using Osteopathic Manipulative Treatment

Purpose of Review

This review highlights the importance of osteopathic manipulative treatment (OMT) in headache sufferers. OMT is a viable option for patients who either do not wish to use pharmaceuticals or who have contraindications to pharmaceuticals. Patients with headaches that are refractory to other treatment options may also be candidates for OMT. Multiple headache etiologies are amenable to this non-invasive treatment option and they will be reviewed here. Although there are advantages to using this treatment method, there are also shortcomings in the literature, which will be discussed.

Recent Findings

Roughly 45 million Americans suffer from headaches every year. Many headache sufferers are unable to find relief through conventional treatment options. OMT is a useful non-invasive treatment option with little to no side effects. There are multiple headache types. Migraine, tension-type headache, combat-related events, post-traumatic headache, sinusitis, tooth extraction, concussions, and others have all shown benefit from OMT.

Summary

OMT is a non-invasive treatment option for individuals suffering from various types of headaches. This treatment option is tailored to the individual needs of the patient and is delivered by licensed and experienced osteopathic physicians. This review of literature also highlights where there is need for further research in the field.

     

Beryllium presentation to CD4+ T cells underlies disease-susceptibility HLA-DP alleles in chronic beryllium disease

Chronic beryllium disease results from beryllium exposure in the workplace and is characterized by CD4(+) T cell-mediated inflammation in the lung. Susceptibility to this disease is associated with particular HLA-DP alleles. We isolated beryllium-specific T cell lines from the lungs of affected patients. These CD4(+) T cell lines specifically responded to beryllium in culture in the presence of antigen-presenting cells that expressed class II MHC molecules HLA-DR, -DQ, and -DP. The response to beryllium was nearly completely and selectively blocked by mAb to HLA-DP. Additional studies showed that only certain HLA-DP alleles allowed presentation of beryllium. Overall, the DP alleles that presented beryllium to disease-specific T cell lines match those implicated in disease susceptibility, providing a mechanism for this association. Based on amino acid residues shared by these restricting and susceptibility DP alleles, our results provide insight into the residues of the DP beta-chain required for beryllium presentation.     

Patient-specific transfusion-related acute lung injury

Transfusion-related acute lung injury (TRALI) is one of the leading causes of transfusion-associated mortality. The inadvertent transfusion of neutrophil antibodies can cause pulmonary transfusion reactions and TRALI. However, not all patients transfused with neutrophil antibodies experience transfusion reactions. A 22-year-old man with severe aplastic anaemia (SAA) experienced TRALI after a platelet transfusion. The donor was found to be alloimmunized to human neutrophil antigen (HNA)-3a, an antigen expressed by neutrophils from approximately 90% of Caucasians. Eleven other platelet components from this donor were transfused prior to this event and two caused reactions: one chills and one TRALI. Both episodes of TRALI occurred in the same male patient with SAA. The fact that one patient experienced TRALI following both exposures to anti-HNA-3a from the same donor whereas nine other recipients did not adds evidence to the observation that patient factors make a significant contribution to neutrophil antibody-mediated transfusion reactions.     

Microalbuminuria as a screening tool in cystic fibrosis-related diabetes

The improving longevity of cystic fibrosis (CF) subjects has resulted in an increased prevalence and duration of cystic fibrosis-related diabetes (CFRD). Microvascular complications were reported in CFRD. Microalbuminuria is well-established as a sensitive indicator of progression to diabetic nephropathy in non-CF diabetes, but confounding factors may make it less sensitive for CF subjects. We performed a cross-sectional study to look for the presence of microalbuminuria in samples from 40 CF subjects (34 without diabetes; CFND) attending the Exeter CF Clinic, compared with 43 nondiabetic, non-CF controls. The albumin-creatinine ratio (ACR) was raised in CF subjects both with (P < 0.001) and without (P < 0.0001) diabetes compared to controls. This reflected an increase in urinary albumin and a reduction in urinary creatinine in CF subjects. In single samples, microalbuminuria was present in 66.7%, 32.4%, and 15.4% of subjects in CFRD, CFND, and control groups. Repeat samples showed that 12% of CFND subjects and 17% of CFRD subjects met the criteria for a diagnosis of persistent microalbuminuria. In conclusion, CF subjects, even when not diabetic, have increased urinary albumin excretion due to chronic infection, and reduced urinary creatinine excretion due to low muscle mass. This results in subjects, who are not developing diabetic nephropathy, meeting the conventional criteria for microalbuminuria. We feel that further studies are required to clarify whether this measure is a useful tool to predict progression to diabetic nephropathy in subjects with CFRD.     

Regulation of insulin and glucagon secretion from a human islet cell adenoma.

The regulation of insulin biosynthesis, and insulin and glucagon secretion have been investigated in a human islet cell adenoma, by incubation of tumour fragments. Both biosynthesis and secretion of insulin were strongly stimulated by incubation of islet tumour cells in the presence of increasing glucose concentrations in the range 2-8 mmol/1. However, 20 mM-glucose or 20 mM-glucose plus isobutyl methylxanthine (IBMX), both of which provide potent secretagogues for normal B cells, failed to stimulate proinsulin biosynthesis and secretion from the tumour cells. Overall rates of secretion, expressed as a proportion of total insulin content, were up to 20-fold higher than those expected for normal pancreatic tissue. Glucagon secretion from the tumour was stimulated by low glucose concentrations; normal A cells also respond in this way under these conditions. However, no stimulation of glucagon secretion occurred in the presence of IBMX. There was therefore a major alteration in the regulation both of insulin and glucagon secretion, in that release of neither hormone was stimulated by cyclic AMP. Ultrastructural examination showed the tumour to be rather heterogeneous. A and B cells with normal storage granule content and structure were seen, as well as a rather larger number of B cells containing some granules of atypical appearance. The insulin content of the tumour (13 i.u./g wet wt) was consistent with 6-8% of the tumour cells being B cells.     

Perioperative myocardial infarction related to coronary bypass surgery.

Frank lead electrocardiograms were recorded from 149 normal and abnormal adult males using four different electrode placements. All chest electrodes were placed at: (1) the fourth intercostal space level, (2) the fifth intercostal space level, (3) the fourth intercostal space level with V₄ substituted for C, and (4) the fifth intercostal space level with V₄ substituted for C.Differences in mean values of many commonly used amplitudes and orientations were not statistically significant among the four recording methods, but amplitude differences for individual subjects were often large and difficult to predict. When V₄ is substituted for C, as commonly done in some laboratories, R_x decreased and R_z increased by more than 10 per cent in about 40 per cent of the cases. In about 70 per cent of the cases, R_x and R_z changed significantly when electrode level was shifted from the fifth to the fourth intercostal space. For these 70 per cent, it does not appear possible to accurately predict increase or decrease of R_x, R_z, or QRS_m.Analysis programs which depend on individual amplitude measurements are likely to be significantly affected by electrode placement. It is suggested that criteria for analysis programs developed using a specified version of the Frank system should ideally be applied only to electrocardiograms recorded in the same manner.     

Implanted hair follicle stem cells form Schwann cells that support repair of severed peripheral nerves

The hair follicle bulge area is an abundant, easily accessible source of actively growing, pluripotent adult stem cells. Nestin, a protein marker for neural stem cells, also is expressed in follicle stem cells and their immediate, differentiated progeny. The fluorescent protein GFP, whose expression is driven by the nestin regulatory element in transgenic mice, served to mark the follicle cell fate. The pluripotent nestin-driven GFP stem cells are positive for the stem cell marker CD34 but negative for keratinocyte marker keratin 15, suggesting their relatively undifferentiated state. These cells can differentiate into neurons, glia, keratinocytes, smooth muscle cells, and melanocytes in vitro. In vivo studies show the nestin-driven GFP hair follicle stem cells can differentiate into blood vessels and neural tissue after transplantation to the subcutis of nude mice. Equivalent hair follicle stem cells derived from transgenic mice with beta-actin-driven GFP implanted into the gap region of a severed sciatic nerve greatly enhance the rate of nerve regeneration and the restoration of nerve function. The follicle cells transdifferentiate largely into Schwann cells, which are known to support neuron regrowth. Function of the rejoined sciatic nerve was measured by contraction of the gastrocnemius muscle upon electrical stimulation. After severing the tibial nerve and subsequent transplantation of hair follicle stem cells, walking print length and intermediate toe spread significantly recovered, indicating that the transplanted mice recovered the ability to walk normally. These results suggest that hair follicle stem cells provide an important, accessible, autologous source of adult stem cells for regenerative medicine.