Opioid-like medications (OLM) are commonly used by patients with various types of chronic pain, but their long-term benefit is questionable. Electroacupuncture (EA) has been previously shown beneficial in reducing post-operative acute OLM consumption. In this pilot randomized controlled trial, the effect of EA on OLM usage and associated side effects in chronic pain patients was evaluated. After a two-week baseline assessment, participants using OLM for their non-malignant chronic pain were randomly assigned to receive either real EA (REA, n=17) or sham EA (SEA, n=18) treatment twice weekly for 6 weeks before entering a 12-week follow-up. Pain, OLM consumption and their side effects were recorded daily. Participants also completed the McGill Pain Questionnaire (MPQ), SF-36 and Beck Depression Inventory (BDI) at baseline, and at the 5th, 8th, 12th, 16th and 20th week. Nine participants withdrew during the treatment period with another three during the follow-up period. Intention to treat analysis was applied. At the end of treatment period, reductions of OLM consumption in REA and SEA were 39% and 25%, respectively (p=0.056), but this effect did not last more than 8 weeks after treatment. There was no difference between the two groups with respect to reduction of side effects and pain and the improvement of depression and quality of life. In conclusion, REA demonstrates promising short-term reduction of OLM for participants with chronic non-malignant pain, but such effect needs to be confirmed by trials with adequate sample sizes.

The long asymptomatic period before the onset of chronic diseases offers good opportunities for disease prevention. Indeed, many chronic diseases may be preventable by avoiding those factors that trigger the disease process (primary prevention) or by use of therapy that modulates the disease process before the onset of clinical symptoms (secondary prevention). Accurate prediction is vital for disease prevention so that therapy can be given to those individuals who are most likely to develop the disease. The utility of predictive markers is dependent on three parameters, which must be carefully assessed: sensitivity, specificity and positive predictive value. Specificity is important if a biomarker is to be used to identify individuals either for counseling or for preventive therapy. However, a reciprocal relationship exists between sensitivity and specificity. Thus, successful biomarkers will be highly specific without sacrificing sensitivity. Unfortunately, biomarkers with ideal specificity and sensitivity are difficult to find for many diseases. One potential solution is to use the combinatorial power of a large number of biomarkers, each of which alone may not offer satisfactory specificity and sensitivity. Recent technological advances in genetics, genomics, proteomics, and bioinformatics offer a great opportunity for biomarker discovery. The newly identified biomarkers have the potential to bring increased accuracy in disease diagnosis and classification, as well as therapeutic monitoring. In this review, we will use type 1 diabetes (T1D) as an example, when appropriate, to discuss pertinent issues related to high throughput biomarker discovery.

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse can be delayed by administration of insulin or specific insulin peptides. To better understand how insulin treatment delays diabetes development, NOD mice treated with an insulin peptide (B9-23) were compared with age-matched NOD and NOD congenic mice for gene expression changes in spleen using cDNA microarray. Fifty genes were identified that were significantly altered by B9-23 treatment. Thirty-three of these genes are downregulated by the treatment while they are upregulated during the natural disease progression in NOD from immature (3-4 weeks) to mature (10 weeks) stages. Taken together, our data suggest that the B9-23 treatment, like the protective genes in NOD congenic strains, reduces pro-inflammatory activation of lymphocytes that normally occurs in NOD mice. Furthermore, our studies discovered two genes (Irf4 and Tra1) with increased expression in B9-23-treated mice that promote the Th2 response, providing a molecular basis for the B9-23-protective therapy.

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D) 1 , 2 , but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene ( SUMO4 ), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D ( P = 1.9 × 10 −7 ). SUMO4 conjugates to IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B , an NFκB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high-risk non-diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non-progressors, as opposed to progressors, there was no fall in C-peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C-peptide production in the prediabetic period appears to indicate non-progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.

Newborn screening programs that use only high TSH levels as a marker for hypothyroidism may overlook neonates with congenital hypothyroidism (CH) due to TSH deficiency. We sought the cause of TSH deficiency in a neonate with low levels of thyroxine and TSH. The coding region of the TSHbeta gene was amplified and its sequence examined for mutations. Two mutations in exon 3 were identified: 1) a nucleotide deletion of T410 in codon 105 resulting in a frameshift in one allele, and 2) a previously unreported nucleotide deletion of T266 in codon 57, causing a frameshift and a premature stop at codon 62 in the other allele. We describe a compound heterozygous patient with TSHbeta mutations at codons 57 and 105 that interfered with a critical disulfide bond in the TSH molecule and caused CH. State screening programs that measure both T4 and TSH levels have the potential to detect newborns with congenital central hypothyroidism.

METHODS:We examined monocyte prostaglandin synthase 2 (PGS2/COX2) expression in individuals at risk for or with type 1 diabetes including: (i) 58 established type 1 and 2 diabetic patients; (ii) 34 autoantibody positive (AA+) children and adults; (iii) 164 infants and young children with insulin-dependent diabetes mellitus (IDDM) susceptibility human leukocyte antigen (HLA) alleles; and (iv) 37 healthy control individuals, over a 5-yr period.RESULTS:Established type 1 diabetic patients (1 month to 30+ yr post-disease onset) had significantly higher PGS2 expression than healthy controls; by contrast, insulin-treated type 2 diabetic patients had significantly lower PGS2 expression than healthy controls. Longitudinal studies of AA+ subjects at risk for type 1 diabetes indicated that 73% (11/15) of individuals who developed this disease during the study period expressed high levels of PGS2 prior to or after onset. We also found high level PGS2 expression in genetically at-risk infants and young children that correlated with having a first-degree relative with type 1 diabetes, but not with age, gender, or HLA genotype. In this population, high level PGS2 expression coincided with or preceded autoantibody detection in 30% (3/10) of subjects.CONCLUSIONS:These findings suggest that high level monocyte PGS2 expression, although subject to fluctuation, is present in at-risk subjects at an early age and is maintained during progression to and after type 1 diabetes onset.

Over the past two decades wilderness as a protectedarea category has continued to gain visibility and momentum worldwide. Encouraging this progress has been the influence of global nongovernment organizations such as The WILD Foundation, Conservation International, recently the Sierra Club foundation, and international organizations like The World Conservation Union (IUCN). The future of wilderness—like that of sustainable development—is critically dependent on the efforts of all such organizations, and the building of broad coalitions of partners among them. Only together can we successfully address issues such as how to integrate the needs for development with conservation of the environment, and to bring into full play the value of wilderness as benchmark and control areas for judging the effects of human development on natural systems. South Africa (SA) has been a leader in wilderness conservation on the African continent and is earning respect among developing nations with wilderness. This is in large part due to our wilderness pioneers such as Dr. Ian Player (Player 1995, 1998, Martin 2001), Bill Bainbridge (2001a, 2001b), and others. South Africa is the only African country to make provision for the protected area category “Wilderness Area” (WA) in its legislation. The first areas were protected in the present-day KwaZulu region of Natal Province, being the Umfolozi and St. Lucia wilderness areas established by administrative means nearly fifty years ago (Player 1998). Then countrywide provision was made in the Forest Act to set aside national wilderness areas in the early 1970s. The first areas set aside as wilderness under the Forest Act were the Drakensberg and the Cedarberg Wilderness Areas in 1973. South Africa is proud of these wilderness accomplishments, coming some twenty years before the IUCN Commission on National Parks and Protected Areas included wilderness as one of the international protected area categories in 1994 (Bainbridge 2001a and b). Related to these wilderness accomplishments has been South Africa’s hosting of the first and seventh World Wilderness Congresses in 1977 and 2001, respectively (Player 1978; Martin and Muir 2002). S O U L O F T H E W I L D E R N E S S FEATURES

As the sequence of the entire human genome is completed, the paradigm of analyzing a single gene effect in a biological system has shifted to a global systems analysis. This change in perspective can be attributed, in part, to the recognition that complex diseases such as diabetes or other autoimmune disorders do not arise from a single gene defect. Rather, they arise from a complex interaction of genes in a system that changes over the life span of the patients. In the past, researchers had a limited resource for the discovery of new genes important in the etiology of the disease they investigated. They were forced to take a gene-by-gene approach, which only scratched the surface of their biological problem. The sheer magnitude of currently available gene sequences compels researchers to take a more global view of the etiology of disease. Global gene expression analyses at the RNA level offer the first glimpse into the future of organizing and using this type of information. Investigators can simultaneously monitor the RNA levels of a large number of genes, or even the entire genome, in the context of their biological system.

The development of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice provides for their use as a model of human type 1 diabetes. To test the feasibility of muscle-directed gene therapy to prevent type 1 diabetes, we developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL-4 or IL-10. Skeletal muscle transduction of female NOD mice with IL-10, but not IL-4, completely abrogated diabetes. rAAV-IL-10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained islet insulin content, and altered splenocyte cytokine responses to mitogenic stimulation. The beneficial effects were host specific, as adoptive transfer of splenocytes from rAAV IL-10-treated animals rapidly imparted diabetes in naive hosts, and the cells contained no protective immunomodulatory capacity, as defined through adoptive cotransfer analyses. These results indicate the utility for rAAV, a vector with advantages for therapeutic gene delivery, to transfer immunoregulatory cytokines capable of preventing type 1 diabetes. In addition, these studies provide foundational support for the concept of using immunoregulatory agents delivered by rAAV to modulate a variety of disorders associated with deleterious immune responses, including allergic reactions, transplantation rejection, immunodeficiencies, and autoimmune disorders.

Although cerebral edema occurs infrequently during the treatment of diabetic ketoacidosis (DKA), this unpredictable and often devastating complication is of such concern to pediatricians that they tailor treatments specifically to prevent it. Protocols that replace fluid deficit over 48 h and prolong the use of isotonic fluids to avoid rapid decline of serum osmolality have become the standards of care (1). Nonetheless, there is little experimental evidence to prove that these ‘conservative’ rehydration methods are safer than other rehydration regimens. Nor does epidemiologic evidence demonstrate a reduction of the incidence of cerebral edema because cautious rehydration protocols have become more widely used (2–4). This Hot Topic review will discuss papers that sought predictors of cerebral edema and those that assessed the pathogenic role of DKA therapy in the development of this complication.

This number is a surrogate for a more physiologic concentration level in serum water, but it is in the units ordinarily used by clinicians and varies in identical fashion.This adjusts for the "osmotic space" filled by the excess glucose.If the corrected number is outside the physiologic range for sodium concentration (i.e.Ͼ149 meq/L), the patient is hypernatremic, and less sodium than usual will be needed.Conversely, if the corrected sodium is less than 132 meq/L, more is needed.If the patient either before or after the start of therapy has a headache or any other evidence of new neurological impairment, administer hypertonic mannitol to reduce intracranial pressure.Do not wait for fixed dilated pupils; it will already be too late.Applying these principles, Harris and Fiordilese (Ref. 3 and personal communication regarding the current number in the series and the lack of mortality and sequelae) have treated over 400 episodes of DKA without a fatality or sequelae.Twelve of their patients exhibited either headache or other neurological manifestations, which led to the use of hypertonic mannitol infusion, sometimes advised and given at a referring hospital before arrival at their institution.All of these patients recovered neurologically and are otherwise intact; a remarkable record.Errors of the past aggravated the already abnormal distribution of water in the brain.In particular, the administration of too much fluid (usually diluted below isotonic for sodium chloride) caused water influx into the brain, causing an increase in intracerebral pressure and the administration of an iv bolus of insulin, which increased ECF water from glucose metabolism.These events may cause hemorrhage, thrombosis, or cerebral herniation.Thus, there is a pathophysiologic explanation for cerebral "edema" during ill-advised management of DKA, and there are a set of principles which when carefully followed have permitted successful correction of the disturbance.

Previous studies have shown the immunoregulatory functions IL-4 in type 1 diabetes mellitus. Therefore, the genes involved in the IL-4 regulatory pathway are candidates for diabetes susceptibility genes. Here we have evaluated IL4 and the alpha subunit of the IL-4 receptor (IL4R α) genes using the affected sibpair (ASP) and transmission/disequilibrium test (TDT). We analyzed 309 diabetic families from the United States and 87 families from various European countries. There was no evidence that either of these two genes are linked or associated with type 1 diabetes. Means by which IL-4 directed signals could indirectly alter diabetes susceptibility are proposed.