US military medical ethics in the War on Terror.

Military medical ethics has been challenged by the post-11 September 2001 'War on Terror'. Two recurrent questions are whether military physicians are officers first or physicians first, and whether military physicians need a separate code of ethics. In this article, we focus on how the War on Terror has affected the way we have addressed these questions since 2001. Two examples frame this discussion: the use of military physicians to force-feed hunger strikers held in Guantanamo Bay prison camp, and the uncertain fate of the Department of Defense's report on 'Ethical Guidelines and Practices for US Military Medical Professionals'.

Comparative efficacy of enrofloxacin to that of tulathromycin for the control of bovine respiratory disease and prevalence of antimicrobial resistance in Mannheimia haemolytica in calves at high risk of developing bovine respiratory disease.

Bovine respiratory disease (BRD) is the most common cause of morbidity and mortality in North American beef cattle. Mannheimia haemolytica is the bacterial pathogen most often isolated from cattle with BRD, and the prevalence of antimicrobial resistance (AMR) in this organism has increased in recent years. Antimicrobials are commonly used to prevent BRD in cattle at high risk of developing BRD; however, recent work would suggest that this practice might be one factor contributing to the increased prevalence of AMR in M. haemolytica. We hypothesized that the administration of the short-acting fluoroquinolone, enrofloxacin, would be just as effective as the long-acting triamilide, tulathromycin, in preventing BRD but would be less likely to select for AMR M. haemolytica in stocker calves at high risk of developing BRD. Three hundred forty-one stocker calves were enrolled in the study with 172 calves in 4 pens being randomly assigned to treatment with enrofloxacin and 169 calves in 4 pens randomly assigned to treatment with tulathromycin. Calves within each treatment group were allocated to one of 4 replicate pens based on the week of enrollment. Of calves receiving enrofloxacin, 33.7% required treatment for BRD at least once within 45 d after arrival, compared with 18.3% of calves receiving tulathromycin (P = 0.040). The percentages of calves that required more than one treatment for BRD within 45 d after arrival did not differ statistically for those receiving enrofloxacin compared with those receiving tulathromycin (10.5% and 4.7%, respectively; P = 0.107) Likewise, the percentages of calves that died during the 45-d follow-up period did not differ for those receiving enrofloxacin compared with those receiving tulathromycin (12.2% and 10.1%, respectively; P = 0.592). Mannheimia haemolytica was cultured from 11% of calves sampled at arrival and from 50% of calves sampled at revaccination 14 to 17 d later. There was a significanst effect of sampling time on the proportion of calves carrying multidrug-resistant (MDR) isolates, with calves having a higher prevalence of MDR isolates at revaccination than arrival (100% vs. 13%; P < 0.001). Future research evaluating the impact of MDR on response to antimicrobial therapy is necessary.

Learning from UJAMBO: Perspectives on Gynecologic Care in African Immigrant and Refugee Women in Boston, Massachusetts.

African-born immigrant women, and particularly refugees and asylum seekers, are at risk for reproductive health disparities but inadequately use relevant gynecologic services. We sought to elucidate perspectives on gynecologic care in a population of Congolese and Somali immigrants. We conducted a secondary qualitative analysis of focus group data using a grounded theory approach and the Integrated Behavioral Model as our theoretical framework. Thirty one women participated in six focus groups. Participant beliefs included the states of pregnancy and/or pain as triggers for care, preferences included having female providers and those with familiarity with female genital cutting. Barriers included stigma, lack of partner support, and lack of resources to access care. Experiential attitudes, normative beliefs, and environmental constraints significantly mediated care preferences for/barriers to gynecologic health service utilization in this population. Centering of patient perspectives to adapt delivery of gynecologic care to immigrants and refugees may improve utilization and reduce disparities.

Periscapular amputation as treatment for brachial plexopathy secondary to recurrent breast carcinoma: a case series and review of the literature.

AIMS: Recurrent breast carcinoma with brachial plexus involvement is often misinterpreted as a radiation- or chemotherapy-induced brachial plexopathy. We review a case series of 4 patients at our institution within a 1-year period, and describe their diagnostic workup and treatment with a palliative periscapular amputation. Our aim is to describe this entity, indications and benefits of this procedure, when required for progressive disease, with the goal of raising a collective index of suspicion to aid in earlier diagnosis. METHODS: Four patients with recurrent axillary breast cancer and symptoms consistent with a brachial plexopathy were prospectively collected over a 1-year period. A Pubmed search was conducted; pertinent articles were reviewed and reported. RESULTS: Patients presented with intractable pain and flaccid paralysis of the ipsilateral limb. All had been previously treated with surgical resection, axillary lymph node dissection, chemotherapy, and radiation therapy. Average time from breast surgery to presentation was 78.75 months (range 11-216 months.) Workup included MRI and biopsy to confirm recurrence. Periscapular amputation was performed for each patient, all of who experienced subjective pain relief postoperatively. Three of the 4 patients are still living; one patient died of disease. CONCLUSION: Breast cancer survivors presenting with a brachial plexopathy should raise suspicion for recurrent disease. Close evaluation with MRI is the best first step in diagnosis. Although periscapular amputation is an aggressive surgical treatment, it is an acceptable option when disease has progressed to neurovascular involvement and a functionless limb.

Evaluation of a nonlinear Hertzian-based model reveals prostate cancer cells respond differently to force than normal prostate cells.

Understanding how the mechanical properties of cells alter with disease may help with the development of novel diagnostics and treatment regimes. The emergence of tools such as the atomic force microscope (AFM) has enabled us to physically measure the mechanical properties of cells. However, suitable models for the analysis of real experimental data are either absent, or fail to provide a simple analysis tool in which experimental data can be analyzed quickly and reliably. The Hertz model has been widely used to study AFM data on living cells, however it makes assumptions that are untrue for cells, namely that cells behave as linear elastic bodies. This article presents and evaluates an alternative nonlinear Hertz model, which allows the Young's modulus to vary according to a second order polynomial function of indentation depth. Evaluation of the model revealed that prostate cancer cells (PC3) responded more uniformly to force compared to the normal PNT2 cells. Also, more energy (J) was needed to deform the normal prostate cells compared to the prostate cancer cells. Finally, the model described here suggests that overall the normal prostate cells behave in a more linear fashion to applied force compared to the prostate cancer cells.

Amputation for extremity soft tissue sarcoma does not increase overall survival: a retrospective cohort study.

To determine if amputation increases survival when compared to limb salvage surgery in patients with a soft tissue sarcoma (STS) of the extremity when there is often a misconception among physicians and patients that ablative surgery eliminates local recurrence and increases overall survival. This retrospective cohort study assessed 278 patients with STS and compared 18 patients who had undergone amputations for soft tissue sarcomas of the extremities to a comparative cohort of 260 patients who underwent limb salvage surgery during the same time period. Our limb salvage surgery (LSS) rate was 94% overall for soft tissue sarcomas with a median follow-up of 3.1 years. Patients undergoing amputations either had tumors that involved a critical neurovascular bundle (in particular nerve rather than vessel resection was more responsible for a decision toward ablation), or underlying bone or had neoplasms whose large size would require such an enormous resection that a functional limb would not remain. In comparing prognostic effects, mainly death due to sarcoma, distant metastasis and local recurrence, it was found that there was no statistically significant difference between patients undergoing amputation to those undergoing limb salvage surgery (p > 0.05). While amputations do not increase overall survival in soft tissue sarcomas of the extremity as compared to LSS, they are still a valuable option in a surgeon's arsenal. In particular, amputations can provide improved local control and symptomatic treatment in patients who might not be candidates for limb salvage surgery.

Clinical and molecular delineation of the 17q21.31 microdeletion syndrome.

BACKGROUND: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. AIM: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. RESULTS: We estimate the prevalence of the syndrome to be 1 in 16,000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (chr17: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau (MAPT). Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a <500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p<10(-5)). CONCLUSION: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

Prevalence of hemangiosarcoma in anemic dogs with a splenic mass and hemoperitoneum requiring a transfusion: 71 cases (2003-2005).

OBJECTIVE: To determine prevalence of splenic hemangiosarcoma in anemic dogs with a splenic mass and hemoperitoneum requiring a transfusion and to identify factors that could differentiate between dogs with hemangiosarcoma and dogs with other splenic masses at the time of hospital admission. DESIGN: Retrospective case series. ANIMALS: 71 dogs. PROCEDURES: Medical records, blood bank logs, and histologic reports of dogs with a splenic mass and hemoperitoneum that required a transfusion between 2003 and 2005 were reviewed. Dogs that received a transfusion of packed RBCs, were splenectomized, and had a definitive histologic diagnosis were included. RESULTS: Signalment of dogs was similar to that in other reports. Malignant splenic neoplasia was identified in 54 of 71 (76.1%) dogs, whereas 17 of 71 (23.9%) dogs had a benign splenic lesion. Of 54 dogs with malignant splenic neoplasia, 50 (92.6% [70.4% of all dogs]) had splenic hemangiosarcoma. In addition, dogs with splenic hemangiosarcoma had significantly lower total solids (TS) concentrations and platelet counts at admission. Finally, hemoperitoneum was strongly associated with a diagnosis of splenic hemangiosarcoma. CONCLUSIONS AND CLINICAL RELEVANCE: In this clinical population of dogs, prevalence of hemangiosarcoma was higher than in other studies. Dogs with hemangiosarcoma in this study had significantly lower TS concentrations and platelet counts at the time of admission, compared with values for dogs with other splenic masses. No other markers were useful in differentiating dogs with hemangiosarcoma. It is important to discuss the prevalence of and poor prognosis associated with hemangiosarcoma with owners when they are contemplating whether to proceed with treatment.

Differential regulation of calcitonin secretion in normal and neoplastic pulmonary neuroendocrine cells in vitro.

Within the mammalian lung, cells with a neuroendocrine phenotype are few in number and are sparsely distributed. In contrast, neuroendocrine neoplasms represent a major group of lung cancers. The aim of this study was to develop a model of mammalian PNECs and to compare glucocorticoid regulation of calcitonin secretion in normal and neoplastic cells with neuroendocrine differentiation. Cell cultures of PNECs were initiated after the disaggregation of neonatal hamster lungs with 0.1% collagenase and fractionation of the resultant cell suspension on a gradient of iodixanol (1.320 g/mL). Cell fractions enriched in PNECs were identified by positive staining for 5-hydroxytryptamine and the presence of calcitonin. Calcitonin secretion was investigated after exposure to hydrocortisone (0 to 1,000 nM). A dose-dependant inhibition of calcitonin secretion was seen after 7 days between 10 nM (55% of control), and 1,000 nM (29%) hydrocortisone. Cell cultures grown in the presence of hydrocortisone also contained significantly fewer PNECs between 10 nM (90% of control), and 1,000 nM (45%). Human bronchial carcinoid cells (NCIH727) cultured under identical conditions showed a similar inhibition of calcitonin secretion between 10 nM (53%) and 1,000 nM (52%), although at these concentrations, no reduction in cell number was seen. In contrast, 2 human small cell lung cancer cell lines (DMS-79 and COR-L24 cells) showed no dose-dependent inhibition of calcitonin secretion and no effect on cell proliferation in response to hydrocortisone. These results show that enriched cultures of mammalian PNECs can be used to investigate functional aspects of their biology, including peptide secretion in response to potential regulators. Furthermore, calcitonin secretion is inhibited in normal PNECs and bronchial carcinoid cells at physiological concentrations of glucocorticoids, but this feature appears not to be present in the 2 more invasive neuroendocrine neoplasms (small cell lung cancer cells) investigated in this study.

Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics.

The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half-lives (t 1/2 approximately 55 hours), permitting once-daily dose regimens. The protein-binding characteristics of these drugs, however, vary widely. This study examines the effect of these binding differences on the drugs' disposition kinetics at steady state. A total of 52 participants (26 young healthy volunteers, and 26 elderly osteoarthritic patients, 15 men and 37 women (2 of them poor metabolizers of debrisoquine [CYP2D6]) completed the two-period, two-treatment, randomized, single-dose and 21-day, once-daily multiple-dose, cross-over study. Doses of oxaprozin and piroxicam were 1,200 mg once daily and 20 mg once daily, respectively. Mean single-dose kinetic parameters of oxaprozin versus piroxicam did not differ more than +/-14% (t1/2, 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70-kg body weight [Clpo], 0.139 versus 0.121 L/hr; apparent volume of distribution adjusted for 70-kg body weight [Vd/F]; 10.2 L versus 9.13 L). Protein binding was plasma-concentration dependent with oxaprozin (range, 10-400 mg/L) but not with piroxicam (range, 1-30 mg/ L). Steady-state conditions were established within 3 days with oxaprozin but took almost 12 days with piroxicam. Compared with the single-dose values, steady-state Clpo (Clpo,ss) and Vd/F of total drug increased with oxaprozin by almost 127% but remained within +/-10% with piroxicam. Post-steady-state apparent t 1/2 of the total and unbound drugs of approximately 62 hours were similarly prolonged with piroxicam but differed substantially with oxaprozin (50.6 hours [total drug] versus 23.8 hours [unbound drug]). Single dose Clpo (Clpo,sd) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Clpo in the two poor metabolizers of debrisoquine was within +/-20% of mean values for the population. Clinically important age- and gender-dependent decreases were not observed in the weight-adjusted, Clpo,sd or Vd/F values of the total drug for either NSAID. Clearances of the two NSAIDs were significantly correlated, suggesting that a common P450 isozyme (most likely CYP2C9, in that piroxicam is a known substrate of this isozyme) may be at least partly involved in the oxidative metabolism of these NSAIDs.

Impaired processing of proopiomelanocortin in corticotroph macroadenomas.

The regulation and secretion of the ACTH precursors POMC and pro-ACTH were assessed directly using a 2-site immunoradiometric assay in six patients with pituitary macroadenomas (> or = 1.2 cm in diameter) and 27 patients with Cushing's disease due to a microadenoma. ACTH precursor levels were elevated in patients with macroadenomas (150-3690 pmol/L; normal range, < 5-40 pmol/L) and significantly higher than those in microadenoma patients (median, 29 pmol/L; range, 9-104 pmol/L; P < 0.001). Patients with macroadenomas also had increased ACTH precursor/ACTH ratios (15-181:1) compared with microadenoma patients (median, 5:1, range, 0.7-18.5:1; P < 0.001). ACTH precursors were unresponsive to high dose dexamethasone in patients with macroadenomas, whereas ACTH and cortisol responses varied. After CRH administration, ACTH precursors were unchanged, whereas cortisol increased significantly, suggesting the release of biologically active ACTH. This study clearly demonstrates reduced processing of POMC to ACTH in large pituitary tumors, a characteristic usually associated with tumors causing the ectopic ACTH syndrome, and provides evidence for differential regulation of ACTH precursors and ACTH by glucocorticoid and CRH. Variation in the clinical symptoms of patients with corticotroph macroadenomas may be attributable to differences in biological potency between the ACTH precursors and ACTH.

Binding affinities of tyrosine-phosphorylated peptides to the COOH-terminal SH2 and NH2-terminal phosphotyrosine binding domains of Shc.

The adaptor protein Shc has been implicated in Ras signaling via association with many tyrosine-phosphorylated receptors, including growth factor receptors, antigen receptors on T and B cells, and cytokine receptors. Shc could interact with the activated receptors through the carboxyl-terminal Src homology 2 (SH2) domain or the structurally unrelated amino-terminal phosphotyrosine binding (PTB) domain. Using NMR and surface plasmon resonance techniques, we have measured the binding affinities of the SH2 and the PTB domains of Shc to a series of phosphotyrosine-containing peptides derived from known Shc binding sites. Tyrosine-phosphorylated peptides derived from Trk (pY490), polyoma virus middle T-antigen (pY250), ErbB3 (pY1309), and epidermal growth factor receptor (pY1086, pY1148, and pY1114) that contain NPXpY sequences bind preferentially to the PTB domain of Shc with Kd values of 0.02-5.3 microM. The binding affinities of these peptides to the Shc SH2 domain were in the range of 220-1290 microM. In contrast, tyrosine-phosphorylated peptides from epidermal growth factor receptor (pY992, pY1173) and the zeta chain of the T-cell receptor bind preferentially to the SH2 domain (Kd = 50-130 microM) versus the PTB domain (Kd > 680 microM). From these studies, the relative contribution of the individual domains of Shc for binding to the phosphotyrosine-containing portions of these proteins was determined. In addition, our data indicate that the high affinity binding of the PTB domain to the NPXpY-containing peptides results from a very high association rate and a rapid dissociation rate, which is similar to previous results observed for the SH2-phosphopeptide complexes.

Development of adrenocorticotropin-(1-39) and precursor peptide secretory responses in the fetal sheep during the last third of gestation.

Although it is known that concentrations of immunoreactive ACTH increase during late gestation in fetal sheep plasma, the nature of the ACTH has not been well characterized. We used two-site immunoradiometric assays to separately measure high mol wt ACTH precursors (POMC and pro-ACTH) and ACTH-(1-39) in plasma of fetal sheep with chronic arterial and venous catheters. We compared the ratio of these peptides as a function of gestational age under basal conditions and in response to exogenous vasopressin and/or corticotropin-releasing hormone. Under basal conditions, the concentration of precursors was not changed throughout the last third of gestation; however, ACTH-(1-39) increased significantly approaching term. The molar ratio of precursors to ACTH-(1-39), therefore, decreased from 15.8 +/- 1.0 at 110 days to 7.9 +/- 0.6 at 140 days gestation. At all gestational ages, vasopressin and corticotropin-releasing hormone increased ACTH-(1-39) and precursors, albeit with different time courses. At 120 days gestation, arginine vasopressin plus CRH produced synergistic increases in ACTH-(1-39) and precursors, whereas the response was only additive at other ages. The present results indicate that the elevation in the resting plasma immunoreactive ACTH concentration that occurs near term is constituted by an increase in the concentration of ACTH-(1-39) relative to those of POMC and pro-ACTH, which may have further physiological significance. Also, CRH and AVP are potent stimulators of both ACTH-(1-39) and ACTH precursors.

Multiple nuchal cord entanglements and intrapartum complications.

OBJECTIVE: Our purpose was to evaluate the outcomes of pregnancies complicated by a multiple (double, triple, or quadruple) nuchal cord entanglement. STUDY DESIGN: Computerized data from our University Hospital perinatal database were reviewed between 1990 and 1994. Only singleton, vertex, and term pregnancies undergoing labor were analyzed. Patients with active perinatal complications were eliminated to reduce bias. Pregnancies with infants with either a single or no nuchal cord entanglement served as comparison groups. A comparison of frequencies in the three groups was by chi 2 testing and a comparison of means by a two-tailed Student t test and analysis of variance. RESULTS: Of the 8565 deliveries, the frequency of two or more cord entanglements at delivery was 3.8%. Compared with a single or no cord entanglement, pregnancies with a multiple entanglement were more likely to exhibit an abnormal fetal heart rate pattern during advanced labor (p < 0.001) and to require low or midforceps application (p < 0.001). The study infants were also more likely to have meconium (p = 0.013), a low 1-minute Apgar score (p < 0.001), and an umbilical artery pH < or = 7.10 (odds ratio 2.2, p = 0.013) than the controls. Rates of abruptio placentae, cesarean delivery, and 5-minute Apgar scores < 7 were no more common in the multiple entanglement than the control groups. CONCLUSION: A multiple nuchal cord entanglement was associated with a greater risk of meconium, an abnormal fetal heart rate pattern during advanced labor, the need for operative vaginal delivery, and mild umbilical artery acidosis at birth; however, there was no added risk of an adverse neonatal outcome.

Elevated levels of adrenocorticotropin (ACTH) precursors in post-adrenalectomy Cushing's disease and their regulation by glucocorticoids.

The ACTH precursor pro-opiomelanocortin (POMC) undergoes specific endoproteolytic cleavages in the anterior pituitary gland to give ACTH-(1-39). ACTH precursors circulate in normal subjects and are high both in the ectopic ACTH syndrome and in patients with aggressive pituitary adenomas. This study examines plasma levels of ACTH precursors and ACTH in 24 patients with post-adrenalectomy Cushing's disease, in 10 of whom computed tomography showed evidence of tumor progression. ACTH precursors were higher in post-adrenalectomy Cushing's disease (median 97.5 pmol/L, range 26-647 pmol/L) than in untreated Cushing's disease (median 29 pmol/L, range 9-104 pmol/L) and normal controls (5-40 pmol/L) (P < 0.001) and were significantly higher in patients with larger tumors (median 175 pmol/L, range 52-647 pmol/L) than in the remainder (median 41 pmol/L, range 26-510 pmol/L) (P = 0.02). Surprisingly, pro-opiomelanocortin (POMC) processing to ACTH was enhanced in post-adrenalectomy patients (ratio 1 +/- 0.5) compared with Cushing's disease (5.6 +/- 0.8) and normal subjects (5.3 +/- 0.9). After hydrocortisone ACTH precursors rose in 36% of post-adrenalectomy patients (increase 15-78%) and remained within 10% of basal levels in 46%. Six patients had a rise in precursors and a fall in ACTH suggesting differential regulation of these peptides. In conclusion, whereas ACTH precursors are high in post-adrenalectomy Cushing's disease and higher levels correlate with tumor progression, processing of precursors to ACTH is enhanced.

Biological activity of adrenocorticotropic hormone precursors on ovine adrenal cells.

Adrenocorticotropic hormone (ACTH) is synthesized in the corticotrophs as a precursor, pro-opiomelanocortin (POMC), which is processed via proACTH to ACTH. Both precursors and ACTH are secreted. Although the steroidogenic activity of ACTH is well characterized, that of the precursors is not. This study assessed the capacity of POMC and proACTH to alter cortisol synthesis. POMC and proACTH were prepared by subjecting medium, conditioned by exposure to DMS-79 cells, to Sephadex chromatography, and the bioactivity was assessed in cultured-dissociated ovine adrenal cells. Alone neither POMC (< or = 2.6 nM) nor proACTH (< or = 0.7 nM) showed any consistent acute (6 h) stimulatory or inhibitory action on cortisol in either fetal or adult cells. In contrast, in fetal cells the precursors inhibited steroidogenic response to ACTH-(1-24). POMC at 2.6 nM, but not lower concentrations, decreased the cortisol responses to 0.01, 0.1, and 1 nM ACTH by at least 50%. ProACTH (0.70 and 0.23 nM) decreased the responses to ACTH at 0.01 nM by 89 and 67%, respectively, and at 0.1 nM by 49 and 34%, respectively. At 1 nM ACTH only 0.7 nM proACTH decreased the response to ACTH (by 69%). In contrast, in adult adrenal cells, the precursors did not significantly reduce the response to ACTH (range 0.01-1 nM). Therefore, these data indicate that POMC and proACTH can inhibit the cortisol response to ACTH in fetal adrenal cells, an effect that is concentration dependent. The data suggest that precursors may play a physiological role, possibly regulating fetal plasma cortisol concentrations.

Cerebrospinal fluid levels of beta endorphin in painful and painless diabetic polyneuropathy.

beta endorphin (beta-EP) is an important modulator of central pain pathways. To examine whether changes in central production of beta-EP contribute to the pathogenesis of diabetic neuropathic pain, we compared the cerebrospinal fluid (CSF) levels of beta-EP and its precursor proopiomelanocortin (POMC) between 15 diabetic patients with chronic painful diabetic polyneuropathy, eight patients with severe painless diabetic neuropathy, and ten nondiabetic controls. Both peptides were measured by specific monoclonal antibody-based two-site immunoradiometric assays (IRMAs). In the diabetic patients with painful neuropathy, mean +/- SD CSF beta-EP concentrations (5.7 +/- 2.2 pmol/L) were comparable to those of the diabetic patients with painless neuropathy (6.0 +/- 2.3 pmol/L) and did not correlate with the severity of neuropathic pain. CSF beta-EP, but not POMC, concentrations were lower in the diabetic neuropathic patients overall (5.8 +/- 1.9 pmol/L) compared to the control subjects (7.6 +/- 2.2 pmol/L) (p < 0.05). CSF POMC showed no intergroup differences. However, POMC levels were 80-fold higher than those of beta-EP and should always be considered when interpreting immunoreactive beta-EP or other derivative peptide levels in CSF. We conclude that CSF beta-EP levels appear to be reduced in diabetic polyneuropathy but they do not relate to the presence of neuropathic pain. This might explain why opioid analgesics are of little, if any, help in alleviating diabetic neuropathic pain.

Choice of treatment affects plasma levels of insulin-like growth factor-binding protein-1 in noninsulin-dependent diabetes mellitus.

Insulin-like growth factor (IGF)-binding protein-1 (IGFBP-1) modulates the metabolic and mitogenic effects of IGFs. Although IGFBP-1 levels are abnormally high in insulin-dependent diabetes (IDDM), relatively little is known in NIDDM; conflicting data have suggested both high and low levels. We investigated whether treatment modifies IGFBP-1 levels in two groups of NIDDM patients. Study 1 examined fasting concentrations in groups of patients with NIDDM, comparable except for treatment type (sulfonylurea, n = 23; once daily insulin, n = 15; sulfonylurea plus once daily insulin, n = 14; multiple insulin injections, n = 9) and 25 nondiabetic subjects. In sulfonylurea-treated patients there were markedly reduced plasma IGFBP-1 concentrations (median, interquartile range in parentheses): control, 61.0 (36-96) micrograms/L; sulfonylureas alone, 31.5 (21-61) micrograms/L (P < 0.01); and sulfonylureas plus insulin, 31.5 (9-53) micrograms/L (P < 0.01). Once daily insulin was associated with values similar to those in the control group [62.0 (27-103) micrograms/L; P = NS], whereas IGFBP-1 levels were higher with multiple insulin injection therapy [156.0 (71-184) micrograms/L; P < 0.05]. Proinsulin levels were higher in sulfonylurea-treated patients, but there was no significant correlation between IGFBP-1 and proinsulin within any individual group. Study 2 examined the effects of treatment on the dynamics of IGFBP-1 levels between 0800-1900 h. In control subjects (n = 8), levels fell from 0800 h (mean +/- SEM, 22.4 +/- 5.2 micrograms/L) to 1000 h (14 +/- 5.2 micrograms/L), followed by a rise, more rapid after food, to a peak at 1240 h (20.6 +/- 3.7 micrograms/L). Levels then declined until 1500 h (10.7 +/- 2.9 micrograms/L), with a further postprandial peak at 1840 h (23.1 +/- 3.2 micrograms/L). Sulfonylurea therapy (n = 6) resulted in a complete loss of this pattern, with a marked fall in IGFBP-1 from 0800 h (22 +/- 2.7 micrograms/L) to less than 7 micrograms/L for the remainder of the study (area under the curve, 1150-1400 h, P < 0.001 vs. control). By contrast, in metformin-treated patients (n = 7), neither IGFBP-1 levels nor postprandial peaks were significantly different from those in the control group. Our findings suggest that in patients with NIDDM, the regulation of IGFBP-1 is markedly influenced by the choice of treatment.