A parallel group double-blind RCT of vitamin D3 assessing physical function: is the biochemical response to treatment affected by overweight and obesity?

UNLABELLED: Vitamin D may affect skeletal muscle function. In a double-blind, randomised, placebo-controlled trial, we found that vitamin D3 supplementation (400 or 1,000 I.U. vs. placebo daily for 1 year with bimonthly study visits) does not improve grip strength or reduce falls. INTRODUCTION: This study aimed to test the supplementation effects of vitamin D3 on physical function and examine associations between overweight/obesity and the biochemical response to treatment. METHODS: In a parallel group double-blind RCT, healthy postmenopausal women from North East Scotland (latitude-57° N) aged 60-70 years (body mass index (BMI), 18-45 kg/m(2)) were assigned (computer randomisation) to daily vitamin D3 (400 I.U. (n = 102)/1,000 I.U. (n = 101)) or matching placebo (n = 102) (97, 96 and 100 participants analysed for outcomes, respectively) from identical coded containers for 1 year. Grip strength (primary outcome), falls, diet, physical activity and ultraviolet B radiation exposure were measured bimonthly, as were serum 25(OH)D, adjusted calcium (ACa) and phosphate. Fat/lean mass (dual energy X-ray absorptiometry), anthropometry, 1,25-dihydroxyvitamin D and parathyroid hormone were measured at baseline and 12 months. Participants and researchers were blinded throughout intervention and analysis. RESULTS: Treatment had no effect on grip strength (mean change (SD)/year = -0.5 (2.5), -0.9 (2.7) and -0.4 (3.3) kg force for 400/1,000 I.U. vitamin D3 and placebo groups, respectively (P = .10, ANOVA)) or falls (P = .65, chi-squared test). Biochemical responses were similar across BMI categories (<25.25-29.99, ≥30 kg/m(2)) with the exception of a small change at 12-months in serum ACa in overweight compared to non-overweight participants (P = .01, ANOVA; 1,000 I.U. group). In the placebo group, 25(OH)D peak concentration change (winter to summer) was negatively associated with weight (r = -.268), BMI (r = -.198), total (r = -.278) and trunk fat mass (r = -.251), with total and trunk fat mass predictive of winter to summer 25(OH)D change (P = .01/.004 respectively, linear regression). CONCLUSION: We found no evidence of an improvement in physical function following vitamin D3 supplementation for 1 year.

Statin-fibrate combination: therapy for hyperlipidemia: a review.

Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) <1.0 mmol/l (40 mg/dl) and/or triglycerides> 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Mallory-Weiss tear: predisposing factors and predictors of a complicated course.

OBJECTIVES: Little has been published regarding predictors of a complicated course after Mallory-Weiss tear (MWT). The aims of this study were to identify risk factors for a Mallory-Weiss tear and factors predictive of a complicated course. METHODS: At our university hospital, we searched a computerized endoscopy database. At our Veterans Affairs hospital we manually searched printed endoscopy reports. Proposed risk factors for MWT were: history of alcohol use, recent alcohol binge, nonbloody initial emesis, anticoagulation, other coagulopathy, nonsteroidal anti-inflammatory use, and hiatal hernia. Proposed predictors of a complicated course were: age, hematemesis, melena, hematochezia, visible vessel, adherent clot, active bleeding, multiple tears, other pathology at endoscopy, admission Hct, hypotension or orthostatic changes, and coagulopathy. A complicated course was defined on the basis of >6 U of blood transfused, rebleeding, angiography, surgery, or death. Predictors of a complicated course were evaluated using the Mann-Whitney U test or Fisher exact test. RESULTS: A total of 73 cases were reviewed. The most common risk factor was alcohol use, which was found in 44% of cases. In all, 23% of patients had no risk factors. Of the patients, 17 (23%) had a complicated course. Patients with a complicated course had a lower admission Hct (p = 0.009) and active bleeding at initial endoscopy (p = 0.013). CONCLUSION: The predictive value of active bleeding supports early endoscopy for stratification and intervention.

Acute phase proteins in patients with large and locally advanced breast cancer treated with neo-adjuvant chemotherapy: response and survival.

Seventy-seven patients with locally advanced breast cancer were treated with multimodality therapy comprising of six pulses of neo-adjuvant chemotherapy (doxorubicin, cyclophosphamide, vincristine and prednisolone) at 21-day intervals, followed by surgery (breast conservation or mastectomy) with appropriate axillary surgery, radiotherapy and adjuvant tamoxifen. The serum concentrations of acute phase proteins, C-reactive protein (CRP), á-1-anti-trypsin, albumin and transferrin were measured in serum taken prior to commencement of treatment. Patients were followed up for a median of 31 months and their clinical and histological responses and overall survival recorded. Univariate analyses revealed that tumour stage (p=0.01), clinical lymph node status (p=0. 02) and pre-treatment levels of serum albumin (p=0.002) and á-1-anti-trypsin (p=0.06) predicted overall survival. Using the Cox proportional hazards model reduced pre-treatment levels of serum albumin (p<0.00001), progressive lymph node involvement with tumour (p<0.005), and advancing tumour stage (p<0.01) were independent prognostic indicators for a poorer survival in patients with locally advanced breast cancer receiving neo-adjuvant chemotherapy.

Enteral nutritional support in acute alcoholic pancreatitis.

BACKGROUND: The experience to date with total enteral nutritional (TEN) support in acute alcoholic pancreatitis patients admitted to the University of Kentucky affiliated hospitals was reviewed. METHODS: Standard enteral formulas sufficient to meet patient's needs were administered into the small bowel via endoscopically placed nasoenteric feeding tubes in five patients. Feedings were administered for a mean of 28.4 days. Pancreatitis was mild to moderate in severity by Ranson's criteria in four patients, and severe in one. RESULTS: Four patients developed complications of pancreatitis before initiation of TEN, representing the most common indication for nutritional support. Nutritional status was maintained by TEN with no significant complications from this nutritional support identified. Diarrhea that did not limit tube feeding developed in a single patient. CONCLUSIONS: This experience further supports the safety of TEN in acute pancreatitis and suggests that adequate nutritional support can be delivered by this route.

Gastroesophageal reflux disease and asthma. Diagnosis and management.

Gastroesophageal reflux is common among asthmatics. It not only may worsen during an episode of airways obstruction but also may serve as a trigger for such an attack. Both animal and clinical data suggest that gastroesophageal reflux serves as a trigger of bronchospasm, potentiates the bronchomotor response to additional triggers, or both. Patients with reflux-associated asthma may manifest symptoms of gastroesophageal reflux, either classic or atypical, but approximately 25% to 30% have clinically silent reflux. Despite the use of inadequate doses of acid-suppressive medicines, clinical trials have documented improvement in respiratory symptoms among asthmatics following the treatment of reflux. Recent trials suggest long-term improvement in respiratory symptoms following antireflux surgery. Selected patients with asthma should be evaluated for gastroesophageal reflux. If it is present, such patients may benefit from aggressive antireflux therapy.

Acute phase proteins and recombinant IL-2 therapy: prediction of response and survival in patients with colorectal cancer.

Twenty-four patients with metastatic colorectal cancer were treated with recombinant IL-2 (rIL-2) by continuous intravenous infusion for 5 days (18 x 10(6) U/m2 per 24 h), followed by three injections of 5-fluorouracil (600 mg/m2) and folinic acid (25 mg/m2) at weekly intervals. The response to treatment was assessed using standard UICC criteria (partial or complete response, stasis or progression of disease). The serum concentrations of the acute phase proteins; C-reactive protein (CRP), retinol binding protein (RBP), alpha 1-antitrypsin (alpha 1-AT), transferrin (TF) and albumin were measured. A response to therapy occurred in the tumours of seven (29%) of the 24 patients (two complete and five partial responses). All patients who demonstrated a response to treatment had a serum albumin level of > 37 g/l and a CRP level of < or = 10 mg/l. In contrast, of the 17 patients who did not respond to therapy, 12 (71%) had a serum albumin of less than 37 g/dl and a CRP of greater than 10 mg/l. Examination of the survival times of the 12 patients who had a pretreatment serum albumin level of less than 37 g/l revealed that all had died within 12 months of cessation of therapy. However, 58% of patients with pretreatment serum albumin levels of greater than 37 g/l survived for longer than 12 months. These results have shown that (i) patients who respond to rIL-2-based therapy and (ii) those patients who have prolonged survival times, can be identified by pretreatment measurement of serum levels of acute phase proteins.

In vivo cytokine production and recombinant interleukin 2 immunotherapy: an insight into the possible mechanisms underlying clinical responses.

Recombinant interleukin 2 (rIL-2), when given to patients with advanced malignant disease, induces a limited beneficial effect, with only 20-30% of patients with solid tumours responding. This present study has identified those patients with advanced colorectal cancer most likely to respond to rIL-2 therapy, by analysis of serum cytokine levels, prior to and during rIL-2 treatment, documented in responders and non-responders. Responders were found to have significantly lower pretreatment serum IL-6 and soluble IL-2 receptor levels (sIL-2R) than non-responders (P < 0.01 and P < 0.05 respectively). During rIL-2 infusion, responders developed high circulating levels of IL-6 and had low constant levels of prostaglandin E2 (PGE2). Non-responders failed to produce IL-6 and demonstrated elevated serum concentrations of PGE2, during infusions of rIL-2. Thus, an enhanced ongoing IL-6 and sIL-2R response, prior to therapy, was detrimental to subsequent treatment with rIL-2. Differential production and/or release of cytokines and prostaglandins, during therapy, further determined the likelihood of response to rIL-2.

Disseminated Strongyloides stercoralis infection.

A case of disseminated S stercoralis is an immunosuppressed patient manifested with diarrhea, a rash, and progressive respiratory insufficiency. The parasites were eradicated with thiabendazole despite continued steroid therapy, and the patient survived the hospitalization. The characteristics of S stercoralis allow it to be harbored within a host for prolonged periods of time, only to disseminate once cell-mediated immunity is suppressed. A diagnosis of strongyloidiasis should be considered in an immunocompromised patient with a petechial rash. Prompt diagnosis and initiation of thiabendazole therapy provides the greatest opportunity for patient survival. Secondary bacterial infections should be aggressively sought. Mortality from disseminated strongyloidiasis approaches 80%.

Plasma creatinine and the effect of delay in separation of samples.

There is a prevailing opinion that creatinine is an analyte which may be assayed with confidence in the plasma of ageing whole-blood samples. This is true of continuous flow methods employing dialysis, but in this study, where creatinine was measured in old samples by a kinetic Jaffé method on a discrete analyser, the concentration of creatinine was falsely raised. When plasma was left in contact with cells for 48 h, there was an apparent rise in the plasma creatinine by over 100 mumol/L compared with the 2 h concentration. This method-dependent error is therefore clinically significant.

Management of local recurrence in well-differentiated thyroid carcinoma.

Local recurrence of well-differentiated thyroid carcinoma has a reported mortality approaching 50%. The University of Kentucky experience was reviewed to determine whether aggressive surveillance and treatment with reoperation and/or I-131 ablation increased survival following recurrence. Records of 66 consecutive patients with well-differentiated thyroid carcinoma treated at the University of Kentucky Medical Center (1980-1989) were reviewed. Forty-nine cases of papillary carcinoma and 17 cases of follicular carcinoma were studied; median follow-up was 68 months. At presentation, patients with follicular carcinoma were older (48 versus 35 years; P less than 0.05) and more frequently had metastatic disease (17% versus 2%, P less than 0.05). Fifty-eight (88%) patients were alive and disease-free at last follow-up. Fifteen patients (24%) had developed recurrent disease; median time to recurrence was 24 months. Multivariate regression examined the variables of age, sex, histology, tumor size, cervical adenopathy, capsular and vascular invasion, multicentricity, and surgical procedure. While distant metastases affected actuarial survival, no factor independently predicted local recurrence. In six patients with local recurrence, nonpalpable disease was detected by I-131 scan. All were treated with ablation and remain disease-free (mean follow-up 42 months). Eight patients with local recurrence presented with palpable lesions; seven underwent surgery. While two patients developed repeated local recurrences, the other five remain disease-free (mean follow-up 52 months). Early detection and aggressive treatment of local recurrence improve survival in patients with well-differentiated thyroid carcinoma. To facilitate use of I-131, we advise total thyroidectomy for patients with well-differentiated thyroid carcinoma.

Acquired factor VIII inhibitor.

Development of a circulating inhibitor of the coagulant activity of factor VIII is a rare event producing a clinical picture similar to that of classic hemophilia. A case of autoimmune factor VIII inhibitor has been presented. Although a hemostatic response was rapidly achieved with the infusion of factor IX concentrates, immunosuppressive therapy was initiated. The inhibitor disappeared in less than 20 days from the initiation of therapy.

Medical training in clinical biochemistry (chemical pathology) in Scotland 1985-1989.

A questionnaire was sent to 35 doctors who were believed to have trained in clinical biochemistry in Scotland between 1 January 1985 and 31 December 1989. Thirty replies were received from 23 individuals who were still employed in the specialty (including seven consultants and nine senior registrars) and from seven individuals who had left. Twenty considered that training within the laboratories in which they were employed had not been satisfactory. The main emphasis of training was directed towards reporting duties, clinical liaison, research, teaching and outpatient clinics. Little training was provided for the development of analytical experience, personnel selection and laboratory management. Those surveyed identified poor training in laboratory management as the main aspect of training which required improvement.

Plasma-specific proteins: their response to surgical trauma and tumour load, and modification of this response by post-operative metabolic support.

Concentrations of plasma proteins with short half-life have been suggested as indicators of nutritional state in surgical patients. Trauma also affects the circulating concentrations of these proteins. Serum concentrations of retinol binding protein (RBP), pre-albumin and transferrin were determined pre- and post-operatively on different supporting regimens. The circulating concentration of these liver proteins displayed no differential effect of the supporting regimen during the first 5 post-operative days. None of the patients with tumour demonstrated any indication of hepatic metastases pre-operatively or at the time of laparotomy but, as a group, had lower pre-operative concentrations of RBP (p < 0.001) and pre-albumin (p < 0.01) than patients with no tumour load. In addition 55% of patients (15:27) with tumour had RBP concentrations <3.5 mg/dl; all of the non-tumour bearing patients (13/13) had RBP concentrations >3.5 mg/dl. RBP and pre-albumin appear to act as non-specific tumour markers, but not to serve a useful function as short-term nutritional markers of post-operative support.

Splenic vein thrombosis.

A retrospective review of all admissions to the University of Kentucky Medical Center from 1977 to 1987 revealed six persons in whom splenic vein thrombosis could be documented. The patients had either upper gastrointestinal bleeding from gastroesophageal varices or abdominal pain. Pancreatic disease was present in five patients (83%), three (50%) had splenic enlargement, and five (83%) had normal results of liver function tests. Angiography showed an occluded splenic vein with collateral flow and a patent portal vein in each of the four patients studied. All patients had splenectomy, with or without additional procedures. After a mean follow-up period of 9 1/2 months, five patients (83%) were alive, and none has had further gastrointestinal bleeding. One patient had died of recurrent pancreatic carcinoma at nine months. Our data suggest that localized portal hypertension induced by splenic vein thrombosis is appropriately treated by splenectomy.

Career change: in quest of a controllable lifestyle.

Over the past decade, top medical students are selecting "controllable lifestyle" (CL) specialties at an increasing rate. CL specialties include anesthesiology, dermatology, emergency medicine, neurology, ophthalmology, pathology, psychiatry, and radiology. The choice of "noncontrollable lifestyle" (NCL) specialties such as family practice, internal medicine, obstetrics/gynecology, and pediatrics was negatively affected by this trend. The effect of CL on the selection of surgical training by top medical students was variable. The purpose of this study was to determine if CL is a factor in career change by young surgeons during and after residency. Graduates of the University of Kentucky College of Medicine from 1975 to 1983 (n = 796) were questioned regarding the specialty they entered after graduation and whether they remained in that specialty as of March, 1988. NCL and surgery specialties showed a net loss of practitioners during the study period (P less than 0.005) and CL showed a net gain (P less than 0.005). When physicians changed specialties, the direction of change occurred from NCL and surgery to CL (P less than 0.05). Change from CL to NCL and surgery occurred infrequently.

Acute pericarditis complicated by cardiac tamponade during pregnancy.

A case of acute pericarditis, complicated by pericardial effusion and cardiac tamponade, is described.