Efferent limb stimulation prior to loop ileostomy closure: a systematic review and meta-analysis.

BACKGROUND: Postoperative ileus (POI) remains a common phenomenon following loop ileostomy closure. Our aim was to determine whether preoperative physiological stimulation (PPS) of the efferent limb reduced POI incidence. METHODS: A PRISMA-compliant meta-analysis searching PubMed, EMBASE and CENTRAL databases was performed. The last search was carried out on 30 January 2023. All randomized studies comparing PPS versus no stimulation were included. The primary endpoint was POI incidence. Secondary endpoints included the time to first passage of flatus/stool, time to resume oral diet, need for nasogastric tube (NGT) placement postoperatively, length of stay (LOS) and other complications. Random effects models were used to calculate pooled effect size estimates. Trial sequential analyses (TSA) were also performed. RESULTS: Three randomized studies capturing 235 patients (116 PPS, 119 no stimulation) were included. On random effects analysis, PPS was associated with a quicker time to resume oral diet (MD - 1.47 days, 95% CI - 2.75 to - 0.19, p = 0.02), shorter LOS (MD - 1.47 days, 95% CI - 2.47 to - 0.46, p = 0.004) (MD - 1.41 days, 95% CI - 2.32 to - 0.50, p = 0.002, I2 = 56%) and fewer other complications (OR 0.42, 95% CI 0.18 to 1.01, p = 0.05). However, there was no difference in POI incidence (OR 0.35, 95% CI 0.10 to 1.21, p = 0.10), the requirement for NGT placement (OR 0.50, 95% CI 0.21 to 1.20, p = 0.12) or time to first passage of flatus/stool (MD - 0.60 days, 95% CI - 1.95 to 0.76, p = 0.39). TSA revealed imprecise estimates for all outcomes (except LOS) and further studies are warranted to meet the required information threshold. CONCLUSIONS: PPS prior to stoma closure may reduce LOS and postoperative complications albeit without a demonstrable beneficial effect on POI. Further high-powered studies are required to confirm or refute these findings.

Meta-analysis of the effect of extending the interval after long-course chemoradiotherapy before surgery in locally advanced rectal cancer.

BACKGROUND: The current standard of care in locally advanced rectal cancer (LARC) is neoadjuvant long-course chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). Surgery is conventionally performed approximately 6-8 weeks after nCRT. This study aimed to determine the effect on outcomes of extending this interval. METHODS: A systematic search was performed for studies reporting oncological results that compared the classical interval (less than 8 weeks) from the end of nCRT to TME with a minimum 8-week interval in patients with LARC. The primary endpoint was the rate of pathological complete response (pCR). Secondary endpoints were recurrence-free survival, local recurrence and distant metastasis rates, R0 resection rates, completeness of TME, margin positivity, sphincter preservation, stoma formation, anastomotic leak and other complications. A meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Twenty-six publications, including four RCTs, with 25 445 patients were identified. A minimum 8-week interval was associated with increased odds of pCR (odds ratio (OR) 1·41, 95 per cent c.i. 1·30 to 1·52; P < 0·001) and tumour downstaging (OR 1·18, 1·05 to 1·32; P = 0·004). R0 resection rates, TME completeness, lymph node yield, sphincter preservation, stoma formation and complication rates were similar between the two groups. The increased rate of pCR translated to reduced distant metastasis (OR 0·71, 0·54 to 0·93; P = 0·01) and overall recurrence (OR 0·76, 0·58 to 0·98; P = 0·04), but not local recurrence (OR 0·83, 0·49 to 1·42; P = 0·50). CONCLUSION: A minimum 8-week interval from the end of nCRT to TME increases pCR and downstaging rates, and improves recurrence-free survival without compromising surgical morbidity.

ANTECEDENTES: El tratamiento estándar actual del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) consiste en quimiorradioterapia neoadyuvante de ciclo largo (neoadjuvant, long-course chemoradiation, nCRT) seguida de exéresis total del mesorrecto (total mesorectal excision, TME). De forma convencional, la cirugía se realiza a las 6-8 semanas después de la nCRT. Este estudio tuvo como objetivo determinar el efecto sobre los resultados de ampliar este intervalo. MÉTODOS: Se realizó una búsqueda sistemática de los estudios que analizaban los resultados oncológicos, comparando el intervalo clásico (< 8 semanas) desde el final de la nCRT hasta la TME con un intervalo mínimo de 8 semanas, en pacientes con LARC. El criterio de valoración principal fue la tasa de respuesta patológica completa (pathologic complete response, pCR). Los criterios de valoración secundarios fueron las tasas de supervivencia sin recidiva (recurrence-free survival, RFS), recidiva local (local recurrence, LR) y metástasis a distancia (distant metastasis, DM), tasas de resección R0, integridad (completeness) del mesorrecto, afectación del margen de resección, preservación esfinteriana, formación de estoma, fuga anastomótica y otras complicaciones. Se realizó un metaanálisis utilizando el método de Mantel-Haenszel. RESULTADOS: Se identificaron 26 publicaciones, incluidos cuatro ensayos clínicos aleatorizados, con 17.220 pacientes. Un intervalo mínimo de 8 semanas se asoció con un aumento de la razón de oportunidades (odds ratio, OR) de pCR (OR, 1,68, i.c. del 95% 1,37-2,06, P < 0,001) y de disminución del estadio tumoral (OR 1,18, i.c. del 95% 1,05-1,32, P = 0,004). Los porcentajes de resección R0, integridad del mesorrecto, ganglios linfáticos identificados, preservación esfinteriana, formación de estoma y complicaciones fueron similares entre los dos grupos. El aumento del porcentaje de pCR se tradujo en una disminución de las DM (OR 0,71, i.c. del 95% 0,54-0,93, P = 0,01) y de la recidiva global (OR 0,76, i.c. del 95% 0,58-0,98, P = 0,04), pero no de la LR (OR 0,83, i.c. del 95% 0,49-1,42, P = 0,50). CONCLUSIÓN: Un intervalo mínimo de 8 semanas entre el final de la nCRT y la TME aumenta las tasas de pCR y la reducción del estadio tumoral, así como mejora la RFS sin comprometer la morbilidad quirúrgica.

Transfusion-transmitted hepatitis B virus (HBV) infection from an individual-donation nucleic acid (ID-NAT) non-reactive donor.

Lookback was initiated upon notification of an acute HBV infection in a repeat Irish donor, 108 days post-donation. The donation screened non-reactive by individual-donation nucleic acid testing (ID-NAT) using the Procleix Ultrio Elite multiplex assay and again when the archived sample was retested, but the discriminatory assay for HBV was reactive. The immunocompromised recipient of the implicated red cell component was tested 110 days post-transfusion, revealing a HBV DNA viral load of 470 IU/ml. Genotype C2 sequences identical across two regions of the HBV genome were found in samples from the donor and recipient.

A systematic review of the role of re-laparoscopy in the management of complications following laparoscopic colorectal surgery.

The benefits of laparoscopic versus open surgery for patients with both benign and malignant colorectal disease have been well established. Re-laparoscopy in patients who develop complications following laparoscopic colorectal surgery has recently been reported by some groups and the aim of this systematic review was to summarise this literature. A literature search of PubMed, Medline and EMBASE identified a total of 11 studies that reported laparoscopic re-intervention for complications in 187 patients following laparoscopic colorectal surgery. The majority of these patients required re-intervention in the immediate postoperative period (i.e. less than seven days). Anastomotic leakage was the commonest complication requiring re-laparoscopy reported (n = 139). Other complications included postoperative hernia (n = 12), bleeding (n = 9), adhesions (n = 7), small bowel obstruction (n = 4), colonic ischaemia (n = 4), bowel and ureteric injury (n = 3 respectively) and colocutaneous fistula (n = 1). Ninety-seven percent of patients (n = 182) who underwent re-laparoscopy had their complications successfully managed by re-laparoscopy, maintaining the benefits of the laparoscopic approach and avoiding a laparotomy. We conclude that re-laparoscopy for managing complications following laparoscopic colorectal surgery appears to be safe and effective in highly selected patients.

Incidence and prevalence of multiple sclerosis in the UK 1990-2010: a descriptive study in the General Practice Research Database.

OBJECTIVES: To estimate the incidence and prevalence of multiple sclerosis (MS) by age and describe secular trends and geographic variations within the UK over the 20-year period between 1990 and 2010 and hence to provide updated information on the impact of MS throughout the UK. DESIGN: A descriptive study. SETTING: The study was carried out in the General Practice Research Database (GPRD), a primary care database representative of the UK population. MAIN OUTCOME MEASURES: Incidence and prevalence of MS per 100 000 population. Secular and geographical trends in incidence and prevalence of MS. RESULTS: The prevalence of MS recorded in GPRD increased by about 2.4% per year (95% CI 2.3% to 2.6%) reaching 285.8 per 100 000 in women (95% CI 278.7 to 293.1) and 113.1 per 100 000 in men (95% CI 108.6 to 117.7) by 2010. There was a consistent downward trend in incidence of MS reaching 11.52 per 100 000/year (95% CI 10.96 to 12.11) in women and 4.84 per 100 000/year (95% CI 4.54 to 5.16) in men by 2010. Peak incidence occurred between ages 40 and 50 years and maximum prevalence between ages 55 and 60 years. Women accounted for 72% of prevalent and 71% of incident cases. Scotland had the highest incidence and prevalence rates in the UK. CONCLUSIONS: We estimate that 126 669 people were living with MS in the UK in 2010 (203.4 per 100 000 population) and that 6003 new cases were diagnosed that year (9.64 per 100 000/year). There is an increasing population living longer with MS, which has important implications for resource allocation for MS in the UK.

Collating evidence to support the validation of a simulated laparotomy incision and closure-training model.

BACKGROUND: It is essential to evaluate the functionality of surgical simulation models, in order to determine whether they perform as intended. In this study, we assessed the use of a simulated laparotomy incision and closure-training model by collating validity evidence to determine its utility as well as pre and post-test interval data. METHOD: This was a quantitative study design, informed by Messick's unified validity framework. In total, 93 participants (surgical trainees â€‹= â€‹80, experts â€‹= â€‹13) participated in this study. Evaluation of content validity and the models' relationships with other variables was conducted, along with a pre and post-test confidence assessment. RESULTS: The model was deemed realistic and useful as a teaching tool, providing strong content validity evidence. In assessment of relationships with other variables, the expert group out-performed the novice group conclusively. Pre and post-test evaluation reported a statistically significant increase in confidence levels. CONCLUSION: We present strong validity evidence of a novel laparotomy incision and closure simulation-training model.

Randomized clinical trial of the benefit of laparoscopy with closure of loop ileostomy.

BACKGROUND: The aim was to compare reversal and laparoscopy with standard reversal of loop ileostomy in terms of hospital stay and morbidity in a randomized study. METHODS: Patients having reversal of a loop ileostomy were randomized to either standard reversal of ileostomy or reversal and laparoscopy. Strict discharge criteria were applied: toleration of two meals without nausea and vomiting, passing a bowel motion, and attaining adequate pain control with oral analgesia. Morbidity and cost were also compared between the two groups. RESULTS: A total of 74 patients (reversal and laparoscopy 40, standard reversal 34) with a median age of 61 years underwent loop ileostomy reversal; there were 45 men (61 per cent). Ileostomy was most commonly carried out after laparoscopic low anterior resection (36 patients). Median length of stay, based on discharge criteria, was significantly shorter in the reversal and laparoscopy group than in the standard group: 4 (interquartile range 3-4) versus 5 (4-6) days (P = 0·003). The overall morbidity rate was also lower in patients who had ileostomy reversal and laparoscopy: 10 versus 32 per cent (P = 0·023). The median cost per patient was lower in the reversal and laparoscopy group: €3450 (interquartile range 2766-3450) versus €4527 (3843-7263) (P = 0·015). There was no statistically significant difference in American Society of Anesthesiologists fitness grade or time to reversal between the two groups. CONCLUSION: Reversal of loop ileostomy with laparoscopy was associated with a shorter hospital stay, lower morbidity and reduced cost compared with the standard technique. REGISTRATION NUMBER: ISRCTN46101203 (http://www.controlled-trials.com).

Re-laparoscopy in the diagnosis and treatment of postoperative complications following laparoscopic colorectal surgery.

BACKGROUND: Laparoscopic colorectal surgery has increasingly become the standard of care in the management of both benign and malignant colorectal disease. We herein describe our experience with laparoscopy in the management of complications following laparoscopic colorectal surgery. METHODS: Between November 2010 and July 2012, data were prospectively collected for all patients requiring surgical intervention for colorectal cancer. This was performed by a full-time colorectal cancer data manager. RESULTS: A total of 203 patients had surgery for colorectal cancer during this period, 154 (75.9%) of which were performed laparoscopically and 49 (24.1%) performed by open surgery. Ten patients (4.9%) underwent surgery for complications of which 7 were following laparoscopic surgery. Two of these 7 patients had an exploratory laparotomy due to abdominal distension and haemodynamic instability. Laparoscopic surgical intervention was successful in diagnosing and treating the remaining 5 patients. Three of these patients developed small bowel obstruction which was managed by re-laparoscopy while in 2 patients there was a significant suspicion of an anastomotic leakage despite appropriate diagnostic imaging which was out ruled at laparoscopy. CONCLUSIONS: Laparoscopy can frequently be used to diagnose and treat complications following laparoscopic colorectal surgery. This is another benefit associated with laparoscopic colorectal surgery which is rarely described and allows the benefits associated with the laparoscopic approach to be maintained.

A systematic review of the anal fistula plug for patients with Crohn's and non-Crohn's related fistula-in-ano.

BACKGROUND: The management of fistula-in-ano is a balance between fistula cure and preservation of continence. OBJECTIVE: The aim of this study is to summarize the anal fistula plug literature for Crohn's and non-Crohn's fistula-in-ano in a homogenous patient population. DATA SOURCES: PubMed, MEDLINE, Embase, and Cochrane medical databases were searched from 1995 to 2011. Abstracts from The American Society of Colon and Rectal Surgeons, The Society for Surgery of the Alimentary Tract, The European Society of Coloproctology, and the Association of Coloproctology of Great Britain and Ireland meetings between 2007 and 2010 were also evaluated. STUDY SELECTION: Studies were included if results for patients with and without Crohn's disease could be differentiated. Patients with rectovaginal, anovaginal, rectourethral, or ileal-pouch vaginal fistulas were excluded as were studies where the mean or median follow-up was less than 3 months. Two researchers independently selected studies matching the inclusion criteria. INTERVENTION: Anal fistula plug insertion was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the overall fistula closure rates and length of follow-up. RESULTS: Seventy-six articles or abstracts were identified from the title as being of relevance. Twenty studies (2 abstracts, 18 articles) were finally included. Study sample size ranged from 4 to 60 patients; 530 patients were included in all studies (488 non-Crohn's and 42 Crohn's patients). The plug extrusion rate was 8.7% (46 patients). The proportion of patients achieving fistula closure varied widely between studies for non-Crohn's, ranging from 0.2 (95% CI 0.04-0.48) to 0.86 (95% CI 0.64-0.97). The pooled proportion of patients achieving fistula closure in patients with non-Crohn's fistula-in-ano was 0.54 (95% CI 0.50-0.59). The proportion achieving closure in patients with Crohn's disease was similar (0.55, 95% CI 0.39-0.70). LIMITATIONS: This study was limited by the variability of operative technique and perioperative care between studies. CONCLUSIONS: Fistula closure is achieved by using the anal fistula plug in approximately 54% of patients without Crohn's disease. The anal fistula plug has not been adequately evaluated in the Crohn's population.

Laparoscopic surgery for complicated diverticular disease: a single-centre experience.

AIM: The role of laparoscopic surgery in the management of patients with diverticular disease is still not universally accepted. The aim of our study was to evaluate the results of laparoscopic surgery for diverticular disease in a centre with a specialist interest in minimally invasive surgery. METHOD: All diverticular resections carried out between 2006 and 2010 were reviewed. Data recorded included baseline demographics, indication for surgery, operative details, length of hospital stay and complications. Complicated diverticular disease was defined as diverticulitis with associated abscess, phlegmon, fistula, stricture, obstruction, bleeding or perforation. RESULTS: One hundred and two patients (58 men) who had surgery for diverticular disease were identified (median age 59 years, range 49-70 years). Sixty-four patients (64%) had surgery for complicated diverticular disease. The indications were recurrent acute diverticulitis (37%), colovesical fistula (21%), stricture formation (17%) and colonic perforation (16%). Sixty-nine cases (88%) were completed by elective laparoscopy. Postoperative mortality was 0%. For elective cases there was no difference in morbidity rates between patients with complicated and uncomplicated diverticular disease. The overall anastomotic leakage rate was 1% and the wound infection rate 7%. There was a nonsignificant trend to higher conversion to open surgery in the elective group in complicated (11.4%) compared with uncomplicated patients (5.2%) (P=0.67). Electively, the rate of stoma formation was higher in the complicated (31.6%) than the uncomplicated group (5.2%) (P<0.02). CONCLUSION: Laparoscopic surgery for both complicated and uncomplicated diverticular disease is associated with low rates of postoperative morbidity and relatively low conversion rates. Laparoscopic surgery is now the standard of care for complicated and uncomplicated diverticular disease in our institution.

The efficacy of fibrinogen concentrate compared with cryoprecipitate in major obstetric haemorrhage--an observational study.

BACKGROUND: Fibrinogen replacement is critical in major obstetric haemorrhage (MOH). Purified, pasteurised fibrinogen concentrate appears to have benefit over cryoprecipitate in ease of administration and safety but is unlicensed in pregnancy. In July 2009, the Irish Blood Transfusion Service replaced cryoprecipitate with fibrinogen. OBJECTIVES: To examine the impact of this externally imposed change on blood product use and clinical outcomes in MOH. METHODS: Women with MOH requiring fibrinogen between 1 January 2009 and 30 June 2011 were identified from an MOH database. Aetiology of MOH, medical treatments, blood product use and clinical outcomes were compared between the cryoprecipitate and fibrinogen groups. RESULTS: Of 21 614 deliveries, 77 cases of MOH were identified. Of the 77 cases, 34 (44%) received cryoprecipitate (n = 14) or fibrinogen concentrate (n = 20). The mean (± SEM) dose utilised was 2.21 ± 0.35 pools of cryoprecipitate and 4 ± 0.8 g of fibrinogen. There was a stronger correlation between the increase in fibrinogen level and dose of fibrinogen (Pearson co-efficient 0.5; P = 0.03) than dose of cryoprecipitate (Pearson co-efficient 0.32; P = 0.3). Mean (± SEM) estimated blood loss (EBL), red cell concentrate (RCC) and Octaplas transfused were greater (but not significantly) in the cryoprecipitate group compared with the fibrinogen group; EBL = 5.2 ± 1.1 vs 3.3 ± 0.5 L (P = 0.1); RCC = 7.2 ± 1.2 vs 5.9 ± 1.0 U (P = 0.4); Octaplas = 4.1 ± 0.7 vs 3.2 ± 0.7 U (P = 0.36), respectively. Haemostasis was secured, and there were no adverse reactions or thrombotic complications. CONCLUSION: Purified virally inactivated fibrinogen concentrate is as efficacious as cryoprecipitate in correcting hypofibrinogenaemia in MOH.

Long-term outcome of colectomy and ileorectal anastomosis for Crohn's colitis.

BACKGROUND: Ileorectal anastomosis is an important surgical option for patients with Crohn's colitis with relative rectal sparing. OBJECTIVE: This study aimed to audit outcomes of ileorectal anastomosis for Crohn's and factors associated with proctectomy and reoperation. DESIGN: This retrospective study involved a chart review and contacting patients. SETTINGS: Patients with Crohn's colitis who had an ileorectal anastomosis were identified from the Mount Sinai Hospital Inflammatory Bowel Disease Database. PATIENTS: Demographics, operative and perioperative outcomes, and reoperative data were collected. MAIN OUTCOME MEASURES: Five- and 10-year Kaplan-Meier survival estimates and 95% confidence intervals were calculated for survival from proctectomy and Crohn's-related revisional surgery. Cox proportional hazards models were used to model the hazards of proctectomy and Crohn's-related revision on the clinical characteristics of patients. RESULTS: Eighty-one patients had an ileorectal anastomosis for Crohn's disease from 1982 to 2010. The most common indications for surgery were failed medical management (60/81, 74.1%) and a stricture causing obstruction (14/81, 17.3%). Seventy-seven percent (n = 62) had a 1-stage procedure, whereas 23% (n = 19) had a 2-stage procedure (colectomy followed by ileorectal anastomosis). The overall anastomotic leak rate was 7.4% (n = 6). Fifty-six patients had a functioning ileorectal anastomosis at the time of follow-up. At 5 and 10 years, 87% (95% CI: 75.5-93.3) and 72.2% (95% CI: 55.8-83.4) of individuals had a functioning ileorectal anastomosis. Eighteen patients required proctectomy for poor symptom control, whereas 11 patients required a small-bowel resection plus redo-ileorectal anastomosis. The mean time to proctectomy from the original ileorectal anastomosis was 88.3 months (SD = 62.1). Smoking was associated with both proctectomy (HR 3.93 (95% CI: 1.46-10.55)) and reoperative surgery (HR 2.12 (95% CI: 0.96-4.72)). LIMITATIONS: : This study was retrospective. CONCLUSIONS: Ileorectal anastomosis is an appropriate operation for selected patients with Crohn's colitis with sparing of the rectum. However, patients must be counseled that the reoperation rate and/or proctectomy rate is approximately 30%.

Hereditary mixed polyposis syndrome due to a BMPR1A mutation.

The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)-beta signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

Routine interferon-neutralising antibody testing in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis is a leading cause of disability in young adults, with the Scottish population suffering the highest prevalence in Europe. Disease-modifying therapies, including beta-interferon (IFN-ß), are increasingly used to minimise relapse frequency in the majority of patients who present with a relapsing-remitting disease pattern. Unfortunately, neutralising antibodies (NABs) may develop against IFN-ß and are associated with reduced efficacy. These antibodies may be detected using a serum sample. Despite the importance of this problem, from both a patient's perspective and a wider community and economic standpoint, there is no universally agreed protocol for the use of NAB testing. Authorities variously suggest routine 'screening' testing or, conversely, testing only in specific situations. In Scotland, routine testing is seldom used. We report our experience of routine NAB testing in 105 patients (of whom 35 were NAB-positive) over two years in NHS Tayside and comment on its cost and implications.

Thyrocalcitonin: ultracentrifugation in gradients of sucrose.

Analysis of thyrocalcitonin, by density-gradient ultracentrifugation at high speed, showed that its molecular weight (5000 to 6000) is considerably less than was heretofore recognized.

Tibial plateau levelling osteotomy in an alpaca.

In this report, a case of cranial cruciate ligament (CrCL) rupture treated by tibial plateau levelling osteotomy (TPLO), in a 36-month-old male breeding alpaca, is described. The alpaca was presented with the complaint of acute onset of right pelvic limb lameness. The findings of our clinical and radiographic examinations were consistent with CrCL insufficiency of the right stifle joint. The right tibial plateau angle measured prior to surgery was 19 degrees . A TPLO was performed and this eliminated cranial tibial thrust. Culture of a swab taken from the surgical site prior to wound closure was positive for Pseudomonas aeruginosa . Enrofloxacin was administered parenterally for two weeks postoperatively. There were not any clinical signs of infection noted. Outcome assessments included veterinary examination (two and six weeks) and owner assessment (28 months). At two weeks the animal walked with a grade 2/5 lameness, and at six weeks radiographic examination showed progression of bone healing at the site of tibial osteotomy. A return to full breeding fitness occurred by eight weeks after the surgery. The alpaca remained free from lameness 28 months later, according to the owner.

Two mutations in the hormone binding domain of the vitamin D receptor cause tissue resistance to 1,25 dihydroxyvitamin D3.

We have identified and characterized two mutations in the hormone binding domain of the vitamin D receptor (VDR) in patients with hereditary vitamin D-resistant rickets. One patient was found to have a premature stop mutation (CAG to TAG) in the hinge region affecting amino acid 149 (Q149X) and the other demonstrated a missense mutation (CGC to CTC) resulting in the substitution of arginine 271 by leucine (R271L) in the steroid binding domain. Eukaryotic expression analyses in CV-1 cells showed the inability of both patients' VDR to induce transcription from the osteocalcin hormone gene response element at 10(-7) M 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Normal transcription levels could, however, be elicited by the missense mutated VDR (R271L) in the presence of 1,000-fold higher 1,25-(OH)2D3 concentrations than needed for the wild-type receptor. This shows that Arg 271 directly affects the affinity of the VDR for its ligand and its conversion to leucine decreases its affinity for 1,25(OH)2D3 by a factor of 1,000. Arg 271 is located immediately 3-prime to a 30 amino acid segment (VDR amino acids 241-270) that is conserved among members of the steroid/thyroid/retinoid hormone receptor superfamily. These results represent the first missense mutation identified in the hormone binding domain of VDR and further define the structure-function relationship of 1,25(OH)2D3 ligand binding to its nuclear receptor.