Late-onset and young-onset relapsing-remitting multiple sclerosis: evidence from a retrospective long-term follow-up study.

BACKGROUND AND PURPOSE: Late-onset multiple sclerosis (MS) has a prevalence of about 10-20% in natural history MS studies. Few data have been published about the long-term disease trajectory in the cohort of late-onset relapsing-remitting MS (LORRMS). The aim of this study was to identify the risk factors for reaching an Expanded Disability Status Scale (EDSS) score of 6.0 in LORRMS (onset at >40 years of age) and young-onset relapsing-remitting MS (YORRMS) (onset between 18 and 40 years of age). METHODS: Clinical and radiological [magnetic resonance imaging (MRI) of the brain] follow-up data were collected. Disability was assessed by EDSS score. A Cox proportional hazards model was used to evaluate the demographic and clinical predictors of reaching an EDSS score of 6.0 in the two cohorts. RESULTS: A total of 671 patients with relapsing-remitting MS were enrolled, 143 (21.3%) with LORRMS and 528 (78.7%) with YORRMS. In LORRMS, age at onset was 47.8 ± 5.3 (mean ± SD) years and duration of follow-up was 120.7 ± 52.7 months. In YORRMS, age at onset was 27 ± 2.7 years and duration of follow-up was 149.9 ± 92.7 months. The survival curve analyses showed a higher probability of reaching an EDSS score of 6.0 for LORRMS in a shorter time (months) than for YORRMS (94.2 vs. 103.2 months; log-rank 8.8; P < 0.05). On MRI, YORRMS showed more brain inflammatory features than LORRMS. In the multivariate Cox model, age at onset [Exp(B) value, 6.5; 95% confidence interval, 1.9-22.6; P < 0.001] and male gender [Exp(B) value, 1.7; 95% confidence interval, 1.0-2.8; P < 0.05] were the strongest predictors of reaching an EDSS score of 6.0. CONCLUSIONS: The male population with LORRMS reached severe disability faster than those with YORRMS, even when YORRMS showed more brain inflammatory features on MRI.

Deslorelin implants in pre-pubertal female dogs: short- and long-term effects on the genital tract.

Deslorelin acetate is a GnRH agonist used for contraception in dogs. This study aimed to evaluate the treatment of pre-pubertal female dogs with deslorelin acetate implants, to better investigate the primary stimulatory effect of the drug and the long-term effects on the genital tract, throughout repeated treatments. Sicilian hound female dogs (24) were randomly assigned to treated group, control group 1 and control group 2. First group bitches were implanted at 4.5, 9.0 and 13.5 months and monitored clinically, ultrasonographically and endocrinologically, throughout the study period (13.5 months). Control group 1 bitches were not implanted and clinically monitored for the same period. At 18 months, the animals underwent ovariohysterectomy, thus allowing evaluation of the internal genitalia. Control group 2 bitches were ovariohysterectomized at the age of 4.5 months. The suppression of oestrus was obtained in the treated group despite the fact that the first implant caused a modest increase in plasmatic levels of 17-beta estradiol and an evident cornification of the vaginal mucosa cells (50-80%). Estradiol and progesterone were at baseline levels for the remaining study period, in which no other oestrous manifestations were observed. The external genitalia maintained a juvenile appearance. The ovaries, ultrasonographically, showed no follicular structures and stayed the same size. At 18 months, the genital tract was still juvenile with inactive small ovaries and a thin filiform uterus. Deslorelin suppressed ovarian activity in pre-pubertal bitches, and oestrous induction was not observed despite the presence of the primary stimulatory effect of the drug. Juvenile genitalia were an expected side effect of the treatment.

Pregnancy effect on disease activity in women with multiple sclerosis treated with cladribine.

INTRODUCTION: Cladribine is an oral immune reconstitution therapy for relapsing multiple sclerosis (RMS). Hormonal and immune changes are responsible for the decline of disease activity in the third trimester of pregnancy and disease reactivation in the early post-partum period.We investigate the impact of pregnancy on disease activity in women with MS who conceived after cladribine treatment. METHODS: We recruited women of childbearing age with relapsing-remitting MS (RRMS) who became pregnant or not after being treated with cladribine. For both groups, demographic, clinical and radiological data were collected 1 year before and after treatment during a mean follow-up of 3.53 years. We compared disease activity over time between groups using variance analysis for repeated measures. RESULTS: 48 childbearing women were included. 25 women had a pregnancy after a mean of 1.75 years from the first treatment cycle. Women with or without pregnancy did not differ in demographics or pre-cladribine disease activity. No significant differences in disease activity or EDSS worsening were found between women with or without pregnancy. DISCUSSION: Our findings suggest that pregnancy does not appear to influence disease activity and disability in women previously treated with cladribine; further studies with larger numbers and longer follow-up are needed to confirm this finding.

Expression of CD7, CD20 and CDX-2 in a secondary signet-ring cell tumor of the prostate: a case report.

As is well-known, signet ring cell carcinoma (SRCC) rarely appears as a histological finding in the prostatic tissue. Nevertheless, a differentiation should be made between a primary tumor and a metastatic disease. We describe the case of a 52-year-old man with lower urinary tract symptoms, serum total PSA of 0.2 ng/ml, elevated serum CEA and CA19-9 levels. Two years prior to presentation, he underwent total gastrectomy with histological findings indicating poor differentiated adenocarcinoma with signet-ring cell. A palpable nodule was found on digital rectal examination and for this reason he underwent 12-core transperineal prostate biopsy with a diagnosis of poor differentiated adenocarcinoma with signet-ring cell and adipose tissue infiltration. Immunohistochemical examinations revealed positivity for PAS, CK7 and CDX-2, focal positivity for CK20 and negativity for PSA and PSAP. The diagnosis of a prostatic secondary SRCC was possible given the positivity to CK7, CDX-2, focal positivity to CK20 and negativity to PSA.

Dissemination metastasis after laparoscopic colorectal surgery versus conventional open surgery for colorectal cancer: a metanalysis.

PURPOSE: The purpose of this systematic review is to evaluate and compare the risk of dissemination metastasis (wound, port-side metastases and peritoneal seeding) after laparoscopic colorectal surgery and conventional open surgery for colorectal cancer. MATERIALS AND METHODS: The Authors searched relevant randomized controlled trials between January 1998 and July 2012. RESULTS: Wound, port-site metastases and peritoneal seeding were rare and no significant differences occurred between the two groups. The port-site and extraction site recurrence were likely to be the results of suboptimal surgical techniques and occurred in the early phase of the learning curve. The authors also found no significant differences in overall, local and distant recurrences. No significant differences between laparoscopic and open surgery were found in cancer-related mortality during the follow up period of the study (7 RCTs, 3525 patients, 12.8% vs. 14.00%; OR (fixed) 0.83, 95% CI 0.68-1.02), with no significant heterogeneity (p = 0.35). CONCLUSIONS: The literature supports the implementation of laparoscopic surgery into daily practice. Laparoscopic surgery can be used for safe and radical resection of cancer in the right, left, sigmoid colon and rectum. However further studies should address whether laparoscopic surgery is superior to open surgery in this setting.

Diet and pancreatic cancer: many questions with few certainties.

UNLABELLED: BACKGROUND, OBJECTIVES: Pancreatic cancer ranks fourth for cancer mortality for men and women in the United States. This is a particularly devastating cancer since the case-fatality proportion approaches 90% within 12 months following diagnosis. Therefore, understanding the etiology and identifying the risk factors are essential for the primary prevention of this deadly disease. Of the few potentially modifiable risk factors that have been identified, cigarette smoking, history of diabetes mellitus, and obesity seem to be among the most consistent, but the effect of dietary factors is still unclear. The aim of our study is to review of the literature examining the potential role of carbohydrates, fatty acids, meat, fruit and vegetables, alcohol. DISCUSSION: Although large prospective cohort studies with questionnaire based analyses will continue to have much to offer in defining predisposing factors for difficult diseases, such as pancreatic cancer, unfortunately dietary questionnaires do not reflect the bioavailability of the nutrients from various foods, the level of absorption from the digestive tract, or individual differences in metabolism. CONCLUSIONS: Greater use of participant-derived biological samples, banked plasma, germline DNA, and tumour tissue samples may help to the understanding of pancreatic cancer pathogenesis.

Clinical presentation and outcome of squamous cell carcinoma of the anus in HIV-infected patients in the HAART-era: a GICAT experience.

INTRODUCTION: Squamous cell carcinoma of the anus (SCCA) is a relatively uncommon cancer. In the HIV-positive patients the introduction of the highly active antiretroviral therapy (HAART) did not change the incidence of SCCA. BACKGROUND AND OBJECTIVES: This paper describes the Italian Cooperative Group on AIDS and Tumours (GICAT) experience on HIV-positive patients with SCCA. The purposes of this retrospective study were: first to describe the clinical presentation and outcome of HIV-positive patients with SCCA, second to compare them with the ones reported in the literature. PATIENTS AND METHODS: Between July 2000 and March 2010 we retrospectively collected epidemiological, clinical and survival data from 65 patients with SCCA in HIV infection enrolled within the GICAT. RESULTS: Fifty-three (81.5%) patients were male. The majority of patients (40%) were homosexual Forty-three patients (66.1%) were diagnosed with HIV before 1996. Thirty-five patients (54%) had CD4-positive cells count > 200 / mm3 and 28 patients (43%) had viral load > 50 cp / ml at the time of SCCA diagnosis. The median time difference between HIV and SCCA diagnosis was 120 months (range 10-282 months). Sixty-one patients (96.8%) received HAART at SCCA diagnosis. Fifty-two patients (80%) had performance status (PS) 0-1 at the time of SCCA diagnosis. Twenty-seven patients (41.5%) underwent surgery with curative intent. Thirty-five patients (53.9%) were given combined modality therapy (CMT) consisting of pelvic radiotherapy with concurrent chemotherapy. No grade 3/4 haematological or extra-haematological effects were observed in our patients. CONCLUSIONS: In summary, despite the retrospective nature of analysis, the absence of patient strict criteria of inclusion/exclusion, our data on HIV-positive patients with SCCA, compared both to general population and to small reports on HIV-positive patients present in the literature, are promising.

Discontinuation of teriflunomide and dimethyl fumarate in a large Italian multicentre population: a 24-month real-world experience.

BACKGROUND: Teriflunomide (TRF) and Dimethyl fumarate (DMF) are licensed drugs for relapsing-remitting Multiple Sclerosis (RRMS). OBJECTIVES: We aimed to compare the rate and the time to discontinuation among persons with RRMS (pwRRMS), newly treated with TRF and DMF. MATERIALS AND METHODS: A retrospective study on prospectively collected data was performed in nine tertiary MS centers, in Italy. The 24-month discontinuation rate in the two cohorts was the primary study outcome. We also assessed the time to discontinuation and reasons of therapy withdrawn. Discontinuation of TRF and DMF was defined as a gap of treatment ≥ 60 days. RESULTS: A cohort of 903 pwRRMS (316 on TRF and 587 on DMF) was analyzed. During 24 months of follow-up, pwRRMS on TRF and DMF showed similar discontinuation rates. The analysis of predictors with Cox regression model showed differences between the two groups (p for log-rank test = 0.007); male gender [HR 2.21 (1.00-4.90); p = 0.01] and the number of previous switches [HR 1.47 (1.16-1.86); p = 0.01] were associated with higher hazard of discontinuation in the DMF group. CONCLUSIONS: In a real-world setting, pwRRMS on TRF and DMF had similar discontinuation rates over 24 months. Male pwRRMS on DMF with a previous history of therapeutic failure are at more risk of discontinuation therapy.

Retrospective survey on laparoscopic cholecystectomy in the cirrhotic patient.

Cholelitiasis is a common disease in patients with liver cirrhosis, mainly due to intravascular haemolysis and functional alterations of the gallbladder. In Child A and B cirrhotics laparoscopic cholecystectomy (LC) demonstrated the same advantages and safety as in the non cirrhotic patients. On the contrary, indications for surgery in Child C patients should be carefully evaluated. Nevertheless, the current number of patients with Child C cirrhosis submitted to LC is too low to extrapolate definitive data. Here we report our observations on a retrospective case series of LCs performed for symptomatic biliary disease in patients affected with liver cirrhosis. Both medical records and surgical registers were used to collect pre-operative, intra-operative and post-operative data from 40 cirrhotics out of 921 patients operated by laparoscopic cholecystectomy between November 1996 and November 2006. All patients underwent LC because of symptomatic disease. The average duration of the laparoscopic intervention was 111 minutes (60-220 minutes) distributed as follows according to the severity of liver disease: 66 minutes (48-87) in the Child A group, 108 minutes (91-119) in the Child B group and 138 minutes (110-160) as refers to Child C cirrhotics. Median blood loss was quantified as 80 ml (28-97) in Child A group, 155 ml (130-180) in Child B group and 300 ml (220-500) among Child C cirrhotics. The median length of hospital stay was 6 days (3-9 days) in the Child A group, 9 days (7-13 days) in the Child B group and 21 days (16-27 days) in Child C cirrhotics. Three cases out of 40 (7,5%) died: 2 Child C and 1 Child B. In conclusion, this study confirms that in patients affected with Child A and B cirrhosis LC may be safely performed either in emergency or in election whereas as refers to Child C cases we have observed a slightly higher mortality but a relevant higher impact of non lethal complications.

Lateral switch to IFN beta-1a 44 mcg may be effective as escalation switch to fingolimod in selected persons with relapsing remitting multiple sclerosis: a real-world setting experience.

BACKGROUND: The efficacy of lateral and escalation switch is a challenge in MS. We compared in a real-world setting the efficacy of switching to IFN beta-1a 44 mcg or to fingolimod in persons with relapsing remitting MS (pwRRMS) who failed with others injectable IFNs or glatiramer acetate. RESEARCH DESIGN AND METHODS: retrospective analysis of 24 months prospectively-collected data at the MS center of the University of Catania, Italy was performed. Patients who were switched to IFN-beta 1a 44 mcg or fingolimod were analyzed using propensity-score covariate adjustment model within demographic (e.g. age and gender) and disease (e.g. timing of pre-switch relapse) characteristics. Switching-time was considered the starting-time of the observation. RESULTS: 43 pwRRMS on IFN beta-1a 44 mcg and 49 pwRRMS on fingolimod were included. Baseline characteristics differed for EDSS score and number of T2 lesions (higher in group on fingolimod). At 24 months of follow up, both groups showed no differences in the survival curves of reaching a first new relapse, new T2 and Gd+ MRI brain lesions, even corrected for the propensity score covariate adjustment. CONCLUSIONS: lateral switch to IFN beta-1a 44 mcg and escalation switch to fingolimod showed same ability in influencing RRMS disease activity at 24 months.

Endometrial polypoid adenomyomatosis in a bitch with ovarian granulosa cell tumour and pyometra.

Endometrial polypoid adenomyomatosis in an 8-year-old German shepherd bitch is described. The lesion was associated with ovarian granulosa cell tumour and pyometra; grossly, it consisted of sessile or pedunculated processes with both epithelial and non-epithelial components, in which smooth muscle cells were predominant. The endometrium was diffusely atrophic and showed multifocal squamous metaplasia. The findings are discussed as possible consequences of the functioning ovarian tumour and pyometra, but an involvement of growth factors is also proposed.

Total Thyroidectomy: the first, the best. The recurrent goiter issue.

BACKGROUND: Redo surgery for recurrent goiter is still now, even in experienced hands, followed by higher morbidity than primary total thyroidectomy. Suppressive Levothyroxine therapy failed to improve the recurrence rate, while inducing a subclinical hyperthyroidism. Aim of this study is to verify morbidity after total thyroidectomy for benign thyroid diseases, both primary and after recurrence. MATERIALS AND METHODS: A series of 20 cases of total thyroidectomy for recurrent benign diseases (RG), performed between January 2001 and December 2013 was compared with 225 cases of primary total thyroidectomy (PT) . Cancers, even incidentally diagnosed, were excluded. At least a 12 months follow up was accomplished. Due to the small size of the sample for RG, statistical analysis was performed by Fisher test only. RESULTS: Postoperative complications were Transient hypocalcemia: 5 (25%) in RG and 18 (8%) in PT, Permanent hypocalcemia only 2 (10%) in RG (significant for p <0,05), Transient RLN deficit 5 (25 %) in RG and 6 (2.6%) in PT (significant for p< 0.05). CONCLUSIONS: Differences in incidence of perioperative complications cannot be advocated to justify a less than total thyroidectomy even in benign disease setting. The need for a redo surgery with its burden of morbidity is per se a good reason to avoid a conservative surgery. Further, suppressive therapy with Levothyroxine often fails to avoid recurrence, inducing in some cases a specific morbidity. Our experience confirms the results of our previous experiences and of literature on this topic: the best management of recurrent goiter is its prevention by primary total thyroidectomy.

A pilot study about the oncologic safety of colonic self-expandable metal stents (SEMS) in obstructive colon cancer: is occlusion always better than "silent" perforation?

OBJECTIVE: To evaluate the oncologic safety of colonic self-expandable metal stents (SEMS) in obstructive colon cancer. PATIENTS AND METHODS: We retrospectively reviewed all the patients who were treated with endoscopic placement of a self-expandable metallic stent (SEMS) at our institution. RESULTS: A total of 26 patients were identified during the study period, of which 24 patients (92.30%) were treated with SEMS as a bridge-to-surgery and 2 (7.69%) as palliation. In 22 cases (80.76%), the stenosis was localized to the left side. Clinical success with resolution of bowel obstructions was achieved in 22 (84.61%) patients within a short period of time. Among patients treated successfully with SEMS insertion as bridge to surgery (n = 22), 20 (90.9%) underwent one-stage surgery with primary anastomosis while 2 patients (9.09%) underwent colostomy due to intraoperative evidence of a covered perforation by cancer tissue in the pelvis. Patients with subclinical perforation developed an early peritoneal carcinomatosis, 10 patients treated with curative intent subsequently developed liver metastasis after 24 months. CONCLUSIONS: We reported an overall poor outcome among patients treated with the insertion of SEMS. This led us to think that, in some cases, occlusion may be better than a "silent" perforation.

Cholesterol granuloma (Xanthomatous metritis) in the uterus of a cat.

A case of uterine cholesterol granuloma in a 12-year old mixed breed cat is reported. The lesions were found in the endometrium of the left uterine horn as scattered, raised nodules or foci. Histologically, mononuclear cell infiltrates were seen to surround cholesterol crystals, in both the endometrium and the smooth muscle layer, reaching the serosa. The findings support the role of haemorrhage in promoting chronic inflammatory reactions around interstitial cholesterol ester precipitates.

[Observations of Setaria equina (Nematoda: Setariidae) with the optical microscope and scanning electron microscope]. / Osservazioni su Setaria equina (Nematoda: Setariidae) al microscopio ottico ed al microscopio elettronico a scansione.

Adults of S. equina (Spirurida, Setariidae), 1 male and 2 females, collected from vaginal sac of stallion, were studied by soanning electron microscopy (SEM). The amphids, cephalic and cervical papillae, peribuccal ring, fine transverse bands and bosses of the cuticle, as well as caudal papillae were visualized clearly at this examination. The results of the present survey contribute towards the identification of S. equina, improve the definition of the characters which are demonstrated by common light microscopy and give the exact number of male caudal papillae including the lateral cloacal right papilla considered as a probable anomaly in literature.

[The role of lymphadenectomy in colorectal neoplasms]. / La linfoadenectomia nel carcinoma colo-rettale.

BACKGROUND: The role of lymphadenectomy in the treatment of large bowel cancer is still controversial, not only because it is deemed to be a basic element for a correct postoperative staging, but also because it brings about, according to some authors, an enhancement of survival and of "disease free survival" rates. The difficulty to collect case histories with homogeneous data and the impossibility to identify preoperatively with certainty the lymph nodes involved, makes it difficult to codify the most suitable surgical treatment, even if it is agreed at present, to extend lymph nodes dissection at least as far as Level II nodes. As a matter of fact, despite of slight enhancement of 5-year survival rate (6-8%), a significant increase in morbility occurs, as reported in the literature, particularly in terms of urological and neurological lesions. However, a few authors, perform systematically Level III dessection, reporting a 20% increase in survival. METHODS: Our study, has been carried out on 84 patients affected by large bowel neoplasm and admitted to the Institute of Surgical Pathology I of "Vittorio Emanuele" Hospital of Catania between 1990-1995. RESULTS: This study showed an involvement of Level I lymph nodes in 77% of patients and of Level II in 33%, while Level III nodes were affected only in 4.7% of cases. CONCLUSIONS: On the basis of these data and of those reported in the literature, the conclusion is drawn that the most suitable and responsible attitude is, at present, to perform invariably Level I and Level II dissection, reserving the lymphadenectomy of Level III only to selected cases or when an involvement is documented pre and intraoperatively.

[Ambulatory surgical treatment of primary hernia: our experience]. / Il trattamento chirurgico ambulatoriale delle ernie primitive: nostra esperienza.

The authors report their personal experience (169 pz.) of the primary inguinal hernia repair in day surgery treated in local anaesthesia and by applying prosthesis according to latest "Tension-free and Suture-less" techniques. Results surely confirmed the validity of the method and the utility in creating centres concerning this type of surgery so that we are able to grant to the patient the best comfort that is to say a relevant reduction of the recurrence and a faster reintegration of patient's activities daily living.

Cystic dilatation of common bile duct. Case report and review.

The cystic dilatation of the common bile duct is a rare disease in Europe and in the USA; even rarer in adults. In fact less than 30% of cases are described in the over 20's. There are some reports in the elderly. When observed in adults the diagnosis is usually due to the onset of symptoms of associated pathologies or to complications such as cholangitis or cancer. Ultrasound, CT and ERCP allow, in the majority of cases, an adequate pre-operative characterization of the lesion. Intra-operative cholangiography verifies the completeness of surgery--always resective--and excludes residual biliary pathologies. The treatment in patients who already underwent conservative surgery is more complex, in fact, in symptomatic patients a second observation and resection is mandatory while in asymptomatic patients a careful and complete follow-up is adequate without underestimating the cancer risk. Septic and inflammatory complications, especially if chronic or recurring, can damage the liver; here resection or liver transplantation can be necessary. The case here reported is a 24-year-old woman with recurring cholangitis for at least 2 years in which US, CT and ERCP showed a Todani's type I cystic dilatation of the CBD. The total excision of the cyst with hepatic-jejunal anastomosis was carried out. A two-year follow up demonstrated no symptoms and normal laboratory findings; cholangioscintigraphy showed a good hepatic-biliary and anastomotic function.

Nonparasitic cysts of the liver: laparoscopic treatment and long-term results.

BACKGROUND: In the current debate on the indications for the laparoscopic treatment of symptomatic simple hepatic cysts, we emphasize the importance of the exact indications, practicing in an area endemic for hepatic hydatidosis. 8 years ago we started treating laparoscopically the simple hepatic cysts and the polycystosis. Although the laparoscopic approach to parasitic hepatic cysts has been recently introduced, this method has to be the result of a conscious choice and with a presumptive diagnosis to support it. In fact, reviewing the literature on the subject, we realized how most of the intraoperative complications were due to an erroneous preoperative diagnosis, likely to be attributed to the infrequent observation of hepatic hydatid disease. Hence, it seems of primary importance to review the subject in light of the potential dangerous aspect of the laparoscopic approach. METHODS: From 1992 to 2000 we treated 38 cases of benign liver cystic disease (29 echinococcal cysts, 8 symptomatic simple cysts, 1 polycystosis). Due to the endemic nature of the disease in our territory, the preoperative diagnosis was very meticulous (ultrasonography, CT scan, MRI, serology...). Only 9 cases with a preoperative diagnosis of simple cyst or polycystosis were treated with laparoscopic wide fenestration, combined with cholecystectomy in three cases. The follow-up consisted of ultrasonography in the majority of cases and CT scan in 2. RESULTS: All the 9 laparoscopic cases were uncomplicated and no conversions to open procedures have been recorded. The final pathology confirmed the initial diagnosis in all cases. The follow-up ranged between 1 and 8 years and complete remission has been obtained. CONCLUSIONS: The results of this study demonstrate how a meticulous preoperative clinical evaluation can avoid intraoperative complications, making the laparoscopic approach to non-hydatid hepatic cystic disease safe and efficacious. Although laparoscopy is indicated in parasitic liver pathology, the technical approach is very different from the simple cystic disease. In the former, in fact, hepatic resection or pericystectomy are utilized, the results of which have been currently evaluated and compared with the open technique on a large scale on several ongoing trials.

Adult intestinal intussusception: a case report of a rare clinical entity.

Intussusception in adult is a rare entity that challenges the surgeon opening a wide range of issues in order to define the etiology and therapeutic strategy. Whether to resect or not the bowel is the main question. The answer can be given only after having seen the site of obstruction and the etiology. Colonic intussusception is best treated by resection. Also small bowel intussusception can require resection if a neoplasm is the cause. Peutz Jeghers can be one of these causes as is seen in the case we report.